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Entry
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- *176872 - MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1
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- OMIM
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<p>
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<span class="h4">*176872</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<a href="#mapping">Mapping</a>
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<a href="#geneFunction">Gene Function</a>
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#otherFeatures">Other Features</a>
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<a href="#animalModel">Animal Model</a>
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/176872">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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<h4 class="panel-title">
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<div style="display: table-cell;">External Links</div>
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</div>
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</h4>
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000169032;t=ENST00000307102" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=5604" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=176872" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000169032;t=ENST00000307102" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001411065,NM_002755,XM_011521783,XM_017022411" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_002755" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=176872" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01469&isoform_id=01469_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/MAP2K1" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/188569,400274,5579478,119598171,119598172,119598173,119598174,119598175,141796928,158256432,187953569,194377296,767984706,1034591301,2288045689,2462545140,2462545142" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q02750" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=5604" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000169032;t=ENST00000307102" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=MAP2K1" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=MAP2K1" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+5604" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/MAP2K1" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:5604" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/5604" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr15&hgg_gene=ENST00000307102.10&hgg_start=66386912&hgg_end=66491544&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:6840" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:6840" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://medlineplus.gov/genetics/gene/map2k1" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=176872[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=176872[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/MAP2K1/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000169032" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=MAP2K1" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=MAP2K1" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=MAP2K1" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="http://lovd.bx.psu.edu/home.php?select_db=MAP2K1" class="mim-tip-hint" title="A gene-specific database of variation." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Locus Specific DB', 'domain': 'locus-specific-db.org'})">Locus Specific DBs</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MAP2K1&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA30584" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:6840" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0010269.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:1346866" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/MAP2K1#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:1346866" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/5604/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://omia.org/OMIA001512/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=5604" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://wormbase.org/db/gene/gene?name=WBGene00003186;class=Gene" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name'{'name': 'Wormbase Gene', 'domain': 'wormbase.org'})">Wormbase Gene</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040426-2759" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:5604" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=MAP2K1&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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176872
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
|
<span class="mim-font">
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PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 1; PRKMK1<br />
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MKK1; MAPKK1<br />
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MAPK/ERK KINASE 1; MEK1
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=MAP2K1" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MAP2K1</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/15/310?start=-3&limit=10&highlight=310">15q22.31</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr15:66386912-66491544&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">15:66,386,912-66,491,544</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
|
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</div>
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<div>
|
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<a id="geneMap" class="mim-anchor"></a>
|
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<div style="margin-bottom: 10px;">
|
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<span class="h4 mim-font">
|
|
<strong>Gene-Phenotype Relationships</strong>
|
|
</span>
|
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</div>
|
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<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
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<thead>
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<tr class="active">
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<th>
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|
Location
|
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</th>
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<th>
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|
Phenotype
|
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<span class="hidden-sm hidden-xs pull-right">
|
|
<a href="/clinicalSynopsis/table?mimNumber=615279,155950" class="label label-warning" onclick="gtag('event', 'mim_link', {'source': 'Entry', 'destination': 'clinicalSynopsisTable'})">
|
|
View Clinical Synopses
|
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</a>
|
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</span>
|
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</th>
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<th>
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Phenotype <br /> MIM number
|
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</th>
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<th>
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|
Inheritance
|
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</th>
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<th>
|
|
Phenotype <br /> mapping key
|
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</th>
|
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</tr>
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</thead>
|
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<tbody>
|
|
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|
<tr>
|
|
<td rowspan="2">
|
|
<span class="mim-font">
|
|
<a href="/geneMap/15/310?start=-3&limit=10&highlight=310">
|
|
15q22.31
|
|
</a>
|
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</span>
|
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</td>
|
|
|
|
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<td>
|
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<span class="mim-font">
|
|
Cardiofaciocutaneous syndrome 3
|
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</span>
|
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</td>
|
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<td>
|
|
<span class="mim-font">
|
|
|
|
<a href="/entry/615279"> 615279 </a>
|
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|
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</span>
|
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</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
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|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
|
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</span>
|
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</td>
|
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<td>
|
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<span class="mim-font">
|
|
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
|
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</span>
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</td>
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</tr>
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<tr>
|
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<td>
|
|
<span class="mim-font">
|
|
Melorheostosis, isolated, somatic mosaic
|
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PheneGene Graphics <span class="caret"></span>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs) (see ERK2, or MAPK1; <a href="/entry/176948">176948</a>), are thought to act as an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals, are rapidly phosphorylated on threonine and tyrosine residues, and are highly conserved in evolution (<a href="#4" class="mim-tip-reference" title="Crews, C. M., Alessandrini, A., Erikson, R. L. <strong>The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.</strong> Science 258: 478-480, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1411546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1411546</a>] [<a href="https://doi.org/10.1126/science.1411546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1411546">Crews et al., 1992</a>). A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. <a href="#4" class="mim-tip-reference" title="Crews, C. M., Alessandrini, A., Erikson, R. L. <strong>The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.</strong> Science 258: 478-480, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1411546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1411546</a>] [<a href="https://doi.org/10.1126/science.1411546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1411546">Crews et al. (1992)</a> cloned a mouse cDNA, denoted Mek1 (for Map/Erk kinase-1) by them, that encodes a member of this protein kinase family. The 393-amino acid, 43.5-kD protein is most closely related in size and sequence to the product encoded by the byr1 gene of S. pombe. The Mek1 gene was highly expressed in murine brain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1411546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Seger, R., Seger, D., Lozeman, F. J., Ahn, N. G., Graves, L. M., Campbell, J. S., Ericsson, L., Harrylock, M., Jensen, A. M., Krebs, E. G. <strong>Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases.</strong> J. Biol. Chem. 267: 25628-25631, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1281467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1281467</a>]" pmid="1281467">Seger et al. (1992)</a> cloned a cDNA encoding the human homolog of Mek1, symbolized MKK1 by them, from a human T-cell cDNA library. The predicted protein has a calculated molecular mass of 43 kD. They also isolated a related cDNA, called MKK1b, that appears to be an alternatively spliced form of MKK1. <a href="#23" class="mim-tip-reference" title="Seger, R., Seger, D., Lozeman, F. J., Ahn, N. G., Graves, L. M., Campbell, J. S., Ericsson, L., Harrylock, M., Jensen, A. M., Krebs, E. G. <strong>Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases.</strong> J. Biol. Chem. 267: 25628-25631, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1281467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1281467</a>]" pmid="1281467">Seger et al. (1992)</a> detected a 2.6-kb MKK1 transcript by Northern blot analysis in all tissues examined. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1281467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#26" class="mim-tip-reference" title="Zheng, C. F., Guan, K. L. <strong>Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.</strong> J. Biol. Chem. 268: 11435-11439, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388392</a>]" pmid="8388392">Zheng and Guan (1993)</a> also cloned a human cDNA corresponding to MEK1. They noted that the 393-amino acid protein shares 99% amino acid identity with murine Mek1 and 80% homology with human MEK2 (<a href="/entry/601263">601263</a>). The authors characterized biochemically the human MEK1 and MEK2 gene products. The gene is also symbolized MAP2K1, or PRKMK1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8388392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Using radiation hybrid mapping, <a href="#16" class="mim-tip-reference" title="Rampoldi, L., Zimbello, R., Bortoluzzi, S., Tiso, N., Valle, G., Lanfranchi, G., Danieli, G. A. <strong>Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5.</strong> Cytogenet. Cell Genet. 78: 301-303, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465908</a>] [<a href="https://doi.org/10.1159/000134677" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9465908">Rampoldi et al. (1997)</a> localized the MAP2K1 gene to 15q22.1-q22.33. By somatic cell hybrid analysis and FISH, <a href="#10" class="mim-tip-reference" title="Meloche, S., Gopalbhai, K., Beatty, B. G., Scherer, S. W., Pellerin, J. <strong>Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32.</strong> Cytogenet. Cell Genet. 88: 249-252, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10828601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10828601</a>] [<a href="https://doi.org/10.1159/000015530" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10828601">Meloche et al. (2000)</a> mapped MAP2K1 to 15q21 and a pseudogene, MAP2K1P1, to 8p21. <a href="#2" class="mim-tip-reference" title="Brott, B. K., Alessandrini, A., Largaespada, D. A., Copeland, N. G., Jenkins, N. A., Crews, C. M., Erikson, R. L. <strong>MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues.</strong> Cell Growth Differ. 4: 921-929, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8297798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8297798</a>]" pmid="8297798">Brott et al. (1993)</a> mapped the mouse Mek1 gene to chromosome 9. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9465908+10828601+8297798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#4" class="mim-tip-reference" title="Crews, C. M., Alessandrini, A., Erikson, R. L. <strong>The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.</strong> Science 258: 478-480, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1411546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1411546</a>] [<a href="https://doi.org/10.1126/science.1411546" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1411546">Crews et al. (1992)</a> found that the mouse Mek1 protein expressed in bacteria phosphorylated the Erk gene product in vitro. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1411546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Seger, R., Seger, D., Lozeman, F. J., Ahn, N. G., Graves, L. M., Campbell, J. S., Ericsson, L., Harrylock, M., Jensen, A. M., Krebs, E. G. <strong>Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases.</strong> J. Biol. Chem. 267: 25628-25631, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1281467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1281467</a>]" pmid="1281467">Seger et al. (1992)</a> found that overexpression of MKK1 in COS cells led to increased phorbol ester-stimulated MAP kinase kinase activity. <a href="#22" class="mim-tip-reference" title="Seger, R., Krebs, E. G. <strong>The MAPK signaling cascade.</strong> FASEB J. 9: 726-735, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7601337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7601337</a>]" pmid="7601337">Seger and Krebs (1995)</a> reviewed the MAP kinase signaling cascade. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=7601337+1281467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Ryan, K. M., Ernst, M. K., Rice, N. R., Vousden, K. H. <strong>Role of NF-kappa-B in p53-mediated programmed cell death.</strong> Nature 404: 892-897, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10786798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10786798</a>] [<a href="https://doi.org/10.1038/35009130" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10786798">Ryan et al. (2000)</a> showed that inhibition of MEK1 blocks p53 (<a href="/entry/191170">191170</a>)-induced NF-kappa-B activation and apoptosis but not cell cycle arrest. They demonstrated that p53 activates NF-kappa-B through the RAF/MEK1/p90(rsk) (see <a href="/entry/601684">601684</a>) pathway rather than the TNFR1 (<a href="/entry/191190">191190</a>)/TRAF2 (<a href="/entry/601895">601895</a>)/IKK (e.g., <a href="/entry/600664">600664</a>) pathway used by TNFA (<a href="/entry/191160">191160</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10786798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To elucidate the mechanism through which MAPK signaling regulates the MYOD (<a href="/entry/159970">159970</a>) family of transcription factors, <a href="#14" class="mim-tip-reference" title="Perry, R. L. S., Parker, M. H., Rudnicki, M. A. <strong>Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation.</strong> Molec. Cell 8: 291-301, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11545732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11545732</a>] [<a href="https://doi.org/10.1016/s1097-2765(01)00302-1" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11545732">Perry et al. (2001)</a> investigated the role of the signaling intermediate MEK1 in myogenesis. Transfection of activated MEK1 strongly repressed gene activation and myogenic conversion by the MYOD family. This repression was not mediated by direct phosphorylation of MYOD or by changes in MYOD stability or subcellular distribution. Deletion mapping revealed that MEK1-mediated repression required the MYOD N-terminal transactivation domain. Moreover, activated MEK1 was nuclearly localized and bound a complex containing MYOD in a manner that was dependent on the presence of the MYOD N terminus. These data demonstrated that MEK1 signaling has a strong negative effect on MYOD activity via a mechanism involving binding of MEK1 to the nuclear MYOD transcriptional complex. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11545732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#25" class="mim-tip-reference" title="Takekawa, M., Tatebayashi, K., Saito, H. <strong>Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.</strong> Molec. Cell 18: 295-306, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15866172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15866172</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15866172">Takekawa et al. (2005)</a> identified a conserved docking site, which they termed 'domain for versatile docking' (DVD), immediately C terminal to the catalytic domains of mammalian MAPKKs, including MEK1. They determined that DVD sites contain about 20 amino acids and bind to specific upstream MAPKKKs. DVD site mutations strongly inhibited MAPKKs from binding to and being activated by their specific MAPKKKs, both in vitro and in vivo. MAPKKs containing DVD site mutations could not be activated by various external stimuli in vivo, and synthetic DVD oligopeptides inhibited specific MAPKK activation, both in vitro and in vivo. <a href="#25" class="mim-tip-reference" title="Takekawa, M., Tatebayashi, K., Saito, H. <strong>Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.</strong> Molec. Cell 18: 295-306, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15866172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15866172</a>] [<a href="https://doi.org/10.1016/j.molcel.2005.04.001" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15866172">Takekawa et al. (2005)</a> concluded that DVD docking is critically important in MAPK signaling. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15866172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A. <strong>Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia.</strong> Dev. Cell 12: 615-629, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17419998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17419998</a>] [<a href="https://doi.org/10.1016/j.devcel.2007.03.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17419998">Scholl et al. (2007)</a> found that conditional deletion of either Mek1 or Mek2 in mouse skin had no effect on epidermal development, but combined Mek1/Mek2 deletion during embryonic development or in adulthood abolished Erk1 (MAPK3; <a href="/entry/601795">601795</a>)/Erk2 phosphorylation and led to hypoproliferation, apoptosis, skin barrier defects, and death. Conversely, a single copy of either allele was sufficient for normal development. Combined Mek1/Mek2 loss also abolished Raf (RAF1; <a href="/entry/164760">164760</a>)-induced hyperproliferation. To examine the effect of combined MEK deletion on human skin, <a href="#19" class="mim-tip-reference" title="Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A. <strong>Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia.</strong> Dev. Cell 12: 615-629, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17419998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17419998</a>] [<a href="https://doi.org/10.1016/j.devcel.2007.03.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17419998">Scholl et al. (2007)</a> used small interfering RNA to delete MEK1 and MEK2 expression in normal primary human keratinocytes and used these cells to regenerate human epidermal tissue on human dermis, which was grafted onto immune-deficient mice. Control keratinocytes or those lacking either MEK1 or MEK2 were able to regenerate 6 days after grafting. In contrast, combined depletion of MEK1 and MEK2 led to either graft failure or markedly hypoplastic epidermis that nonetheless contained an intact stratum corneum. ERK2 expression rescued the defect. <a href="#19" class="mim-tip-reference" title="Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A. <strong>Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia.</strong> Dev. Cell 12: 615-629, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17419998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17419998</a>] [<a href="https://doi.org/10.1016/j.devcel.2007.03.009" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17419998">Scholl et al. (2007)</a> concluded that MEK1 and MEK2 are functionally redundant in the epidermis and function in a linear relay in the MAPK pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17419998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y. <strong>Regulation of pancreatic beta cell mass by neuronal signals from the liver.</strong> Science 322: 1250-1254, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19023081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19023081</a>] [<a href="https://doi.org/10.1126/science.1163971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19023081">Imai et al. (2008)</a> used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiologic compensation for insulin resistance. <a href="#8" class="mim-tip-reference" title="Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y. <strong>Regulation of pancreatic beta cell mass by neuronal signals from the liver.</strong> Science 322: 1250-1254, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19023081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19023081</a>] [<a href="https://doi.org/10.1126/science.1163971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19023081">Imai et al. (2008)</a> found that hepatic activation of extracellular regulated kinase (ERK1; <a href="/entry/601795">601795</a>) signaling by expression of constitutively active MEK1 induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, <a href="#8" class="mim-tip-reference" title="Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y. <strong>Regulation of pancreatic beta cell mass by neuronal signals from the liver.</strong> Science 322: 1250-1254, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19023081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19023081</a>] [<a href="https://doi.org/10.1126/science.1163971" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19023081">Imai et al. (2008)</a> concluded that interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19023081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Chuderland, D., Konson, A., Seger, R. <strong>Identification and characterization of a general nuclear translocation signal in signaling proteins.</strong> Molec. Cell 31: 850-861, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760948</a>] [<a href="https://doi.org/10.1016/j.molcel.2008.08.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18760948">Chuderland et al. (2008)</a> identified an SPS motif in ERK2 and SMAD3 (<a href="/entry/603109">603109</a>) and a similar TPT motif in MEK1 that directed protein nuclear accumulation when phosphorylated. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#1" class="mim-tip-reference" title="Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., Barford, D. <strong>A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.</strong> Nature 472: 366-369, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441910</a>] [<a href="https://doi.org/10.1038/nature09860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441910">Brennan et al. (2011)</a> integrated structural and biochemical studies to understand how kinase suppressor of Ras (KSR) promotes stimulatory Raf phosphorylation of MEK. They showed, from the crystal structure of the kinase domain (KD) of human KSR2 (<a href="/entry/610737">610737</a>) in complex with rabbit MEK1, that interactions between KSR2(KD) and MEK1 are mediated by their respective activation segments and C-lobe alpha-G helices. Analogous to BRAF (<a href="/entry/164757">164757</a>), KSR2 self-associates through a side-to-side interface involving arg718, a residue identified in a genetic screen as a suppressor of Ras signaling. ATP is bound to the KSR2 (KD) catalytic site, and <a href="#1" class="mim-tip-reference" title="Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., Barford, D. <strong>A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.</strong> Nature 472: 366-369, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441910</a>] [<a href="https://doi.org/10.1038/nature09860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441910">Brennan et al. (2011)</a> demonstrated KSR2 kinase activity towards MEK1 by in vitro assays and chemical genetics. In the KSR2(KD)-MEK1 complex, the activation segments of both kinases are mutually constrained, and KSR2 adopts an inactive conformation. BRAF allosterically stimulates the kinase activity of KSR2, which is dependent on formation of a side-to-side KSR2-BRAF heterodimer. Furthermore, KSR2-BRAF heterodimerization results in an increase of BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal from BRAF to release the activation segment of MEK for phosphorylation. <a href="#1" class="mim-tip-reference" title="Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., Barford, D. <strong>A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.</strong> Nature 472: 366-369, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441910</a>] [<a href="https://doi.org/10.1038/nature09860" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21441910">Brennan et al. (2011)</a> proposed that KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK's phosphorylation by a separate catalytic Raf molecule in trans. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21441910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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<a href="#13" class="mim-tip-reference" title="Park, E., Rawson, S., Li, K., Kim, B.-W., Ficarro, S. B., Gonzalez-Del Pino, G., Sharif, H., Marto, J. A., Jeon, H., Eck, M. J. <strong>Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.</strong> Nature 575: 545-550, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31581174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31581174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31581174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1660-y" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31581174">Park et al. (2019)</a> used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer of eta (YWHAH; <a href="/entry/113508">113508</a>) and zeta (YWHAZ; <a href="/entry/601288">601288</a>). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31581174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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In 2 patients with cardiofaciocutaneous syndrome (CFC3; <a href="/entry/615279">615279</a>), <a href="#17" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. <strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong> Science 311: 1287-1290, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>] [<a href="https://doi.org/10.1126/science.1124642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439621">Rodriguez-Viciana et al. (2006)</a> identified mutations (F53S, <a href="#0001">176872.0001</a>; Y130C, <a href="#0002">176872.0002</a>) in the MEK1 gene. Interestingly, 1 patient had a mutation at phe53 (F53), which is equivalent to phe57 (F57) in the MEK2 gene, where another CFC patient had a missense mutation (F57C; <a href="/entry/601263#0001">601263.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 5 patients with CFC3, <a href="#7" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. <strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong> Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551924</a>] [<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17551924">Gripp et al. (2007)</a> identified heterozygous mutations in the MEK1 gene. Three patients had the previously identified Y130C mutation and 2 had novel mutations (<a href="#0004">176872.0004</a> and <a href="#0005">176872.0005</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. <strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong> Clin. Genet. 73: 62-70, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042262</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042262">Schulz et al. (2008)</a> identified mutations in the MAP2K1 gene (see, e.g., <a href="#0003">176872.0003</a>) in 5 (9.8%) of 51 CFC patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutation in Isolated Melorheostosis</em></strong></p><p>
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In samples of affected bone from 8 patients with isolated melorheostosis (MEL; <a href="/entry/155950">155950</a>), <a href="#9" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. <strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong> Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-018-03720-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29643386">Kang et al. (2018)</a> identified somatic mosaicism for missense mutations in the MAP2K1 gene (Q56P, <a href="#0006">176872.0006</a>; K57N, <a href="#0007">176872.0007</a>; and K57E, <a href="#0008">176872.0008</a>) that were not present in unaffected bone or in peripheral blood leukocytes. Mutant allele frequency ranged from 3 to 34% in affected bone. The authors noted that all 3 MAP2K1 variants had previously been shown to cause gain-of-function effects and had been detected in malignancies, including lung cancer, melanoma, and hairy cell leukemia. Functional analysis confirmed enhanced activation, resulting in increased osteoblast proliferation; however, there was also reduced mineralization and differentiation, consistent with histologic findings of massive accumulation of unmineralized osteoid bone in affected bone tissue, as well as increased osteoclast activity, as shown by the intense remodeling that occurs in melorheostotic bone. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Somatic Mutation in Melanoma</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Nikolaev, S. I., Rimoldi, D., Iseli, C., Valsesia, A., Robyr, D., Gehrig, C., Harshman, K., Guipponi, M., Bukach, O., Zoete, V., Michielin, O., Muehlethaler, K., Speiser, D., Beckmann, J. S., Xenarios, I., Halazonetis, T. D., Jongeneel, C. V., Stevenson, B. J., Antonarakis, S. E. <strong>Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.</strong> Nature Genet. 44: 133-139, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22197931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22197931</a>] [<a href="https://doi.org/10.1038/ng.1026" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22197931">Nikolaev et al. (2012)</a> performed exome sequencing to detect somatic mutations in protein-coding regions in 7 melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in 2 metastases derived from the same individual. Two melanomas with noncanonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK2; <a href="/entry/601263">601263</a>) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22197931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Constitutive activation of MEK1 results in cellular transformation. This protein kinase therefore represents a likely target for pharmacologic intervention in proliferative disease. To identity small-molecule inhibitors of this pathway, <a href="#21" class="mim-tip-reference" title="Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., Saltiel, A. R. <strong>Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.</strong> Nature Med. 5: 810-816, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395327</a>] [<a href="https://doi.org/10.1038/10533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10395327">Sebolt-Leopold et al. (1999)</a> developed an in vitro cascade assay using bacterially purified glutathione-S-transferase fusion proteins of MEK1 and MAPK. <a href="#21" class="mim-tip-reference" title="Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., Saltiel, A. R. <strong>Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.</strong> Nature Med. 5: 810-816, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395327</a>] [<a href="https://doi.org/10.1038/10533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10395327">Sebolt-Leopold et al. (1999)</a> reported the discovery of a highly potent and selective inhibitor of MEK1, which they called PD184352 and which is, in fact, 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide. PD184352 is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses (with a 50% inhibitory concentration of 17 nanomolar) with no signs of toxicity, and correlated with a reduction in levels of MAPK in excised tumors. <a href="#21" class="mim-tip-reference" title="Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., Saltiel, A. R. <strong>Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.</strong> Nature Med. 5: 810-816, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395327</a>] [<a href="https://doi.org/10.1038/10533" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10395327">Sebolt-Leopold et al. (1999)</a> concluded that these data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10395327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the extracellular signal-regulated kinase ERK, c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways and inhibition of the nuclear factor kappa B (NF-kappa-B; see <a href="/entry/164011">164011</a>) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, <a href="#12" class="mim-tip-reference" title="Orth, K., Palmer, L. E., Bao, Z. Q., Stewart, S., Rudolph, A. E., Bliska, J. B., Dixon, J. E. <strong>Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector.</strong> Science 285: 1920-1923, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10489373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10489373</a>] [<a href="https://doi.org/10.1126/science.285.5435.1920" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10489373">Orth et al. (1999)</a> identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1, MKK2 (<a href="/entry/601263">601263</a>), and MKK4/SEK1 (<a href="/entry/601335">601335</a>). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3 (<a href="/entry/602315">602315</a>), MKK4, and MKK5 (<a href="/entry/602448">602448</a>). Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10489373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Influenza A viruses are significant causes of morbidity and mortality worldwide. Annually updated vaccines may prevent disease, and antivirals are effective treatment early in disease when symptoms are often nonspecific. Viral replication is supported by intracellular signaling events. Using U0126, a nontoxic inhibitor of MEK1 and MEK2, and thus an inhibitor of the RAF1/MEK/ERK pathway (see <a href="#5" class="mim-tip-reference" title="Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., Van Dyk, D. E., Pitts, W. J., Earl, R. A., Hobbs, F., Copeland, R. A., Magolda, R. L., Scherle, P. A., Trzaskos, J. M. <strong>Identification of a novel inhibitor of mitogen-activated protein kinase kinase.</strong> J. Biol. Chem. 273: 18623-18632, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660836</a>] [<a href="https://doi.org/10.1074/jbc.273.29.18623" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9660836">Favata et al. (1998)</a>), <a href="#15" class="mim-tip-reference" title="Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R., Ludwig, S. <strong>Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade.</strong> Nature Cell Biol. 3: 301-305, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11231581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11231581</a>] [<a href="https://doi.org/10.1038/35060098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11231581">Pleschka et al. (2001)</a> examined the cellular response to infection with influenza A. U0126 suppressed both the early and late ERK activation phases after virus infection. Inhibition of the signaling pathway occurred without impairing the synthesis of viral RNA or protein, or the import of viral ribonucleoprotein complexes (RNP) into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the export of viral RNP without affecting the cellular mRNA export pathway. <a href="#15" class="mim-tip-reference" title="Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R., Ludwig, S. <strong>Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade.</strong> Nature Cell Biol. 3: 301-305, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11231581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11231581</a>] [<a href="https://doi.org/10.1038/35060098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11231581">Pleschka et al. (2001)</a> proposed that ERK regulates a cellular factor involved in the viral nuclear export protein function. They suggested that local application of MEK inhibitors may have only minor toxic effects on the host while inhibiting viral replication without giving rise to drug-resistant virus variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=11231581+9660836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#6" class="mim-tip-reference" title="Giroux, S., Tremblay, M., Bernard, D., Cadrin-Girard, J.-F., Aubry, S., Larouche, L., Rousseau, S., Huot, J., Landry, J., Jeannotte, L., Charron, J. <strong>Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta.</strong> Curr. Biol. 9: 369-372, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10209122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10209122</a>] [<a href="https://doi.org/10.1016/s0960-9822(99)80164-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10209122">Giroux et al. (1999)</a> disrupted the mouse Mek1 gene by insertional mutagenesis. The null mutation was recessive lethal, and homozygous mutant embryos died at 10.5 days of gestation. Histopathologic analysis revealed a marked decrease of vascular endothelial cells in the labyrinthine region, resulting in reduced vascularization of the placenta. Failure to establish a functional placenta was considered a likely cause of embryonic death. Cell migration assays indicated that Mek1-null fibroblasts could not be induced to migrate by fibronectin (<a href="/entry/135600">135600</a>), and reintroduction of Mek1 expression restored their ability to migrate. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10209122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908594 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908594;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908594" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000014278 OR RCV000158002 OR RCV000520164 OR RCV004760331" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000014278, RCV000158002, RCV000520164, RCV004760331" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000014278...</a>
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<p>In a patient with cardiofaciocutaneous syndrome (CFC3; <a href="/entry/615279">615279</a>), <a href="#17" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. <strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong> Science 311: 1287-1290, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>] [<a href="https://doi.org/10.1126/science.1124642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439621">Rodriguez-Viciana et al. (2006)</a> identified a T-to-C transition at nucleotide 158 (c.158T-C, NM_002755) of the MEK1 gene resulting in a phenylalanine-to-serine substitution at codon 53 (F53S). This mutation was not identified in either of the patient's parents. Interestingly, a mutation at the equivalent codon in MEK2 (<a href="/entry/601263">601263</a>) was found in another CFC patient (F57C; <a href="/entry/601263#0001">601263.0001</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By in vitro studies, <a href="#24" class="mim-tip-reference" title="Senawong, T., Phuchareon, J., Ohara, O., McCormick, F., Rauen, K. A., Tetsu, O. <strong>Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.</strong> Hum. Molec. Genet. 17: 419-430, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17981815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17981815</a>] [<a href="https://doi.org/10.1093/hmg/ddm319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17981815">Senawong et al. (2008)</a> found that MEK1 mutants F53S and Y130C and the MEK2 mutant F57C could not induce ERK signaling unless phosphorylated by RAF at 2 homologous serine residues in the regulatory loop. When these serine residues were replaced with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. However, the F57C MEK2 mutant was less dependent on RAF signaling than the other mutants. This difference resulted in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. However, all 3 mutants were sensitive to the MEK inhibitor U0126. <a href="#24" class="mim-tip-reference" title="Senawong, T., Phuchareon, J., Ohara, O., McCormick, F., Rauen, K. A., Tetsu, O. <strong>Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.</strong> Hum. Molec. Genet. 17: 419-430, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17981815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17981815</a>] [<a href="https://doi.org/10.1093/hmg/ddm319" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17981815">Senawong et al. (2008)</a> suggested that MEK inhibition could have potential therapeutic value in CFC. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17981815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown"><span class="text-primary">●</span> rs121908595 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908595;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://gnomad.broadinstitute.org/variant/rs121908595?dataset=gnomad_r2_1" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'gnomad.broadinstitute.org'})" style="padding-left: 8px;"><span class="text-primary">●</span> gnomAD</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043672 OR RCV000207506 OR RCV000208757 OR RCV000541525 OR RCV000763362 OR RCV001197351 OR RCV003450638 OR RCV004532347 OR RCV004984640" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043672, RCV000207506, RCV000208757, RCV000541525, RCV000763362, RCV001197351, RCV003450638, RCV004532347, RCV004984640" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043672...</a>
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<p>In a patient with cardiofaciocutaneous syndrome (CFC3; <a href="/entry/615279">615279</a>), <a href="#17" class="mim-tip-reference" title="Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. <strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong> Science 311: 1287-1290, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>] [<a href="https://doi.org/10.1126/science.1124642" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16439621">Rodriguez-Viciana et al. (2006)</a> identified heterozygosity for an A-to-G transition at nucleotide 389 (c.389A-G, NM_002755) of the MEK1 gene, resulting in a tyrosine-to-cysteine substitution at codon 130 (Y130C) in the protein kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 3 children (patients 136, 146, and 163) with CFC3, <a href="#7" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. <strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong> Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551924</a>] [<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17551924">Gripp et al. (2007)</a> identified heterozygosity for the Y130C mutation in the MEK1 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121908596 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121908596;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs121908596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs121908596" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000043673 OR RCV000207493 OR RCV000211725 OR RCV001234104" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000043673, RCV000207493, RCV000211725, RCV001234104" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000043673...</a>
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<p>In a patient with cardiofaciocutaneous syndrome (CFC3; <a href="/entry/615279">615279</a>), <a href="#20" class="mim-tip-reference" title="Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others. <strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong> Clin. Genet. 73: 62-70, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042262</a>] [<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18042262">Schulz et al. (2008)</a> identified a heterozygous 383G-T transversion in exon 3 of the MAP2K1 gene, resulting in a gly128-to-val (G128V) substitution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025339 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025339;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs869025339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs869025339" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000207500 OR RCV002277569 OR RCV002515536" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000207500, RCV002277569, RCV002515536" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000207500...</a>
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<p>In an 8-year-old girl (patient 144) with cardiofaciocutaneous syndrome-3 (CFC3; <a href="/entry/615279">615279</a>), <a href="#7" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. <strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong> Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551924</a>] [<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17551924">Gripp et al. (2007)</a> identified a 3-bp deletion (AAG) in exon 2 of the MEK1 gene, resulting in deletion of a lysine (K59del) at the beginning of the protein kinase-like domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0005 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
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MAP2K1, PRO124GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397516792 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516792;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397516792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397516792" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV001078439" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV001078439" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV001078439</a>
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<p>In a 7-week-old male (patient 95) with cardiofaciocutaneous syndrome-3 (CFC3; <a href="/entry/615279">615279</a>), <a href="#7" class="mim-tip-reference" title="Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K. <strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong> Am. J. Med. Genet. 143A: 1472-1480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551924</a>] [<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17551924">Gripp et al. (2007)</a> identified a c.371C-A transversion in exon 3 of the MEK1 gene, resulting in a pro124-to-gln (P124Q) substitution in the protein kinase domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0006 MELORHEOSTOSIS, ISOLATED, SOMATIC MOSAIC</strong>
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MAP2K1, GLN56PRO
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1057519729 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1057519729;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1057519729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1057519729" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000418731 OR RCV002051704 OR RCV002254296" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000418731, RCV002051704, RCV002254296" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000418731...</a>
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<p>In samples of affected bone from 3 patients (Melo-4, Melo-9, and Melo-19) with melorheostosis (MEL; <a href="/entry/155950">155950</a>), <a href="#9" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. <strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong> Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-018-03720-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29643386">Kang et al. (2018)</a> identified somatic mosaicism for a c.167A-C transversion (c.167A-C, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a gln56-to-pro (Q56P) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 9 to 28% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in patient Melo-4 showed the variant at an allele frequency of 12.5%. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; <a href="/entry/601795">601795</a>) and ERK2 (MAPK1; <a href="/entry/176948">176948</a>) compared to cells from unaffected bone, confirming a gain-of-function effect with the Q56P variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0007" class="mim-anchor"></a>
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<span class="mim-font">
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<strong>.0007 MELORHEOSTOSIS, ISOLATED, SOMATIC MOSAIC</strong>
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MAP2K1, LYS57ASN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs869025608 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs869025608;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs869025608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs869025608" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000208748 OR RCV002051691 OR RCV002254287" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000208748, RCV002051691, RCV002254287" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000208748...</a>
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<p>In samples of affected bone from 4 patients (Melo-2, Melo-6, Melo-16, and Melo-18) with melorheostosis (MEL; <a href="/entry/155950">155950</a>), <a href="#9" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. <strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong> Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-018-03720-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29643386">Kang et al. (2018)</a> identified somatic mosaicism for a c.171G-T transversion (c.171G-T, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-asn (K57N) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 3 to 34% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in 3 of the patients showed the variant at an allele frequency of 4.1 to 16.2%; the variant was not detected in skin from patient Melo-16, who had a lower disease burden. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; <a href="/entry/601795">601795</a>) and ERK2 (MAPK1; <a href="/entry/176948">176948</a>) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57N variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency. Consistent with enhanced activation, affected osteoblasts showed increased cell proliferation in vitro; however, there was also reduced mineralization and differentiation with affected osteoblasts, as well as increased osteoclast activity. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0008 MELORHEOSTOSIS, ISOLATED, SOMATIC MOSAIC</strong>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs397516790 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs397516790;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs397516790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs397516790" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV002051705" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV002051705" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV002051705</a>
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<p>In samples of affected bone from a patient (Melo-10) with melorheostosis (MEL; <a href="/entry/155950">155950</a>), <a href="#9" class="mim-tip-reference" title="Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T. <strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong> Nature Commun. 9: 1390, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41467-018-03720-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="29643386">Kang et al. (2018)</a> identified somatic mosaicism for a c.169A-G transition (c.169A-G, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-glu (K57E) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency was 18% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; <a href="/entry/601795">601795</a>) and ERK2 (MAPK1; <a href="/entry/176948">176948</a>) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57E variant. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>REFERENCES</strong>
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|
|
<a id="1" class="mim-anchor"></a>
|
|
<a id="Brennan2011" class="mim-anchor"></a>
|
|
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|
|
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|
|
Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., Barford, D.
|
|
<strong>A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.</strong>
|
|
Nature 472: 366-369, 2011.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21441910/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21441910</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21441910" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
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|
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[<a href="https://doi.org/10.1038/nature09860" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="2" class="mim-anchor"></a>
|
|
<a id="Brott1993" class="mim-anchor"></a>
|
|
<div class="">
|
|
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|
|
Brott, B. K., Alessandrini, A., Largaespada, D. A., Copeland, N. G., Jenkins, N. A., Crews, C. M., Erikson, R. L.
|
|
<strong>MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues.</strong>
|
|
Cell Growth Differ. 4: 921-929, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8297798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8297798</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8297798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
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|
|
|
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</p>
|
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</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="3" class="mim-anchor"></a>
|
|
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|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Chuderland, D., Konson, A., Seger, R.
|
|
<strong>Identification and characterization of a general nuclear translocation signal in signaling proteins.</strong>
|
|
Molec. Cell 31: 850-861, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18760948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18760948</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18760948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.molcel.2008.08.007" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="4" class="mim-anchor"></a>
|
|
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|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Crews, C. M., Alessandrini, A., Erikson, R. L.
|
|
<strong>The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.</strong>
|
|
Science 258: 478-480, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1411546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1411546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1411546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
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[<a href="https://doi.org/10.1126/science.1411546" target="_blank">Full Text</a>]
|
|
|
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|
|
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|
|
</li>
|
|
|
|
<li>
|
|
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|
|
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|
|
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|
|
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|
|
Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., Van Dyk, D. E., Pitts, W. J., Earl, R. A., Hobbs, F., Copeland, R. A., Magolda, R. L., Scherle, P. A., Trzaskos, J. M.
|
|
<strong>Identification of a novel inhibitor of mitogen-activated protein kinase kinase.</strong>
|
|
J. Biol. Chem. 273: 18623-18632, 1998.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9660836/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9660836</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9660836" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1074/jbc.273.29.18623" target="_blank">Full Text</a>]
|
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|
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|
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|
|
</li>
|
|
|
|
<li>
|
|
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|
|
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|
|
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|
|
<p class="mim-text-font">
|
|
Giroux, S., Tremblay, M., Bernard, D., Cadrin-Girard, J.-F., Aubry, S., Larouche, L., Rousseau, S., Huot, J., Landry, J., Jeannotte, L., Charron, J.
|
|
<strong>Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta.</strong>
|
|
Curr. Biol. 9: 369-372, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10209122/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10209122</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10209122" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s0960-9822(99)80164-x" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="7" class="mim-anchor"></a>
|
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|
|
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|
|
<p class="mim-text-font">
|
|
Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K.
|
|
<strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong>
|
|
Am. J. Med. Genet. 143A: 1472-1480, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551924/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551924</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551924" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1002/ajmg.a.31815" target="_blank">Full Text</a>]
|
|
|
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|
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|
|
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|
|
</li>
|
|
|
|
<li>
|
|
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|
|
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|
|
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|
|
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|
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Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y.
|
|
<strong>Regulation of pancreatic beta cell mass by neuronal signals from the liver.</strong>
|
|
Science 322: 1250-1254, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19023081/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19023081</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19023081" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1163971" target="_blank">Full Text</a>]
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Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T.
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<strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong>
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Nature Commun. 9: 1390, 2018. Note: Electronic Article.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/29643386/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">29643386</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=29643386[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=29643386" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41467-018-03720-z" target="_blank">Full Text</a>]
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|
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Meloche, S., Gopalbhai, K., Beatty, B. G., Scherer, S. W., Pellerin, J.
|
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<strong>Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32.</strong>
|
|
Cytogenet. Cell Genet. 88: 249-252, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10828601/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10828601</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10828601" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1159/000015530" target="_blank">Full Text</a>]
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|
|
Nikolaev, S. I., Rimoldi, D., Iseli, C., Valsesia, A., Robyr, D., Gehrig, C., Harshman, K., Guipponi, M., Bukach, O., Zoete, V., Michielin, O., Muehlethaler, K., Speiser, D., Beckmann, J. S., Xenarios, I., Halazonetis, T. D., Jongeneel, C. V., Stevenson, B. J., Antonarakis, S. E.
|
|
<strong>Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.</strong>
|
|
Nature Genet. 44: 133-139, 2012.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22197931/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22197931</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22197931" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/ng.1026" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="12" class="mim-anchor"></a>
|
|
<a id="Orth1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Orth, K., Palmer, L. E., Bao, Z. Q., Stewart, S., Rudolph, A. E., Bliska, J. B., Dixon, J. E.
|
|
<strong>Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector.</strong>
|
|
Science 285: 1920-1923, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10489373/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10489373</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10489373" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.285.5435.1920" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="13" class="mim-anchor"></a>
|
|
<a id="Park2019" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Park, E., Rawson, S., Li, K., Kim, B.-W., Ficarro, S. B., Gonzalez-Del Pino, G., Sharif, H., Marto, J. A., Jeon, H., Eck, M. J.
|
|
<strong>Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.</strong>
|
|
Nature 575: 545-550, 2019.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31581174/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31581174</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31581174[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31581174" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/s41586-019-1660-y" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="14" class="mim-anchor"></a>
|
|
<a id="Perry2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Perry, R. L. S., Parker, M. H., Rudnicki, M. A.
|
|
<strong>Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation.</strong>
|
|
Molec. Cell 8: 291-301, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11545732/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11545732</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11545732" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/s1097-2765(01)00302-1" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="15" class="mim-anchor"></a>
|
|
<a id="Pleschka2001" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R., Ludwig, S.
|
|
<strong>Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade.</strong>
|
|
Nature Cell Biol. 3: 301-305, 2001.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11231581/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11231581</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11231581" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35060098" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="16" class="mim-anchor"></a>
|
|
<a id="Rampoldi1997" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rampoldi, L., Zimbello, R., Bortoluzzi, S., Tiso, N., Valle, G., Lanfranchi, G., Danieli, G. A.
|
|
<strong>Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5.</strong>
|
|
Cytogenet. Cell Genet. 78: 301-303, 1997.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9465908/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9465908</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9465908" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1159/000134677" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="17" class="mim-anchor"></a>
|
|
<a id="Rodriguez-Viciana2006" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A.
|
|
<strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong>
|
|
Science 311: 1287-1290, 2006.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16439621/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16439621</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16439621" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1126/science.1124642" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="18" class="mim-anchor"></a>
|
|
<a id="Ryan2000" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Ryan, K. M., Ernst, M. K., Rice, N. R., Vousden, K. H.
|
|
<strong>Role of NF-kappa-B in p53-mediated programmed cell death.</strong>
|
|
Nature 404: 892-897, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10786798/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10786798</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10786798" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/35009130" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="19" class="mim-anchor"></a>
|
|
<a id="Scholl2007" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A.
|
|
<strong>Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia.</strong>
|
|
Dev. Cell 12: 615-629, 2007.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17419998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17419998</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17419998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.devcel.2007.03.009" target="_blank">Full Text</a>]
|
|
|
|
|
|
</p>
|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="20" class="mim-anchor"></a>
|
|
<a id="Schulz2008" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others.
|
|
<strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong>
|
|
Clin. Genet. 73: 62-70, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18042262/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18042262</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18042262" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank">Full Text</a>]
|
|
|
|
|
|
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|
|
</div>
|
|
</li>
|
|
|
|
<li>
|
|
<a id="21" class="mim-anchor"></a>
|
|
<a id="Sebolt-Leopold1999" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., Saltiel, A. R.
|
|
<strong>Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.</strong>
|
|
Nature Med. 5: 810-816, 1999.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10395327/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10395327</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10395327" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1038/10533" target="_blank">Full Text</a>]
|
|
|
|
|
|
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|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="22" class="mim-anchor"></a>
|
|
<a id="Seger1995" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Seger, R., Krebs, E. G.
|
|
<strong>The MAPK signaling cascade.</strong>
|
|
FASEB J. 9: 726-735, 1995.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7601337/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7601337</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7601337" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
</p>
|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="23" class="mim-anchor"></a>
|
|
<a id="Seger1992" class="mim-anchor"></a>
|
|
<div class="">
|
|
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|
|
Seger, R., Seger, D., Lozeman, F. J., Ahn, N. G., Graves, L. M., Campbell, J. S., Ericsson, L., Harrylock, M., Jensen, A. M., Krebs, E. G.
|
|
<strong>Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases.</strong>
|
|
J. Biol. Chem. 267: 25628-25631, 1992.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1281467/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1281467</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1281467" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
|
|
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|
|
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|
|
</li>
|
|
|
|
<li>
|
|
<a id="24" class="mim-anchor"></a>
|
|
<a id="Senawong2008" class="mim-anchor"></a>
|
|
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|
|
<p class="mim-text-font">
|
|
Senawong, T., Phuchareon, J., Ohara, O., McCormick, F., Rauen, K. A., Tetsu, O.
|
|
<strong>Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.</strong>
|
|
Hum. Molec. Genet. 17: 419-430, 2008.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17981815/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17981815</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17981815" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
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[<a href="https://doi.org/10.1093/hmg/ddm319" target="_blank">Full Text</a>]
|
|
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|
|
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|
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|
|
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|
|
|
|
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|
|
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|
|
<a id="Takekawa2005" class="mim-anchor"></a>
|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Takekawa, M., Tatebayashi, K., Saito, H.
|
|
<strong>Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.</strong>
|
|
Molec. Cell 18: 295-306, 2005.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15866172/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15866172</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15866172" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
|
|
|
|
|
|
[<a href="https://doi.org/10.1016/j.molcel.2005.04.001" target="_blank">Full Text</a>]
|
|
|
|
|
|
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|
|
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|
|
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|
|
|
|
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|
|
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|
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|
|
<div class="">
|
|
<p class="mim-text-font">
|
|
Zheng, C. F., Guan, K. L.
|
|
<strong>Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.</strong>
|
|
J. Biol. Chem. 268: 11435-11439, 1993.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8388392/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8388392</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8388392" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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|
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<span class="mim-text-font">
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Ada Hamosh - updated : 02/15/2023
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Marla J. F. O'Neill - updated : 06/22/2020<br>Kelly A. Przylepa - updated : 04/21/2020<br>Ada Hamosh - updated : 2/1/2013<br>Ada Hamosh - updated : 7/8/2011<br>Cassandra L. Kniffin - updated : 1/11/2010<br>Patricia A. Hartz - updated : 5/29/2009<br>Ada Hamosh - updated : 12/30/2008<br>Cassandra L. Kniffin - updated : 3/17/2008<br>Patricia A. Hartz - updated : 5/4/2007<br>Ada Hamosh - updated : 4/19/2006<br>Patricia A. Hartz - updated : 5/26/2005<br>Patricia A. Hartz - updated : 3/25/2003<br>Stylianos E. Antonarakis - updated : 10/23/2001<br>Joanna S. Amberger - updated : 3/6/2001<br>Paul J. Converse - updated : 3/2/2001<br>Paul J. Converse - updated : 4/19/2000<br>Ada Hamosh - updated : 9/15/1999<br>Ada Hamosh - updated : 7/9/1999<br>Victor A. McKusick - updated : 3/16/1998<br>Alan F. Scott - updated : 9/17/1996<br>Mark H. Paalman - updated : 5/20/1996<br>Mark H. Paalman - updated : 5/13/1996
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Creation Date:
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<span class="mim-text-font">
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Victor A. McKusick : 11/2/1992
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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alopez : 02/15/2023
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alopez : 06/23/2020<br>alopez : 06/22/2020<br>carol : 04/21/2020<br>alopez : 06/20/2013<br>alopez : 2/6/2013<br>terry : 2/1/2013<br>alopez : 7/12/2011<br>terry : 7/8/2011<br>terry : 7/8/2011<br>wwang : 1/22/2010<br>ckniffin : 1/11/2010<br>mgross : 6/2/2009<br>terry : 5/29/2009<br>alopez : 1/5/2009<br>terry : 12/30/2008<br>wwang : 3/19/2008<br>ckniffin : 3/17/2008<br>mgross : 5/23/2007<br>terry : 5/4/2007<br>alopez : 4/20/2006<br>terry : 4/19/2006<br>mgross : 6/6/2005<br>terry : 5/26/2005<br>mgross : 3/25/2003<br>terry : 2/1/2002<br>mgross : 12/10/2001<br>mgross : 10/23/2001<br>mgross : 10/23/2001<br>mgross : 10/23/2001<br>mgross : 10/23/2001<br>terry : 3/7/2001<br>joanna : 3/6/2001<br>mgross : 3/2/2001<br>mgross : 12/5/2000<br>terry : 12/4/2000<br>alopez : 4/19/2000<br>alopez : 2/28/2000<br>carol : 9/17/1999<br>carol : 9/17/1999<br>terry : 9/15/1999<br>mgross : 9/14/1999<br>alopez : 7/9/1999<br>terry : 7/9/1999<br>psherman : 4/21/1998<br>psherman : 3/16/1998<br>terry : 3/4/1998<br>mark : 3/16/1997<br>mark : 9/17/1996<br>mark : 5/20/1996<br>mark : 5/20/1996<br>terry : 5/17/1996<br>mark : 5/13/1996<br>carol : 11/4/1994<br>carol : 6/9/1993<br>carol : 3/18/1993<br>carol : 12/14/1992<br>carol : 11/2/1992
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<span class="mim-font">
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<strong>*</strong> 176872
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MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1
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<em>Alternative titles; symbols</em>
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PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 1; PRKMK1<br />
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MKK1; MAPKK1<br />
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MAPK/ERK KINASE 1; MEK1
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MAP2K1</em></strong>
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Cytogenetic location: 15q22.31
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Genomic coordinates <span class="small">(GRCh38)</span> : 15:66,386,912-66,491,544 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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15q22.31
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Cardiofaciocutaneous syndrome 3
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<span class="mim-font">
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615279
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Autosomal dominant
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<span class="mim-font">
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3
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Melorheostosis, isolated, somatic mosaic
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155950
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<span class="mim-font">
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3
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<span class="mim-font">
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<strong>TEXT</strong>
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<h4>
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<strong>Cloning and Expression</strong>
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<span class="mim-text-font">
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<p>Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs) (see ERK2, or MAPK1; 176948), are thought to act as an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals, are rapidly phosphorylated on threonine and tyrosine residues, and are highly conserved in evolution (Crews et al., 1992). A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. Crews et al. (1992) cloned a mouse cDNA, denoted Mek1 (for Map/Erk kinase-1) by them, that encodes a member of this protein kinase family. The 393-amino acid, 43.5-kD protein is most closely related in size and sequence to the product encoded by the byr1 gene of S. pombe. The Mek1 gene was highly expressed in murine brain. </p><p>Seger et al. (1992) cloned a cDNA encoding the human homolog of Mek1, symbolized MKK1 by them, from a human T-cell cDNA library. The predicted protein has a calculated molecular mass of 43 kD. They also isolated a related cDNA, called MKK1b, that appears to be an alternatively spliced form of MKK1. Seger et al. (1992) detected a 2.6-kb MKK1 transcript by Northern blot analysis in all tissues examined. </p><p>Zheng and Guan (1993) also cloned a human cDNA corresponding to MEK1. They noted that the 393-amino acid protein shares 99% amino acid identity with murine Mek1 and 80% homology with human MEK2 (601263). The authors characterized biochemically the human MEK1 and MEK2 gene products. The gene is also symbolized MAP2K1, or PRKMK1. </p>
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<span class="mim-font">
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<strong>Mapping</strong>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Using radiation hybrid mapping, Rampoldi et al. (1997) localized the MAP2K1 gene to 15q22.1-q22.33. By somatic cell hybrid analysis and FISH, Meloche et al. (2000) mapped MAP2K1 to 15q21 and a pseudogene, MAP2K1P1, to 8p21. Brott et al. (1993) mapped the mouse Mek1 gene to chromosome 9. </p>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</div>
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<span class="mim-text-font">
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<p>Crews et al. (1992) found that the mouse Mek1 protein expressed in bacteria phosphorylated the Erk gene product in vitro. </p><p>Seger et al. (1992) found that overexpression of MKK1 in COS cells led to increased phorbol ester-stimulated MAP kinase kinase activity. Seger and Krebs (1995) reviewed the MAP kinase signaling cascade. </p><p>Ryan et al. (2000) showed that inhibition of MEK1 blocks p53 (191170)-induced NF-kappa-B activation and apoptosis but not cell cycle arrest. They demonstrated that p53 activates NF-kappa-B through the RAF/MEK1/p90(rsk) (see 601684) pathway rather than the TNFR1 (191190)/TRAF2 (601895)/IKK (e.g., 600664) pathway used by TNFA (191160). </p><p>To elucidate the mechanism through which MAPK signaling regulates the MYOD (159970) family of transcription factors, Perry et al. (2001) investigated the role of the signaling intermediate MEK1 in myogenesis. Transfection of activated MEK1 strongly repressed gene activation and myogenic conversion by the MYOD family. This repression was not mediated by direct phosphorylation of MYOD or by changes in MYOD stability or subcellular distribution. Deletion mapping revealed that MEK1-mediated repression required the MYOD N-terminal transactivation domain. Moreover, activated MEK1 was nuclearly localized and bound a complex containing MYOD in a manner that was dependent on the presence of the MYOD N terminus. These data demonstrated that MEK1 signaling has a strong negative effect on MYOD activity via a mechanism involving binding of MEK1 to the nuclear MYOD transcriptional complex. </p><p>Takekawa et al. (2005) identified a conserved docking site, which they termed 'domain for versatile docking' (DVD), immediately C terminal to the catalytic domains of mammalian MAPKKs, including MEK1. They determined that DVD sites contain about 20 amino acids and bind to specific upstream MAPKKKs. DVD site mutations strongly inhibited MAPKKs from binding to and being activated by their specific MAPKKKs, both in vitro and in vivo. MAPKKs containing DVD site mutations could not be activated by various external stimuli in vivo, and synthetic DVD oligopeptides inhibited specific MAPKK activation, both in vitro and in vivo. Takekawa et al. (2005) concluded that DVD docking is critically important in MAPK signaling. </p><p>Scholl et al. (2007) found that conditional deletion of either Mek1 or Mek2 in mouse skin had no effect on epidermal development, but combined Mek1/Mek2 deletion during embryonic development or in adulthood abolished Erk1 (MAPK3; 601795)/Erk2 phosphorylation and led to hypoproliferation, apoptosis, skin barrier defects, and death. Conversely, a single copy of either allele was sufficient for normal development. Combined Mek1/Mek2 loss also abolished Raf (RAF1; 164760)-induced hyperproliferation. To examine the effect of combined MEK deletion on human skin, Scholl et al. (2007) used small interfering RNA to delete MEK1 and MEK2 expression in normal primary human keratinocytes and used these cells to regenerate human epidermal tissue on human dermis, which was grafted onto immune-deficient mice. Control keratinocytes or those lacking either MEK1 or MEK2 were able to regenerate 6 days after grafting. In contrast, combined depletion of MEK1 and MEK2 led to either graft failure or markedly hypoplastic epidermis that nonetheless contained an intact stratum corneum. ERK2 expression rescued the defect. Scholl et al. (2007) concluded that MEK1 and MEK2 are functionally redundant in the epidermis and function in a linear relay in the MAPK pathway. </p><p>Imai et al. (2008) used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiologic compensation for insulin resistance. Imai et al. (2008) found that hepatic activation of extracellular regulated kinase (ERK1; 601795) signaling by expression of constitutively active MEK1 induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, Imai et al. (2008) concluded that interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes. </p><p>Chuderland et al. (2008) identified an SPS motif in ERK2 and SMAD3 (603109) and a similar TPT motif in MEK1 that directed protein nuclear accumulation when phosphorylated. </p>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Brennan et al. (2011) integrated structural and biochemical studies to understand how kinase suppressor of Ras (KSR) promotes stimulatory Raf phosphorylation of MEK. They showed, from the crystal structure of the kinase domain (KD) of human KSR2 (610737) in complex with rabbit MEK1, that interactions between KSR2(KD) and MEK1 are mediated by their respective activation segments and C-lobe alpha-G helices. Analogous to BRAF (164757), KSR2 self-associates through a side-to-side interface involving arg718, a residue identified in a genetic screen as a suppressor of Ras signaling. ATP is bound to the KSR2 (KD) catalytic site, and Brennan et al. (2011) demonstrated KSR2 kinase activity towards MEK1 by in vitro assays and chemical genetics. In the KSR2(KD)-MEK1 complex, the activation segments of both kinases are mutually constrained, and KSR2 adopts an inactive conformation. BRAF allosterically stimulates the kinase activity of KSR2, which is dependent on formation of a side-to-side KSR2-BRAF heterodimer. Furthermore, KSR2-BRAF heterodimerization results in an increase of BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal from BRAF to release the activation segment of MEK for phosphorylation. Brennan et al. (2011) proposed that KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK's phosphorylation by a separate catalytic Raf molecule in trans. </p><p><strong><em>Cryoelectron Microscopy</em></strong></p><p>
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Park et al. (2019) used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer of eta (YWHAH; 113508) and zeta (YWHAZ; 601288). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer. </p>
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<h4>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<span class="mim-text-font">
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<p><strong><em>Cardiofaciocutaneous Syndrome</em></strong></p><p>
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In 2 patients with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified mutations (F53S, 176872.0001; Y130C, 176872.0002) in the MEK1 gene. Interestingly, 1 patient had a mutation at phe53 (F53), which is equivalent to phe57 (F57) in the MEK2 gene, where another CFC patient had a missense mutation (F57C; 601263.0001). </p><p>In 5 patients with CFC3, Gripp et al. (2007) identified heterozygous mutations in the MEK1 gene. Three patients had the previously identified Y130C mutation and 2 had novel mutations (176872.0004 and 176872.0005). </p><p>Schulz et al. (2008) identified mutations in the MAP2K1 gene (see, e.g., 176872.0003) in 5 (9.8%) of 51 CFC patients. </p><p><strong><em>Somatic Mutation in Isolated Melorheostosis</em></strong></p><p>
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In samples of affected bone from 8 patients with isolated melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for missense mutations in the MAP2K1 gene (Q56P, 176872.0006; K57N, 176872.0007; and K57E, 176872.0008) that were not present in unaffected bone or in peripheral blood leukocytes. Mutant allele frequency ranged from 3 to 34% in affected bone. The authors noted that all 3 MAP2K1 variants had previously been shown to cause gain-of-function effects and had been detected in malignancies, including lung cancer, melanoma, and hairy cell leukemia. Functional analysis confirmed enhanced activation, resulting in increased osteoblast proliferation; however, there was also reduced mineralization and differentiation, consistent with histologic findings of massive accumulation of unmineralized osteoid bone in affected bone tissue, as well as increased osteoclast activity, as shown by the intense remodeling that occurs in melorheostotic bone. </p><p><strong><em>Somatic Mutation in Melanoma</em></strong></p><p>
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Nikolaev et al. (2012) performed exome sequencing to detect somatic mutations in protein-coding regions in 7 melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in 2 metastases derived from the same individual. Two melanomas with noncanonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK2; 601263) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Other Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Constitutive activation of MEK1 results in cellular transformation. This protein kinase therefore represents a likely target for pharmacologic intervention in proliferative disease. To identity small-molecule inhibitors of this pathway, Sebolt-Leopold et al. (1999) developed an in vitro cascade assay using bacterially purified glutathione-S-transferase fusion proteins of MEK1 and MAPK. Sebolt-Leopold et al. (1999) reported the discovery of a highly potent and selective inhibitor of MEK1, which they called PD184352 and which is, in fact, 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide. PD184352 is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses (with a 50% inhibitory concentration of 17 nanomolar) with no signs of toxicity, and correlated with a reduction in levels of MAPK in excised tumors. Sebolt-Leopold et al. (1999) concluded that these data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer. </p><p>A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the extracellular signal-regulated kinase ERK, c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways and inhibition of the nuclear factor kappa B (NF-kappa-B; see 164011) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al. (1999) identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1, MKK2 (601263), and MKK4/SEK1 (601335). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315), MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection. </p><p>Influenza A viruses are significant causes of morbidity and mortality worldwide. Annually updated vaccines may prevent disease, and antivirals are effective treatment early in disease when symptoms are often nonspecific. Viral replication is supported by intracellular signaling events. Using U0126, a nontoxic inhibitor of MEK1 and MEK2, and thus an inhibitor of the RAF1/MEK/ERK pathway (see Favata et al. (1998)), Pleschka et al. (2001) examined the cellular response to infection with influenza A. U0126 suppressed both the early and late ERK activation phases after virus infection. Inhibition of the signaling pathway occurred without impairing the synthesis of viral RNA or protein, or the import of viral ribonucleoprotein complexes (RNP) into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the export of viral RNP without affecting the cellular mRNA export pathway. Pleschka et al. (2001) proposed that ERK regulates a cellular factor involved in the viral nuclear export protein function. They suggested that local application of MEK inhibitors may have only minor toxic effects on the host while inhibiting viral replication without giving rise to drug-resistant virus variants. </p>
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</span>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Animal Model</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Giroux et al. (1999) disrupted the mouse Mek1 gene by insertional mutagenesis. The null mutation was recessive lethal, and homozygous mutant embryos died at 10.5 days of gestation. Histopathologic analysis revealed a marked decrease of vascular endothelial cells in the labyrinthine region, resulting in reduced vascularization of the placenta. Failure to establish a functional placenta was considered a likely cause of embryonic death. Cell migration assays indicated that Mek1-null fibroblasts could not be induced to migrate by fibronectin (135600), and reintroduction of Mek1 expression restored their ability to migrate. </p>
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</span>
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<div>
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<h4>
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<span class="mim-font">
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MAP2K1, PHE53SER
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<br />
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SNP: rs121908594,
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ClinVar: RCV000014278, RCV000158002, RCV000520164, RCV004760331
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified a T-to-C transition at nucleotide 158 (c.158T-C, NM_002755) of the MEK1 gene resulting in a phenylalanine-to-serine substitution at codon 53 (F53S). This mutation was not identified in either of the patient's parents. Interestingly, a mutation at the equivalent codon in MEK2 (601263) was found in another CFC patient (F57C; 601263.0001). </p><p>By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S and Y130C and the MEK2 mutant F57C could not induce ERK signaling unless phosphorylated by RAF at 2 homologous serine residues in the regulatory loop. When these serine residues were replaced with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. However, the F57C MEK2 mutant was less dependent on RAF signaling than the other mutants. This difference resulted in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. However, all 3 mutants were sensitive to the MEK inhibitor U0126. Senawong et al. (2008) suggested that MEK inhibition could have potential therapeutic value in CFC. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MAP2K1, TYR130CYS
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<br />
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SNP: rs121908595,
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gnomAD: rs121908595,
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ClinVar: RCV000043672, RCV000207506, RCV000208757, RCV000541525, RCV000763362, RCV001197351, RCV003450638, RCV004532347, RCV004984640
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified heterozygosity for an A-to-G transition at nucleotide 389 (c.389A-G, NM_002755) of the MEK1 gene, resulting in a tyrosine-to-cysteine substitution at codon 130 (Y130C) in the protein kinase domain. </p><p>In 3 children (patients 136, 146, and 163) with CFC3, Gripp et al. (2007) identified heterozygosity for the Y130C mutation in the MEK1 gene. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0003 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MAP2K1, GLY128VAL
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<br />
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SNP: rs121908596,
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ClinVar: RCV000043673, RCV000207493, RCV000211725, RCV001234104
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Schulz et al. (2008) identified a heterozygous 383G-T transversion in exon 3 of the MAP2K1 gene, resulting in a gly128-to-val (G128V) substitution. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
|
<strong>.0004 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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MAP2K1, 3-BP DEL, AAG, EX2
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<br />
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SNP: rs869025339,
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ClinVar: RCV000207500, RCV002277569, RCV002515536
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</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In an 8-year-old girl (patient 144) with cardiofaciocutaneous syndrome-3 (CFC3; 615279), Gripp et al. (2007) identified a 3-bp deletion (AAG) in exon 2 of the MEK1 gene, resulting in deletion of a lysine (K59del) at the beginning of the protein kinase-like domain. </p>
|
|
</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOFACIOCUTANEOUS SYNDROME 3</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
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|
|
MAP2K1, PRO124GLN
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<br />
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|
|
SNP: rs397516792,
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|
|
ClinVar: RCV001078439
|
|
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|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 7-week-old male (patient 95) with cardiofaciocutaneous syndrome-3 (CFC3; 615279), Gripp et al. (2007) identified a c.371C-A transversion in exon 3 of the MEK1 gene, resulting in a pro124-to-gln (P124Q) substitution in the protein kinase domain. </p>
|
|
</span>
|
|
</div>
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|
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|
<div>
|
|
<br />
|
|
</div>
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|
|
</div>
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<div>
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|
|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 MELORHEOSTOSIS, ISOLATED, SOMATIC MOSAIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K1, GLN56PRO
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|
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|
|
<br />
|
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|
|
SNP: rs1057519729,
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|
|
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|
|
|
|
ClinVar: RCV000418731, RCV002051704, RCV002254296
|
|
|
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|
|
</span>
|
|
</div>
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|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In samples of affected bone from 3 patients (Melo-4, Melo-9, and Melo-19) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.167A-C transversion (c.167A-C, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a gln56-to-pro (Q56P) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 9 to 28% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in patient Melo-4 showed the variant at an allele frequency of 12.5%. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the Q56P variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
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|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 MELORHEOSTOSIS, ISOLATED, SOMATIC MOSAIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
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|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K1, LYS57ASN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs869025608,
|
|
|
|
|
|
|
|
ClinVar: RCV000208748, RCV002051691, RCV002254287
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
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|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In samples of affected bone from 4 patients (Melo-2, Melo-6, Melo-16, and Melo-18) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.171G-T transversion (c.171G-T, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-asn (K57N) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 3 to 34% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in 3 of the patients showed the variant at an allele frequency of 4.1 to 16.2%; the variant was not detected in skin from patient Melo-16, who had a lower disease burden. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57N variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency. Consistent with enhanced activation, affected osteoblasts showed increased cell proliferation in vitro; however, there was also reduced mineralization and differentiation with affected osteoblasts, as well as increased osteoclast activity. </p>
|
|
</span>
|
|
</div>
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<div>
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|
<br />
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|
</div>
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|
</div>
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|
<div>
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|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 MELORHEOSTOSIS, ISOLATED, SOMATIC MOSAIC</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K1, LYS57GLU
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs397516790,
|
|
|
|
|
|
|
|
ClinVar: RCV002051705
|
|
|
|
|
|
</span>
|
|
</div>
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<div>
|
|
<span class="mim-text-font">
|
|
<p>In samples of affected bone from a patient (Melo-10) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.169A-G transition (c.169A-G, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-glu (K57E) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency was 18% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57E variant. </p>
|
|
</span>
|
|
</div>
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<div>
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<br />
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</div>
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</div>
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</div>
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<div>
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|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
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</h4>
|
|
<div>
|
|
<p />
|
|
</div>
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<div>
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<ol>
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<li>
|
|
<p class="mim-text-font">
|
|
Brennan, D. F., Dar, A. C., Hertz, N. T., Chao, W. C. H., Burlingame, A. L., Shokat, K. M., Barford, D.
|
|
<strong>A Raf-induced allosteric transition of KSR stimulates phosphorylation of MEK.</strong>
|
|
Nature 472: 366-369, 2011.
|
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|
[PubMed: 21441910]
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[Full Text: https://doi.org/10.1038/nature09860]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
|
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Brott, B. K., Alessandrini, A., Largaespada, D. A., Copeland, N. G., Jenkins, N. A., Crews, C. M., Erikson, R. L.
|
|
<strong>MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues.</strong>
|
|
Cell Growth Differ. 4: 921-929, 1993.
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[PubMed: 8297798]
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</p>
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</li>
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<li>
|
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<p class="mim-text-font">
|
|
Chuderland, D., Konson, A., Seger, R.
|
|
<strong>Identification and characterization of a general nuclear translocation signal in signaling proteins.</strong>
|
|
Molec. Cell 31: 850-861, 2008.
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|
|
[PubMed: 18760948]
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[Full Text: https://doi.org/10.1016/j.molcel.2008.08.007]
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</p>
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Crews, C. M., Alessandrini, A., Erikson, R. L.
|
|
<strong>The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product.</strong>
|
|
Science 258: 478-480, 1992.
|
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|
|
[PubMed: 1411546]
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[Full Text: https://doi.org/10.1126/science.1411546]
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</p>
|
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</li>
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<li>
|
|
<p class="mim-text-font">
|
|
Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., Van Dyk, D. E., Pitts, W. J., Earl, R. A., Hobbs, F., Copeland, R. A., Magolda, R. L., Scherle, P. A., Trzaskos, J. M.
|
|
<strong>Identification of a novel inhibitor of mitogen-activated protein kinase kinase.</strong>
|
|
J. Biol. Chem. 273: 18623-18632, 1998.
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|
|
[PubMed: 9660836]
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|
[Full Text: https://doi.org/10.1074/jbc.273.29.18623]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Giroux, S., Tremblay, M., Bernard, D., Cadrin-Girard, J.-F., Aubry, S., Larouche, L., Rousseau, S., Huot, J., Landry, J., Jeannotte, L., Charron, J.
|
|
<strong>Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta.</strong>
|
|
Curr. Biol. 9: 369-372, 1999.
|
|
|
|
|
|
[PubMed: 10209122]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s0960-9822(99)80164-x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gripp, K. W., Lin, A. E., Nicholson, L., Allen, W., Cramer, A., Jones, K. L., Kutz, W., Peck, D., Rebolledo, M. A., Wheeler, P. G., Wilson, W., Al-Rahawan, M. M., Stabley, D. L., Sol-Church, K.
|
|
<strong>Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome.</strong>
|
|
Am. J. Med. Genet. 143A: 1472-1480, 2007.
|
|
|
|
|
|
[PubMed: 17551924]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.31815]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Imai, J., Katagiri, H., Yamada, T., Ishigaki, Y., Suzuki, T., Kudo, H., Uno, K., Hasegawa, Y., Gao, J., Kaneko, K., Ishihara, H., Niijima, A., Nakazato, M., Asano, T., Minokoshi, Y., Oka, Y.
|
|
<strong>Regulation of pancreatic beta cell mass by neuronal signals from the liver.</strong>
|
|
Science 322: 1250-1254, 2008.
|
|
|
|
|
|
[PubMed: 19023081]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1163971]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Kang, H., Jha, S., Deng, Z., Fratzl-Zelman, N., Cabral, W. A., Ivovic, A., Meylan, F., Hanson, E. P., Lange, E., Katz, J., Roschger, P., Klaushofer, K., Cowen, E. W., Siegel, R. M., Marini, J. C., Bhattacharyya, T.
|
|
<strong>Somatic activating mutations in MAP2K1 cause melorheostosis.</strong>
|
|
Nature Commun. 9: 1390, 2018. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 29643386]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41467-018-03720-z]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Meloche, S., Gopalbhai, K., Beatty, B. G., Scherer, S. W., Pellerin, J.
|
|
<strong>Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32.</strong>
|
|
Cytogenet. Cell Genet. 88: 249-252, 2000.
|
|
|
|
|
|
[PubMed: 10828601]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1159/000015530]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Nikolaev, S. I., Rimoldi, D., Iseli, C., Valsesia, A., Robyr, D., Gehrig, C., Harshman, K., Guipponi, M., Bukach, O., Zoete, V., Michielin, O., Muehlethaler, K., Speiser, D., Beckmann, J. S., Xenarios, I., Halazonetis, T. D., Jongeneel, C. V., Stevenson, B. J., Antonarakis, S. E.
|
|
<strong>Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma.</strong>
|
|
Nature Genet. 44: 133-139, 2012.
|
|
|
|
|
|
[PubMed: 22197931]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/ng.1026]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Orth, K., Palmer, L. E., Bao, Z. Q., Stewart, S., Rudolph, A. E., Bliska, J. B., Dixon, J. E.
|
|
<strong>Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector.</strong>
|
|
Science 285: 1920-1923, 1999.
|
|
|
|
|
|
[PubMed: 10489373]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.285.5435.1920]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Park, E., Rawson, S., Li, K., Kim, B.-W., Ficarro, S. B., Gonzalez-Del Pino, G., Sharif, H., Marto, J. A., Jeon, H., Eck, M. J.
|
|
<strong>Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes.</strong>
|
|
Nature 575: 545-550, 2019.
|
|
|
|
|
|
[PubMed: 31581174]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41586-019-1660-y]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Perry, R. L. S., Parker, M. H., Rudnicki, M. A.
|
|
<strong>Activated MEK1 binds the nuclear MyoD transcriptional complex to repress transactivation.</strong>
|
|
Molec. Cell 8: 291-301, 2001.
|
|
|
|
|
|
[PubMed: 11545732]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/s1097-2765(01)00302-1]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R., Ludwig, S.
|
|
<strong>Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade.</strong>
|
|
Nature Cell Biol. 3: 301-305, 2001.
|
|
|
|
|
|
[PubMed: 11231581]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35060098]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rampoldi, L., Zimbello, R., Bortoluzzi, S., Tiso, N., Valle, G., Lanfranchi, G., Danieli, G. A.
|
|
<strong>Chromosomal localization of four MAPK signaling cascade genes: MEK1, MEK3, MEK4 and MEKK5.</strong>
|
|
Cytogenet. Cell Genet. 78: 301-303, 1997.
|
|
|
|
|
|
[PubMed: 9465908]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1159/000134677]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A.
|
|
<strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong>
|
|
Science 311: 1287-1290, 2006.
|
|
|
|
|
|
[PubMed: 16439621]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1126/science.1124642]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Ryan, K. M., Ernst, M. K., Rice, N. R., Vousden, K. H.
|
|
<strong>Role of NF-kappa-B in p53-mediated programmed cell death.</strong>
|
|
Nature 404: 892-897, 2000.
|
|
|
|
|
|
[PubMed: 10786798]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/35009130]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A.
|
|
<strong>Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia.</strong>
|
|
Dev. Cell 12: 615-629, 2007.
|
|
|
|
|
|
[PubMed: 17419998]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.devcel.2007.03.009]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Schulz, A. L., Albrecht, B., Arici, C., van der Burgt, I., Buske, A., Gillessen-Kaesbach, G., Heller, R., Horn, D., Hubner, C. A., Korenke, G. C., Konig, R., Kress, W., and 15 others.
|
|
<strong>Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome</strong>
|
|
Clin. Genet. 73: 62-70, 2008.
|
|
|
|
|
|
[PubMed: 18042262]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1111/j.1399-0004.2007.00931.x]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., Saltiel, A. R.
|
|
<strong>Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo.</strong>
|
|
Nature Med. 5: 810-816, 1999.
|
|
|
|
|
|
[PubMed: 10395327]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/10533]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Seger, R., Krebs, E. G.
|
|
<strong>The MAPK signaling cascade.</strong>
|
|
FASEB J. 9: 726-735, 1995.
|
|
|
|
|
|
[PubMed: 7601337]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Seger, R., Seger, D., Lozeman, F. J., Ahn, N. G., Graves, L. M., Campbell, J. S., Ericsson, L., Harrylock, M., Jensen, A. M., Krebs, E. G.
|
|
<strong>Human T-cell mitogen-activated protein kinase kinases are related to yeast signal transduction kinases.</strong>
|
|
J. Biol. Chem. 267: 25628-25631, 1992.
|
|
|
|
|
|
[PubMed: 1281467]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Senawong, T., Phuchareon, J., Ohara, O., McCormick, F., Rauen, K. A., Tetsu, O.
|
|
<strong>Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.</strong>
|
|
Hum. Molec. Genet. 17: 419-430, 2008.
|
|
|
|
|
|
[PubMed: 17981815]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1093/hmg/ddm319]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Takekawa, M., Tatebayashi, K., Saito, H.
|
|
<strong>Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases.</strong>
|
|
Molec. Cell 18: 295-306, 2005.
|
|
|
|
|
|
[PubMed: 15866172]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1016/j.molcel.2005.04.001]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Zheng, C. F., Guan, K. L.
|
|
<strong>Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.</strong>
|
|
J. Biol. Chem. 268: 11435-11439, 1993.
|
|
|
|
|
|
[PubMed: 8388392]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
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