Alternative titles; symbols
HGNC Approved Gene Symbol: MAP2K1
Cytogenetic location: 15q22.31 Genomic coordinates (GRCh38) : 15:66,386,912-66,491,544 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q22.31 | Cardiofaciocutaneous syndrome 3 | 615279 | Autosomal dominant | 3 |
| Melorheostosis, isolated, somatic mosaic | 155950 | 3 |
Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated kinases (ERKs) (see ERK2, or MAPK1; 176948), are thought to act as an integration point for multiple biochemical signals because they are activated by a wide variety of extracellular signals, are rapidly phosphorylated on threonine and tyrosine residues, and are highly conserved in evolution (Crews et al., 1992). A critical protein kinase lies upstream of MAP kinase and stimulates the enzymatic activity of MAP kinase. Crews et al. (1992) cloned a mouse cDNA, denoted Mek1 (for Map/Erk kinase-1) by them, that encodes a member of this protein kinase family. The 393-amino acid, 43.5-kD protein is most closely related in size and sequence to the product encoded by the byr1 gene of S. pombe. The Mek1 gene was highly expressed in murine brain.
Seger et al. (1992) cloned a cDNA encoding the human homolog of Mek1, symbolized MKK1 by them, from a human T-cell cDNA library. The predicted protein has a calculated molecular mass of 43 kD. They also isolated a related cDNA, called MKK1b, that appears to be an alternatively spliced form of MKK1. Seger et al. (1992) detected a 2.6-kb MKK1 transcript by Northern blot analysis in all tissues examined.
Zheng and Guan (1993) also cloned a human cDNA corresponding to MEK1. They noted that the 393-amino acid protein shares 99% amino acid identity with murine Mek1 and 80% homology with human MEK2 (601263). The authors characterized biochemically the human MEK1 and MEK2 gene products. The gene is also symbolized MAP2K1, or PRKMK1.
Using radiation hybrid mapping, Rampoldi et al. (1997) localized the MAP2K1 gene to 15q22.1-q22.33. By somatic cell hybrid analysis and FISH, Meloche et al. (2000) mapped MAP2K1 to 15q21 and a pseudogene, MAP2K1P1, to 8p21. Brott et al. (1993) mapped the mouse Mek1 gene to chromosome 9.
Crews et al. (1992) found that the mouse Mek1 protein expressed in bacteria phosphorylated the Erk gene product in vitro.
Seger et al. (1992) found that overexpression of MKK1 in COS cells led to increased phorbol ester-stimulated MAP kinase kinase activity. Seger and Krebs (1995) reviewed the MAP kinase signaling cascade.
Ryan et al. (2000) showed that inhibition of MEK1 blocks p53 (191170)-induced NF-kappa-B activation and apoptosis but not cell cycle arrest. They demonstrated that p53 activates NF-kappa-B through the RAF/MEK1/p90(rsk) (see 601684) pathway rather than the TNFR1 (191190)/TRAF2 (601895)/IKK (e.g., 600664) pathway used by TNFA (191160).
To elucidate the mechanism through which MAPK signaling regulates the MYOD (159970) family of transcription factors, Perry et al. (2001) investigated the role of the signaling intermediate MEK1 in myogenesis. Transfection of activated MEK1 strongly repressed gene activation and myogenic conversion by the MYOD family. This repression was not mediated by direct phosphorylation of MYOD or by changes in MYOD stability or subcellular distribution. Deletion mapping revealed that MEK1-mediated repression required the MYOD N-terminal transactivation domain. Moreover, activated MEK1 was nuclearly localized and bound a complex containing MYOD in a manner that was dependent on the presence of the MYOD N terminus. These data demonstrated that MEK1 signaling has a strong negative effect on MYOD activity via a mechanism involving binding of MEK1 to the nuclear MYOD transcriptional complex.
Takekawa et al. (2005) identified a conserved docking site, which they termed 'domain for versatile docking' (DVD), immediately C terminal to the catalytic domains of mammalian MAPKKs, including MEK1. They determined that DVD sites contain about 20 amino acids and bind to specific upstream MAPKKKs. DVD site mutations strongly inhibited MAPKKs from binding to and being activated by their specific MAPKKKs, both in vitro and in vivo. MAPKKs containing DVD site mutations could not be activated by various external stimuli in vivo, and synthetic DVD oligopeptides inhibited specific MAPKK activation, both in vitro and in vivo. Takekawa et al. (2005) concluded that DVD docking is critically important in MAPK signaling.
Scholl et al. (2007) found that conditional deletion of either Mek1 or Mek2 in mouse skin had no effect on epidermal development, but combined Mek1/Mek2 deletion during embryonic development or in adulthood abolished Erk1 (MAPK3; 601795)/Erk2 phosphorylation and led to hypoproliferation, apoptosis, skin barrier defects, and death. Conversely, a single copy of either allele was sufficient for normal development. Combined Mek1/Mek2 loss also abolished Raf (RAF1; 164760)-induced hyperproliferation. To examine the effect of combined MEK deletion on human skin, Scholl et al. (2007) used small interfering RNA to delete MEK1 and MEK2 expression in normal primary human keratinocytes and used these cells to regenerate human epidermal tissue on human dermis, which was grafted onto immune-deficient mice. Control keratinocytes or those lacking either MEK1 or MEK2 were able to regenerate 6 days after grafting. In contrast, combined depletion of MEK1 and MEK2 led to either graft failure or markedly hypoplastic epidermis that nonetheless contained an intact stratum corneum. ERK2 expression rescued the defect. Scholl et al. (2007) concluded that MEK1 and MEK2 are functionally redundant in the epidermis and function in a linear relay in the MAPK pathway.
Imai et al. (2008) used mouse models to explore the mechanism whereby obesity enhances pancreatic beta cell mass, pathophysiologic compensation for insulin resistance. Imai et al. (2008) found that hepatic activation of extracellular regulated kinase (ERK1; 601795) signaling by expression of constitutively active MEK1 induced pancreatic beta cell proliferation through a neuronal-mediated relay of metabolic signals. This metabolic relay from the liver to the pancreas is involved in obesity-induced islet expansion. In mouse models of insulin-deficient diabetes, liver-selective activation of ERK signaling increased beta cell mass and normalized serum glucose levels. Thus, Imai et al. (2008) concluded that interorgan metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.
Chuderland et al. (2008) identified an SPS motif in ERK2 and SMAD3 (603109) and a similar TPT motif in MEK1 that directed protein nuclear accumulation when phosphorylated.
Crystal Structure
Brennan et al. (2011) integrated structural and biochemical studies to understand how kinase suppressor of Ras (KSR) promotes stimulatory Raf phosphorylation of MEK. They showed, from the crystal structure of the kinase domain (KD) of human KSR2 (610737) in complex with rabbit MEK1, that interactions between KSR2(KD) and MEK1 are mediated by their respective activation segments and C-lobe alpha-G helices. Analogous to BRAF (164757), KSR2 self-associates through a side-to-side interface involving arg718, a residue identified in a genetic screen as a suppressor of Ras signaling. ATP is bound to the KSR2 (KD) catalytic site, and Brennan et al. (2011) demonstrated KSR2 kinase activity towards MEK1 by in vitro assays and chemical genetics. In the KSR2(KD)-MEK1 complex, the activation segments of both kinases are mutually constrained, and KSR2 adopts an inactive conformation. BRAF allosterically stimulates the kinase activity of KSR2, which is dependent on formation of a side-to-side KSR2-BRAF heterodimer. Furthermore, KSR2-BRAF heterodimerization results in an increase of BRAF-induced MEK phosphorylation via the KSR2-mediated relay of a signal from BRAF to release the activation segment of MEK for phosphorylation. Brennan et al. (2011) proposed that KSR interacts with a regulatory Raf molecule in cis to induce a conformational switch of MEK, facilitating MEK's phosphorylation by a separate catalytic Raf molecule in trans.
Cryoelectron Microscopy
Park et al. (2019) used cryoelectron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer of eta (YWHAH; 113508) and zeta (YWHAZ; 601288). The reconstruction revealed an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of 2 BRAFs, which drives the formation of an active, back-to-back BRAF dimer.
Cardiofaciocutaneous Syndrome
In 2 patients with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified mutations (F53S, 176872.0001; Y130C, 176872.0002) in the MEK1 gene. Interestingly, 1 patient had a mutation at phe53 (F53), which is equivalent to phe57 (F57) in the MEK2 gene, where another CFC patient had a missense mutation (F57C; 601263.0001).
In 5 patients with CFC3, Gripp et al. (2007) identified heterozygous mutations in the MEK1 gene. Three patients had the previously identified Y130C mutation and 2 had novel mutations (176872.0004 and 176872.0005).
Schulz et al. (2008) identified mutations in the MAP2K1 gene (see, e.g., 176872.0003) in 5 (9.8%) of 51 CFC patients.
Somatic Mutation in Isolated Melorheostosis
In samples of affected bone from 8 patients with isolated melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for missense mutations in the MAP2K1 gene (Q56P, 176872.0006; K57N, 176872.0007; and K57E, 176872.0008) that were not present in unaffected bone or in peripheral blood leukocytes. Mutant allele frequency ranged from 3 to 34% in affected bone. The authors noted that all 3 MAP2K1 variants had previously been shown to cause gain-of-function effects and had been detected in malignancies, including lung cancer, melanoma, and hairy cell leukemia. Functional analysis confirmed enhanced activation, resulting in increased osteoblast proliferation; however, there was also reduced mineralization and differentiation, consistent with histologic findings of massive accumulation of unmineralized osteoid bone in affected bone tissue, as well as increased osteoclast activity, as shown by the intense remodeling that occurs in melorheostotic bone.
Somatic Mutation in Melanoma
Nikolaev et al. (2012) performed exome sequencing to detect somatic mutations in protein-coding regions in 7 melanoma cell lines and donor-matched germline cells. All melanoma samples had high numbers of somatic mutations, which showed the hallmark of UV-induced DNA repair. Such a hallmark was absent in tumor sample-specific mutations in 2 metastases derived from the same individual. Two melanomas with noncanonical BRAF mutations harbored gain-of-function MAP2K1 and MAP2K2 (MEK2; 601263) mutations, resulting in constitutive ERK phosphorylation and higher resistance to MEK inhibitors. Screening a larger cohort of individuals with melanoma revealed the presence of recurring somatic MAP2K1 and MAP2K2 mutations, which occurred at an overall frequency of 8%.
Constitutive activation of MEK1 results in cellular transformation. This protein kinase therefore represents a likely target for pharmacologic intervention in proliferative disease. To identity small-molecule inhibitors of this pathway, Sebolt-Leopold et al. (1999) developed an in vitro cascade assay using bacterially purified glutathione-S-transferase fusion proteins of MEK1 and MAPK. Sebolt-Leopold et al. (1999) reported the discovery of a highly potent and selective inhibitor of MEK1, which they called PD184352 and which is, in fact, 2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide. PD184352 is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses (with a 50% inhibitory concentration of 17 nanomolar) with no signs of toxicity, and correlated with a reduction in levels of MAPK in excised tumors. Sebolt-Leopold et al. (1999) concluded that these data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
A virulence factor from Yersinia pseudotuberculosis, YopJ, is a 33-kD protein that perturbs a multiplicity of signaling pathways. These include inhibition of the extracellular signal-regulated kinase ERK, c-jun NH2-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways and inhibition of the nuclear factor kappa B (NF-kappa-B; see 164011) pathway. The expression of YopJ has been correlated with the induction of apoptosis by Yersinia. Using a yeast 2-hybrid screen based on a LexA-YopJ fusion protein and a HeLa cDNA library, Orth et al. (1999) identified mammalian binding partners of YopJ. These included the fusion proteins of the GAL4 activation domain with MAPK kinases MKK1, MKK2 (601263), and MKK4/SEK1 (601335). YopJ was found to bind directly to MKKs in vitro, including MKK1, MKK3 (602315), MKK4, and MKK5 (602448). Binding of YopJ to the MKK blocked both phosphorylation and subsequent activation of the MKKs. These results explain the diverse activities of YopJ in inhibiting the ERK, JNK, p38, and NF-kappa-B signaling pathways, preventing cytokine synthesis and promoting apoptosis. YopJ-related proteins that are found in a number of bacterial pathogens of animals and plants may function to block MKKs so that host signaling responses can be modulated upon infection.
Influenza A viruses are significant causes of morbidity and mortality worldwide. Annually updated vaccines may prevent disease, and antivirals are effective treatment early in disease when symptoms are often nonspecific. Viral replication is supported by intracellular signaling events. Using U0126, a nontoxic inhibitor of MEK1 and MEK2, and thus an inhibitor of the RAF1/MEK/ERK pathway (see Favata et al. (1998)), Pleschka et al. (2001) examined the cellular response to infection with influenza A. U0126 suppressed both the early and late ERK activation phases after virus infection. Inhibition of the signaling pathway occurred without impairing the synthesis of viral RNA or protein, or the import of viral ribonucleoprotein complexes (RNP) into the nucleus. Instead, U0126 inhibited RAF/MEK/ERK signaling and the export of viral RNP without affecting the cellular mRNA export pathway. Pleschka et al. (2001) proposed that ERK regulates a cellular factor involved in the viral nuclear export protein function. They suggested that local application of MEK inhibitors may have only minor toxic effects on the host while inhibiting viral replication without giving rise to drug-resistant virus variants.
Giroux et al. (1999) disrupted the mouse Mek1 gene by insertional mutagenesis. The null mutation was recessive lethal, and homozygous mutant embryos died at 10.5 days of gestation. Histopathologic analysis revealed a marked decrease of vascular endothelial cells in the labyrinthine region, resulting in reduced vascularization of the placenta. Failure to establish a functional placenta was considered a likely cause of embryonic death. Cell migration assays indicated that Mek1-null fibroblasts could not be induced to migrate by fibronectin (135600), and reintroduction of Mek1 expression restored their ability to migrate.
In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified a T-to-C transition at nucleotide 158 (c.158T-C, NM_002755) of the MEK1 gene resulting in a phenylalanine-to-serine substitution at codon 53 (F53S). This mutation was not identified in either of the patient's parents. Interestingly, a mutation at the equivalent codon in MEK2 (601263) was found in another CFC patient (F57C; 601263.0001).
By in vitro studies, Senawong et al. (2008) found that MEK1 mutants F53S and Y130C and the MEK2 mutant F57C could not induce ERK signaling unless phosphorylated by RAF at 2 homologous serine residues in the regulatory loop. When these serine residues were replaced with alanines, ERK phosphorylation was significantly reduced in the presence of RAF. However, the F57C MEK2 mutant was less dependent on RAF signaling than the other mutants. This difference resulted in F57C MEK2 being resistant to the selective RAF inhibitor SB-590885. However, all 3 mutants were sensitive to the MEK inhibitor U0126. Senawong et al. (2008) suggested that MEK inhibition could have potential therapeutic value in CFC.
In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Rodriguez-Viciana et al. (2006) identified heterozygosity for an A-to-G transition at nucleotide 389 (c.389A-G, NM_002755) of the MEK1 gene, resulting in a tyrosine-to-cysteine substitution at codon 130 (Y130C) in the protein kinase domain.
In 3 children (patients 136, 146, and 163) with CFC3, Gripp et al. (2007) identified heterozygosity for the Y130C mutation in the MEK1 gene.
In a patient with cardiofaciocutaneous syndrome (CFC3; 615279), Schulz et al. (2008) identified a heterozygous 383G-T transversion in exon 3 of the MAP2K1 gene, resulting in a gly128-to-val (G128V) substitution.
In an 8-year-old girl (patient 144) with cardiofaciocutaneous syndrome-3 (CFC3; 615279), Gripp et al. (2007) identified a 3-bp deletion (AAG) in exon 2 of the MEK1 gene, resulting in deletion of a lysine (K59del) at the beginning of the protein kinase-like domain.
In a 7-week-old male (patient 95) with cardiofaciocutaneous syndrome-3 (CFC3; 615279), Gripp et al. (2007) identified a c.371C-A transversion in exon 3 of the MEK1 gene, resulting in a pro124-to-gln (P124Q) substitution in the protein kinase domain.
In samples of affected bone from 3 patients (Melo-4, Melo-9, and Melo-19) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.167A-C transversion (c.167A-C, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a gln56-to-pro (Q56P) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 9 to 28% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in patient Melo-4 showed the variant at an allele frequency of 12.5%. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the Q56P variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency.
In samples of affected bone from 4 patients (Melo-2, Melo-6, Melo-16, and Melo-18) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.171G-T transversion (c.171G-T, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-asn (K57N) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency ranged from 3 to 34% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Analysis of overlying skin in 3 of the patients showed the variant at an allele frequency of 4.1 to 16.2%; the variant was not detected in skin from patient Melo-16, who had a lower disease burden. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57N variant, and the level of ERK1/2 activation by MEK1 generally correlated with mutant allele frequency. Consistent with enhanced activation, affected osteoblasts showed increased cell proliferation in vitro; however, there was also reduced mineralization and differentiation with affected osteoblasts, as well as increased osteoclast activity.
In samples of affected bone from a patient (Melo-10) with melorheostosis (MEL; 155950), Kang et al. (2018) identified somatic mosaicism for a c.169A-G transition (c.169A-G, NM_002755) in exon 2 of the MAP2K1 gene, resulting in a lys57-to-glu (K57E) substitution within the alpha-helix of the negative regulatory domain. Mutant allele frequency was 18% in affected bone; the variant was not found in unaffected bone or in peripheral blood leukocytes, or in the ExAC database. Western blot analysis of cultured patient osteoblasts showed increased phosphorylation of MAP2K1 target kinases ERK1 (MAPK3; 601795) and ERK2 (MAPK1; 176948) compared to cells from unaffected bone, confirming a gain-of-function effect with the K57E variant.
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