3370 lines
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Entry
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- *601263 - MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; MAP2K2
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*601263</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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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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<li role="presentation">
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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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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</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/601263">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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<li role="presentation">
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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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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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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="mimGenome">
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<span class="panel-title">
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<span class="small">
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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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</span>
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</span>
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</div>
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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=ENSG00000126934;t=ENST00000262948" 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=5605" 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=601263" 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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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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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 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=ENSG00000126934;t=ENST00000262948" 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_030662,XM_006722799,XM_047439100" 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_030662" 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=601263" 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=03164&isoform_id=03164_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/MAP2K2" 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/547915,12653403,13489054,17391417,31874214,34526154,119589668,119589669,119589670,119589671,193787453,578833393,2217322026,2462566316,2462566318" 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/P36507" 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=5605" 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=ENSG00000126934;t=ENST00000262948" 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=MAP2K2" 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=MAP2K2" 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+5605" 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/MAP2K2" 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:5605" 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/5605" 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=chr19&hgg_gene=ENST00000262948.10&hgg_start=4090321&hgg_end=4124122&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>
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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:6842" 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:6842" 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/map2k2" 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=601263[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=601263[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/MAP2K2/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/ENSG00000126934" 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=MAP2K2" 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=MAP2K2" 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=MAP2K2" 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="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=MAP2K2&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/PA30587" 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:6842" 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:1346867" 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/MAP2K2#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:1346867" 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/5605/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/OMIA002381/" 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=5605" 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-041027-1" 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:5605" 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=MAP2K2&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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601263
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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 2; MAP2K2
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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">
|
|
PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 2; PRKMK2<br />
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MKK2; MAPKK2<br />
|
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MAPK/ERK KINASE 2; MEK2
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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=MAP2K2" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">MAP2K2</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/19/126?start=-3&limit=10&highlight=126">19p13.3</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr19:4090321-4124122&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'})">19:4,090,321-4,124,122</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">
|
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<strong>Gene-Phenotype Relationships</strong>
|
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</span>
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</div>
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<div>
|
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<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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</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>
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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>
|
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<td rowspan="1">
|
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<span class="mim-font">
|
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<a href="/geneMap/19/126?start=-3&limit=10&highlight=126">
|
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19p13.3
|
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</a>
|
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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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Cardiofaciocutaneous syndrome 4
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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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<a href="/entry/615280"> 615280 </a>
|
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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="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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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
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</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/601263" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/601263" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<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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</div>
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<div>
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<br />
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</div>
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<p><a href="#16" 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> isolated and sequenced 2 human cDNAs encoding members of the MAP kinase kinase (MAP2K) family, designated MEK1 (<a href="/entry/176872">176872</a>) and MEK2 by them. The MEK2 cDNA encodes a predicted 400-amino acid protein that shares 80% sequence identity with human MEK1. <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><p><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> cloned the mouse Mek2 gene. <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'})"><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="#16" 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> showed that recombinant MEK2 and MEK1 both could activate human ERK1 (<a href="/entry/601795">601795</a>) in vitro. They further characterized biochemically the 2 MAP2Ks. <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><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 (MAPK) 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="#8" 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 (<a href="/entry/176872">176872</a>), MKK2, 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><a href="#6" class="mim-tip-reference" title="Mittal, R., Peak-Chew, S.-Y., McMahon, H. T. <strong>Acetylation of MEK2 and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits signaling.</strong> Proc. Nat. Acad. Sci. 103: 18574-18579, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116858[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/10.1073/pnas.0608995103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17116858">Mittal et al. (2006)</a> found that the Yersinia YopJ virulence factor inhibited the host inflammatory response and induced apoptosis of immune cells by catalyzing acetylation of 2 ser residues in the activation loop of MEK2, thereby blocking MEK2 activation and signal propagation. YopJ also caused acetylation of a thr residue in the activation loop of both IKKA (CHUK; <a href="/entry/600664">600664</a>) and IKKB (IKBKB; <a href="/entry/603258">603258</a>). <a href="#6" class="mim-tip-reference" title="Mittal, R., Peak-Chew, S.-Y., McMahon, H. T. <strong>Acetylation of MEK2 and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits signaling.</strong> Proc. Nat. Acad. Sci. 103: 18574-18579, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116858[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/10.1073/pnas.0608995103" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17116858">Mittal et al. (2006)</a> concluded that ser/thr acetylation is a mode of action for bacterial toxins that may also occur under nonpathogenic conditions to regulate protein function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17116858" 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 (<a href="/entry/164760">164760</a>)/MEK/ERK pathway (see <a href="#3" 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="#9" 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="#9" 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=9660836+11231581" 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="#13" 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/Erk2 (MAPK1; <a href="/entry/176948">176948</a>) 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-induced hyperproliferation. To examine the effect of combined MEK deletion on human skin, <a href="#13" 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="#13" 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>
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<p><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 Mek2 gene to chromosome 10. <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'})"><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="#10" class="mim-tip-reference" title="Puttagunta, P., Gordon, L. A., Meyer, G. E., Kapfhamer, D., Lamerdin, J. E., Kantheti, P., Portman, K. M., Chung, W. K., Jenne, D. E., Olsen, A. S., Burmeister, M. <strong>Comparative maps of human 19p13.3 and mouse chromosome 10 allow identification of sequences at evolutionary breakpoints.</strong> Genome Res. 10: 1369-1380, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10984455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10984455</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10984455[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/10.1101/gr.145200" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10984455">Puttagunta et al. (2000)</a> constructed a cosmid/BAC map of human chromosome 19p13.3 and localized over 50 genes, including MAP2K2, to the contig. The 19p13.3 region shows syntenic homology with mouse chromosome 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10984455" 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="#5" 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> had erroneously mapped the MAP2K2 gene to 7q32. <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'})"><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 23 patients with cardiofaciocutaneous syndrome (CFC4; <a href="/entry/615280">615280</a>), <a href="#12" 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> searched for mutations in downstream effectors of RAS and found a missense mutation in MEK2 in 1 patient (F57C; <a href="#0001">601263.0001</a>). The F57 codon of MEK2 is equivalent to codon F53 of MEK1, which was mutated in another CFC patient (<a href="/entry/176872#0001">176872.0001</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 3 (5.9%) of 51 CFC patients, <a href="#14" 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 2 different mutations in the MAP2K2 gene (F57V; <a href="#0002">601263.0002</a> and Y134H; <a href="#0003">601263.0003</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'})"><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="#11" class="mim-tip-reference" title="Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., Lacassie, Y. <strong>Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.</strong> Am. J. Med. Genet. 152A: 807-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20358587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20358587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20358587[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/10.1002/ajmg.a.33342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20358587">Rauen et al. (2010)</a> and <a href="#4" class="mim-tip-reference" title="Linden, H. C., Price, S. M. <strong>Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation.</strong> Clin. Dysmorph. 20: 86-88, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21178588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21178588</a>] [<a href="https://doi.org/10.1097/MCD.0b013e32833ff29d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21178588">Linden and Price (2011)</a> independently reported 2 unrelated families with autosomal dominant transmission of CFC due to heterozygous mutations in the MAP2K2 gene (P128Q, <a href="#0004">601263.0004</a> and G132D, <a href="#0005">601263.0005</a>, respectively). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=21178588+20358587" 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 Mutations</em></strong></p><p>
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<a href="#7" 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 (MEK1; <a href="/entry/176872">176872</a>) and MAP2K2 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><a href="#1" class="mim-tip-reference" title="Belanger, L.-F., Roy, S., Tremblay, M., Brott, B., Steff, A.-M., Mourad, W., Hugo, P., Erikson, R., Charron, J. <strong>Mek2 is dispensable for mouse growth and development.</strong> Molec. Cell. Biol. 23: 4778-4787, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12832465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12832465</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12832465[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/10.1128/MCB.23.14.4778-4787.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12832465">Belanger et al. (2003)</a> developed Mek2-deficient mice. Mutant mice were viable and fertile and showed no phenotypic abnormalities. Mutant embryonic fibroblasts and purified lymphocytes proliferated normally, demonstrating that Mek2 is not required for reentry into the cell cycle or for T-cell development. <a href="#1" class="mim-tip-reference" title="Belanger, L.-F., Roy, S., Tremblay, M., Brott, B., Steff, A.-M., Mourad, W., Hugo, P., Erikson, R., Charron, J. <strong>Mek2 is dispensable for mouse growth and development.</strong> Molec. Cell. Biol. 23: 4778-4787, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12832465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12832465</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12832465[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/10.1128/MCB.23.14.4778-4787.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12832465">Belanger et al. (2003)</a> concluded that MEK1 can compensate for a lack of MEK2 function. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12832465" 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">rs121434497 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434497;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=rs121434497" 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=rs121434497" 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=RCV000008761 OR RCV000158038 OR RCV000208756" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008761, RCV000158038, RCV000208756" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008761...</a>
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<p>In a patient with cardiofaciocutaneous syndrome (CFC4; <a href="/entry/615280">615280</a>), <a href="#12" 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-G transversion at nucleotide 170 of the MEK2 gene, resulting in a phenylalanine-to-cysteine substitution at codon 57 (F57C). <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="#15" 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 (<a href="/entry/176872#0001">176872.0001</a>) and Y130C (<a href="/entry/176872#0002">176872.0002</a>) 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="#15" 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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<p>In 2 patients with cardiofaciocutaneous syndrome (CFC4; <a href="/entry/615280">615280</a>), <a href="#14" 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 de novo 169T-G transversion in exon 2 of the MAP2K2 gene, resulting in a phe57-to-val (F57V) substitution. This same codon is affected in F57C (<a href="#0001">601263.0001</a>). Both patients had a unique facial phenotype with a long narrow face, tall forehead, low-set ears, severe ptosis, epicanthal folds, and prominent supraorbital ridges. <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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MAP2K2, TYR134HIS
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs121434499 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs121434499;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=rs121434499" 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=rs121434499" 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=RCV000008763 OR RCV000043675 OR RCV000158022 OR RCV000521479 OR RCV001813182 OR RCV003390660 OR RCV003450621" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008763, RCV000043675, RCV000158022, RCV000521479, RCV001813182, RCV003390660, RCV003450621" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008763...</a>
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<p>In a patient with CFC (CFC4; <a href="/entry/615280">615280</a>), <a href="#14" 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 400T-C transition in exon 3 of the MAP2K2 gene, resulting in a tyr134-to-his (Y134H) 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 4</strong>
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MAP2K2, PRO128GLN
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs267607230 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs267607230;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=rs267607230" 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=rs267607230" 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=RCV000008764 OR RCV000158021 OR RCV000208770 OR RCV004760323" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000008764, RCV000158021, RCV000208770, RCV004760323" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000008764...</a>
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<p>In affected members of a 4-generation Caucasian Cajun family with CFC (CFC4; <a href="/entry/615280">615280</a>), <a href="#11" class="mim-tip-reference" title="Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., Lacassie, Y. <strong>Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.</strong> Am. J. Med. Genet. 152A: 807-814, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20358587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20358587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20358587[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/10.1002/ajmg.a.33342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20358587">Rauen et al. (2010)</a> identified a heterozygous 383C-A transversion in exon 3 of the MAP2K2 gene, resulting in a pro128-to-gln (P128Q) substitution. In vitro functional expression studies showed that the mutant protein had increased kinase activity, but not as much as other CFC-associated MAP2K2 mutations (e.g., F57C; <a href="#0001">601263.0001</a>), and was considered a weak hypermorphic mutation. This was the first reported case of vertical transmission of a MAP2K2 mutation in CFC. The phenotype was variable, and included the classic craniofacial features, pulmonic stenosis, ectodermal abnormalities, and variable degrees of learning delays and disabilities. One of the mutation carriers died of acute lymphocytic leukemia (ALL) at age 41 years, which the authors postulated may have resulted from increased activity of the RAS pathway. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20358587" 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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<span class="mim-font">
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<strong>.0005 CARDIOFACIOCUTANEOUS SYNDROME 4</strong>
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MAP2K2, GLY132ASP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387906800 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387906800;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=rs387906800" 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=rs387906800" 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=RCV000023088 OR RCV000149835 OR RCV000413893" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000023088, RCV000149835, RCV000413893" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000023088...</a>
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<span class="mim-text-font">
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<p>In a mother and her 2 sons with CFC4 (<a href="/entry/615280">615280</a>), <a href="#4" class="mim-tip-reference" title="Linden, H. C., Price, S. M. <strong>Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation.</strong> Clin. Dysmorph. 20: 86-88, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21178588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21178588</a>] [<a href="https://doi.org/10.1097/MCD.0b013e32833ff29d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21178588">Linden and Price (2011)</a> identified a heterozygous 395G-A transition in exon 3 of the MAP2K2 gene, resulting in a gly132-to-asp (G132D) substitution in a conserved residue. The proband was a 46-year-old man with mildly delayed development, pulmonary stenosis as a child, myopia, short stature, tightly curled short hair, absent eyebrows, hyperelastic skin, and multiple lentigines. His 40-year-old brother and 68-year-old mother had similar features. <a href="#4" class="mim-tip-reference" title="Linden, H. C., Price, S. M. <strong>Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation.</strong> Clin. Dysmorph. 20: 86-88, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21178588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21178588</a>] [<a href="https://doi.org/10.1097/MCD.0b013e32833ff29d" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21178588">Linden and Price (2011)</a> emphasized the rarity of autosomal dominant transmission of CFC, and noted that the mild cognitive phenotype in these patients suggests greater reproductive success. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21178588" 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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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Belanger2003" class="mim-anchor"></a>
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Belanger, L.-F., Roy, S., Tremblay, M., Brott, B., Steff, A.-M., Mourad, W., Hugo, P., Erikson, R., Charron, J.
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<strong>Mek2 is dispensable for mouse growth and development.</strong>
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Molec. Cell. Biol. 23: 4778-4787, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12832465/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12832465</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12832465[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=12832465" 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/10.1128/MCB.23.14.4778-4787.2003" target="_blank">Full Text</a>]
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Brott, B. K., Alessandrini, A., Largaespada, D. A., Copeland, N. G., Jenkins, N. A., Crews, C. M., Erikson, R. L.
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<strong>MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues.</strong>
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Cell Growth Differ. 4: 921-929, 1993.
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[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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<a id="Favata1998" class="mim-anchor"></a>
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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.
|
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<strong>Identification of a novel inhibitor of mitogen-activated protein kinase kinase.</strong>
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J. Biol. Chem. 273: 18623-18632, 1998.
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[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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Linden, H. C., Price, S. M.
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<strong>Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation.</strong>
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Clin. Dysmorph. 20: 86-88, 2011.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21178588/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21178588</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21178588" 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/10.1097/MCD.0b013e32833ff29d" target="_blank">Full Text</a>]
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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>
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Cytogenet. Cell Genet. 88: 249-252, 2000.
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[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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Mittal, R., Peak-Chew, S.-Y., McMahon, H. T.
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<strong>Acetylation of MEK2 and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits signaling.</strong>
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Proc. Nat. Acad. Sci. 103: 18574-18579, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17116858/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17116858</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=17116858[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=17116858" 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/10.1073/pnas.0608995103" target="_blank">Full Text</a>]
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<a id="Nikolaev2012" class="mim-anchor"></a>
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<p class="mim-text-font">
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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>]
|
|
|
|
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|
</p>
|
|
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|
|
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|
|
|
|
<li>
|
|
<a id="8" class="mim-anchor"></a>
|
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<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>]
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[<a href="https://doi.org/10.1126/science.285.5435.1920" target="_blank">Full Text</a>]
|
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</p>
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|
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|
|
|
|
<li>
|
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<a id="9" class="mim-anchor"></a>
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<a id="Pleschka2001" class="mim-anchor"></a>
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|
<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>]
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[<a href="https://doi.org/10.1038/35060098" target="_blank">Full Text</a>]
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</p>
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|
|
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|
<li>
|
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<a id="10" class="mim-anchor"></a>
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<a id="Puttagunta2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Puttagunta, P., Gordon, L. A., Meyer, G. E., Kapfhamer, D., Lamerdin, J. E., Kantheti, P., Portman, K. M., Chung, W. K., Jenne, D. E., Olsen, A. S., Burmeister, M.
|
|
<strong>Comparative maps of human 19p13.3 and mouse chromosome 10 allow identification of sequences at evolutionary breakpoints.</strong>
|
|
Genome Res. 10: 1369-1380, 2000.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10984455/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10984455</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10984455[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=10984455" 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/10.1101/gr.145200" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="11" class="mim-anchor"></a>
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<a id="Rauen2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., Lacassie, Y.
|
|
<strong>Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.</strong>
|
|
Am. J. Med. Genet. 152A: 807-814, 2010.
|
|
|
|
|
|
[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20358587/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20358587</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20358587[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=20358587" 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/10.1002/ajmg.a.33342" target="_blank">Full Text</a>]
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</p>
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<li>
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<a id="12" class="mim-anchor"></a>
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<a id="Rodriguez-Viciana2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A.
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<strong>Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.</strong>
|
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Science 311: 1287-1290, 2006.
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[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>]
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[<a href="https://doi.org/10.1126/science.1124642" target="_blank">Full Text</a>]
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Scholl2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A.
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<strong>Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia.</strong>
|
|
Dev. Cell 12: 615-629, 2007.
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[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>]
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[<a href="https://doi.org/10.1016/j.devcel.2007.03.009" target="_blank">Full Text</a>]
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Schulz2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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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>
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Clin. Genet. 73: 62-70, 2008.
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[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>]
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[<a href="https://doi.org/10.1111/j.1399-0004.2007.00931.x" target="_blank">Full Text</a>]
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Senawong2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Senawong, T., Phuchareon, J., Ohara, O., McCormick, F., Rauen, K. A., Tetsu, O.
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<strong>Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options.</strong>
|
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Hum. Molec. Genet. 17: 419-430, 2008.
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[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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</p>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Zheng1993" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Zheng, C. F., Guan, K. L.
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<strong>Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2.</strong>
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J. Biol. Chem. 268: 11435-11439, 1993.
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[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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</p>
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</div>
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</ol>
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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="contributors" class="mim-anchor"></a>
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 2/1/2013
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</span>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 4/28/2011<br>Cassandra L. Kniffin - updated : 11/11/2010<br>Cassandra L. Kniffin - updated : 1/11/2010<br>Joanna S. Amberger - updated : 7/17/2009<br>Cassandra L. Kniffin - updated : 3/17/2008<br>Patricia A. Hartz - updated : 5/4/2007<br>Paul J. Converse - updated : 5/1/2007<br>Ada Hamosh - updated : 4/19/2006<br>Patricia A. Hartz - updated : 10/23/2003<br>Joanna S. Amberger - updated : 3/6/2001<br>Paul J. Converse - updated : 3/2/2001<br>Ada Hamosh - updated : 9/15/1999
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</span>
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</div>
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</div>
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</div>
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<div>
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<a id="creationDate" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Mark H. Paalman : 5/16/1996
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</span>
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<a id="editHistory" class="mim-anchor"></a>
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 09/16/2016
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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alopez : 06/20/2013<br>alopez : 2/6/2013<br>terry : 2/1/2013<br>wwang : 5/10/2011<br>ckniffin : 4/28/2011<br>wwang : 11/15/2010<br>ckniffin : 11/11/2010<br>wwang : 1/22/2010<br>terry : 1/20/2010<br>ckniffin : 1/11/2010<br>carol : 7/17/2009<br>joanna : 7/17/2009<br>wwang : 3/19/2008<br>ckniffin : 3/17/2008<br>mgross : 5/23/2007<br>terry : 5/4/2007<br>mgross : 5/1/2007<br>alopez : 4/20/2006<br>terry : 4/19/2006<br>mgross : 10/23/2003<br>alopez : 7/11/2002<br>terry : 3/7/2001<br>joanna : 3/6/2001<br>mgross : 3/2/2001<br>alopez : 2/28/2000<br>carol : 9/17/1999<br>terry : 9/15/1999<br>mgross : 9/14/1999<br>psherman : 4/21/1998<br>psherman : 3/17/1998<br>mark : 5/20/1996<br>terry : 5/17/1996<br>mark : 5/16/1996
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</span>
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<div class="container visible-print-block">
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<h3>
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<span class="mim-font">
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<strong>*</strong> 601263
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<div>
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<h3>
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<span class="mim-font">
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MITOGEN-ACTIVATED PROTEIN KINASE KINASE 2; MAP2K2
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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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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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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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PROTEIN KINASE, MITOGEN-ACTIVATED, KINASE 2; PRKMK2<br />
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MKK2; MAPKK2<br />
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MAPK/ERK KINASE 2; MEK2
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</span>
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</h4>
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</div>
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<div>
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<br />
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: MAP2K2</em></strong>
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</span>
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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: 19p13.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 19:4,090,321-4,124,122 </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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</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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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed 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>
|
|
Phenotype
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</th>
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<th>
|
|
Phenotype <br /> MIM number
|
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</th>
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<th>
|
|
Inheritance
|
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</th>
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<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td rowspan="1">
|
|
<span class="mim-font">
|
|
19p13.3
|
|
</span>
|
|
</td>
|
|
|
|
|
|
<td>
|
|
<span class="mim-font">
|
|
Cardiofaciocutaneous syndrome 4
|
|
</span>
|
|
</td>
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<td>
|
|
<span class="mim-font">
|
|
615280
|
|
</span>
|
|
</td>
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<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
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|
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|
|
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</tr>
|
|
|
|
|
|
</tbody>
|
|
</table>
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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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<h4>
|
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<span class="mim-font">
|
|
<strong>TEXT</strong>
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|
</span>
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</h4>
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<div>
|
|
<h4>
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<span class="mim-font">
|
|
<strong>Cloning and Expression</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">
|
|
<p>Zheng and Guan (1993) isolated and sequenced 2 human cDNAs encoding members of the MAP kinase kinase (MAP2K) family, designated MEK1 (176872) and MEK2 by them. The MEK2 cDNA encodes a predicted 400-amino acid protein that shares 80% sequence identity with human MEK1. </p><p>Brott et al. (1993) cloned the mouse Mek2 gene. </p>
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</span>
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<div>
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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">
|
|
<strong>Gene Function</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
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<span class="mim-text-font">
|
|
<p>Zheng and Guan (1993) showed that recombinant MEK2 and MEK1 both could activate human ERK1 (601795) in vitro. They further characterized biochemically the 2 MAP2Ks. </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 (MAPK) 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 (176872), MKK2, 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>Mittal et al. (2006) found that the Yersinia YopJ virulence factor inhibited the host inflammatory response and induced apoptosis of immune cells by catalyzing acetylation of 2 ser residues in the activation loop of MEK2, thereby blocking MEK2 activation and signal propagation. YopJ also caused acetylation of a thr residue in the activation loop of both IKKA (CHUK; 600664) and IKKB (IKBKB; 603258). Mittal et al. (2006) concluded that ser/thr acetylation is a mode of action for bacterial toxins that may also occur under nonpathogenic conditions to regulate protein function. </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 (164760)/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><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/Erk2 (MAPK1; 176948) 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-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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Mapping</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Brott et al. (1993) mapped the mouse Mek2 gene to chromosome 10. </p><p>Puttagunta et al. (2000) constructed a cosmid/BAC map of human chromosome 19p13.3 and localized over 50 genes, including MAP2K2, to the contig. The 19p13.3 region shows syntenic homology with mouse chromosome 10. </p><p>Meloche et al. (2000) had erroneously mapped the MAP2K2 gene to 7q32. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Cardiofaciocutaneous Syndrome</em></strong></p><p>
|
|
In 23 patients with cardiofaciocutaneous syndrome (CFC4; 615280), Rodriguez-Viciana et al. (2006) searched for mutations in downstream effectors of RAS and found a missense mutation in MEK2 in 1 patient (F57C; 601263.0001). The F57 codon of MEK2 is equivalent to codon F53 of MEK1, which was mutated in another CFC patient (176872.0001). </p><p>In 3 (5.9%) of 51 CFC patients, Schulz et al. (2008) identified 2 different mutations in the MAP2K2 gene (F57V; 601263.0002 and Y134H; 601263.0003). </p><p>Rauen et al. (2010) and Linden and Price (2011) independently reported 2 unrelated families with autosomal dominant transmission of CFC due to heterozygous mutations in the MAP2K2 gene (P128Q, 601263.0004 and G132D, 601263.0005, respectively). </p><p><strong><em>Somatic Mutations</em></strong></p><p>
|
|
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 (MEK1; 176872) and MAP2K2 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>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Animal Model</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Belanger et al. (2003) developed Mek2-deficient mice. Mutant mice were viable and fertile and showed no phenotypic abnormalities. Mutant embryonic fibroblasts and purified lymphocytes proliferated normally, demonstrating that Mek2 is not required for reentry into the cell cycle or for T-cell development. Belanger et al. (2003) concluded that MEK1 can compensate for a lack of MEK2 function. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>ALLELIC VARIANTS</strong>
|
|
</span>
|
|
<strong>5 Selected Examples):</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0001 CARDIOFACIOCUTANEOUS SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K2, PHE57CYS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434497,
|
|
|
|
|
|
|
|
ClinVar: RCV000008761, RCV000158038, RCV000208756
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with cardiofaciocutaneous syndrome (CFC4; 615280), Rodriguez-Viciana et al. (2006) identified a T-to-G transversion at nucleotide 170 of the MEK2 gene, resulting in a phenylalanine-to-cysteine substitution at codon 57 (F57C). </p><p>By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S (176872.0001) and Y130C (176872.0002) 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>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0002 CARDIOFACIOCUTANEOUS SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K2, PHE57VAL
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434498,
|
|
|
|
|
|
|
|
ClinVar: RCV000008762, RCV000521375
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In 2 patients with cardiofaciocutaneous syndrome (CFC4; 615280), Schulz et al. (2008) identified a heterozygous de novo 169T-G transversion in exon 2 of the MAP2K2 gene, resulting in a phe57-to-val (F57V) substitution. This same codon is affected in F57C (601263.0001). Both patients had a unique facial phenotype with a long narrow face, tall forehead, low-set ears, severe ptosis, epicanthal folds, and prominent supraorbital ridges. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0003 CARDIOFACIOCUTANEOUS SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K2, TYR134HIS
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs121434499,
|
|
|
|
|
|
|
|
ClinVar: RCV000008763, RCV000043675, RCV000158022, RCV000521479, RCV001813182, RCV003390660, RCV003450621
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a patient with CFC (CFC4; 615280), Schulz et al. (2008) identified a heterozygous 400T-C transition in exon 3 of the MAP2K2 gene, resulting in a tyr134-to-his (Y134H) substitution. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0004 CARDIOFACIOCUTANEOUS SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K2, PRO128GLN
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs267607230,
|
|
|
|
|
|
|
|
ClinVar: RCV000008764, RCV000158021, RCV000208770, RCV004760323
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In affected members of a 4-generation Caucasian Cajun family with CFC (CFC4; 615280), Rauen et al. (2010) identified a heterozygous 383C-A transversion in exon 3 of the MAP2K2 gene, resulting in a pro128-to-gln (P128Q) substitution. In vitro functional expression studies showed that the mutant protein had increased kinase activity, but not as much as other CFC-associated MAP2K2 mutations (e.g., F57C; 601263.0001), and was considered a weak hypermorphic mutation. This was the first reported case of vertical transmission of a MAP2K2 mutation in CFC. The phenotype was variable, and included the classic craniofacial features, pulmonic stenosis, ectodermal abnormalities, and variable degrees of learning delays and disabilities. One of the mutation carriers died of acute lymphocytic leukemia (ALL) at age 41 years, which the authors postulated may have resulted from increased activity of the RAS pathway. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 CARDIOFACIOCUTANEOUS SYNDROME 4</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
MAP2K2, GLY132ASP
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs387906800,
|
|
|
|
|
|
|
|
ClinVar: RCV000023088, RCV000149835, RCV000413893
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a mother and her 2 sons with CFC4 (615280), Linden and Price (2011) identified a heterozygous 395G-A transition in exon 3 of the MAP2K2 gene, resulting in a gly132-to-asp (G132D) substitution in a conserved residue. The proband was a 46-year-old man with mildly delayed development, pulmonary stenosis as a child, myopia, short stature, tightly curled short hair, absent eyebrows, hyperelastic skin, and multiple lentigines. His 40-year-old brother and 68-year-old mother had similar features. Linden and Price (2011) emphasized the rarity of autosomal dominant transmission of CFC, and noted that the mild cognitive phenotype in these patients suggests greater reproductive success. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
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</div>
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|
</div>
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|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Belanger, L.-F., Roy, S., Tremblay, M., Brott, B., Steff, A.-M., Mourad, W., Hugo, P., Erikson, R., Charron, J.
|
|
<strong>Mek2 is dispensable for mouse growth and development.</strong>
|
|
Molec. Cell. Biol. 23: 4778-4787, 2003.
|
|
|
|
|
|
[PubMed: 12832465]
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|
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|
|
[Full Text: https://doi.org/10.1128/MCB.23.14.4778-4787.2003]
|
|
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|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
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: 8297798]
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|
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|
|
</p>
|
|
</li>
|
|
|
|
<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.
|
|
|
|
|
|
[PubMed: 9660836]
|
|
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|
|
[Full Text: https://doi.org/10.1074/jbc.273.29.18623]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Linden, H. C., Price, S. M.
|
|
<strong>Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation.</strong>
|
|
Clin. Dysmorph. 20: 86-88, 2011.
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|
|
|
|
|
[PubMed: 21178588]
|
|
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|
|
[Full Text: https://doi.org/10.1097/MCD.0b013e32833ff29d]
|
|
|
|
|
|
</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">
|
|
Mittal, R., Peak-Chew, S.-Y., McMahon, H. T.
|
|
<strong>Acetylation of MEK2 and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits signaling.</strong>
|
|
Proc. Nat. Acad. Sci. 103: 18574-18579, 2006.
|
|
|
|
|
|
[PubMed: 17116858]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.0608995103]
|
|
|
|
|
|
</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">
|
|
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">
|
|
Puttagunta, P., Gordon, L. A., Meyer, G. E., Kapfhamer, D., Lamerdin, J. E., Kantheti, P., Portman, K. M., Chung, W. K., Jenne, D. E., Olsen, A. S., Burmeister, M.
|
|
<strong>Comparative maps of human 19p13.3 and mouse chromosome 10 allow identification of sequences at evolutionary breakpoints.</strong>
|
|
Genome Res. 10: 1369-1380, 2000.
|
|
|
|
|
|
[PubMed: 10984455]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1101/gr.145200]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., Lacassie, Y.
|
|
<strong>Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations.</strong>
|
|
Am. J. Med. Genet. 152A: 807-814, 2010.
|
|
|
|
|
|
[PubMed: 20358587]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/ajmg.a.33342]
|
|
|
|
|
|
</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">
|
|
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">
|
|
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">
|
|
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]
|
|
|
|
|
|
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