Alternative titles; symbols
HGNC Approved Gene Symbol: MAP2K2
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:4,090,321-4,124,122 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.3 | Cardiofaciocutaneous syndrome 4 | 615280 | Autosomal dominant | 3 |
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.
Brott et al. (1993) cloned the mouse Mek2 gene.
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.
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.
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.
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.
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.
Brott et al. (1993) mapped the mouse Mek2 gene to chromosome 10.
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.
Meloche et al. (2000) had erroneously mapped the MAP2K2 gene to 7q32.
Cardiofaciocutaneous Syndrome
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).
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).
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).
Somatic Mutations
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%.
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.
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).
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.
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.
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.
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.
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.
Belanger, L.-F., Roy, S., Tremblay, M., Brott, B., Steff, A.-M., Mourad, W., Hugo, P., Erikson, R., Charron, J. Mek2 is dispensable for mouse growth and development. Molec. Cell. Biol. 23: 4778-4787, 2003. [PubMed: 12832465] [Full Text: https://doi.org/10.1128/MCB.23.14.4778-4787.2003]
Brott, B. K., Alessandrini, A., Largaespada, D. A., Copeland, N. G., Jenkins, N. A., Crews, C. M., Erikson, R. L. MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell Growth Differ. 4: 921-929, 1993. [PubMed: 8297798]
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. Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273: 18623-18632, 1998. [PubMed: 9660836] [Full Text: https://doi.org/10.1074/jbc.273.29.18623]
Linden, H. C., Price, S. M. Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation. Clin. Dysmorph. 20: 86-88, 2011. [PubMed: 21178588] [Full Text: https://doi.org/10.1097/MCD.0b013e32833ff29d]
Meloche, S., Gopalbhai, K., Beatty, B. G., Scherer, S. W., Pellerin, J. Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenet. Cell Genet. 88: 249-252, 2000. [PubMed: 10828601] [Full Text: https://doi.org/10.1159/000015530]
Mittal, R., Peak-Chew, S.-Y., McMahon, H. T. Acetylation of MEK2 and I-kappa-B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc. Nat. Acad. Sci. 103: 18574-18579, 2006. [PubMed: 17116858] [Full Text: https://doi.org/10.1073/pnas.0608995103]
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. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nature Genet. 44: 133-139, 2012. [PubMed: 22197931] [Full Text: https://doi.org/10.1038/ng.1026]
Orth, K., Palmer, L. E., Bao, Z. Q., Stewart, S., Rudolph, A. E., Bliska, J. B., Dixon, J. E. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science 285: 1920-1923, 1999. [PubMed: 10489373] [Full Text: https://doi.org/10.1126/science.285.5435.1920]
Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R., Ludwig, S. Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nature Cell Biol. 3: 301-305, 2001. [PubMed: 11231581] [Full Text: https://doi.org/10.1038/35060098]
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. Comparative maps of human 19p13.3 and mouse chromosome 10 allow identification of sequences at evolutionary breakpoints. Genome Res. 10: 1369-1380, 2000. [PubMed: 10984455] [Full Text: https://doi.org/10.1101/gr.145200]
Rauen, K. A., Tidyman, W. E., Estep, A. L., Sampath, S., Peltier, H. M., Bale, S. J., Lacassie, Y. Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. Am. J. Med. Genet. 152A: 807-814, 2010. [PubMed: 20358587] [Full Text: https://doi.org/10.1002/ajmg.a.33342]
Rodriguez-Viciana, P., Tetsu, O., Tidyman, W. E., Estep, A. L., Conger, B. A., Santa Cruz, M., McCormick, F., Rauen, K. A. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311: 1287-1290, 2006. [PubMed: 16439621] [Full Text: https://doi.org/10.1126/science.1124642]
Scholl, F. A., Dumesic, P. A., Barragan, D. I., Harada, K., Bissonauth, V., Charron, J., Khavari, P. A. Mek1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev. Cell 12: 615-629, 2007. [PubMed: 17419998] [Full Text: https://doi.org/10.1016/j.devcel.2007.03.009]
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. Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome Clin. Genet. 73: 62-70, 2008. [PubMed: 18042262] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00931.x]
Senawong, T., Phuchareon, J., Ohara, O., McCormick, F., Rauen, K. A., Tetsu, O. Germline mutations of MEK in cardio-facio-cutaneous syndrome are sensitive to MEK and RAF inhibition: implications for therapeutic options. Hum. Molec. Genet. 17: 419-430, 2008. [PubMed: 17981815] [Full Text: https://doi.org/10.1093/hmg/ddm319]
Zheng, C. F., Guan, K. L. Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J. Biol. Chem. 268: 11435-11439, 1993. [PubMed: 8388392]