MAP2K mutants constitutively phosphorylate MAPKs

Stable Identifier
Reaction [transition]
Homo sapiens
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Although they occur at much lower frequently than mutations in upstream components of the RAS signaling pathway, activating mutations in MAP2K proteins, encoding MEK1 and MEK2, have been identified in a number of cancers and germline disorders (Marks et al, 2008; Murugan et al, 2009). These mutations cluster in the N-terminal autoinhibitory domain or in the catalytic domain and lead to constitutively active forms of the proteins that phosphorylate MAPK1 and MAPK2 (ERK2 and ERK1) independent of upstream signaling (Nikolaev et al, 2011; Rodriguez-Viciana and Rauen, 2008; Borttoff et al, 1995; Marks et al, 2008; Estep et al, 2007; Van Allen et al, 2014; Chen et al, 2014; Wagle et al, 2011; Waterfall et al, 2014; Rauen et al, 2010; reviewed in Samatar and Poulikakos, 2014; Rauen, 2013; Bezniakow et al, 2014).

Literature References
PubMed ID Title Journal Year
7651428 RAS signalling is abnormal in a c-raf1 MEK1 double mutant

Bottorff, D, Stang, S, Agellon, S, Stone, JC

Mol. Cell. Biol. 1995
20358587 Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations

Rauen, KA, Tidyman, WE, Estep, AL, Sampath, S, Peltier, HM, Bale, SJ, Lacassie, Y

Am. J. Med. Genet. A 2010
24241536 High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias

Waterfall, JJ, Arons, E, Walker, RL, Pineda, M, Roth, L, Killian, JK, Abaan, OD, Davis, SR, Kreitman, RJ, Meltzer, PS

Nat. Genet. 2014
18632602 Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma

Marks, JL, Gong, Y, Chitale, D, Golas, B, McLellan, MD, Kasai, Y, Ding, L, Mardis, ER, Wilson, RK, Solit, D, Levine, R, Michel, K, Thomas, RK, Rusch, VW, Ladanyi, M, Pao, W

Cancer Res. 2008
24265153 The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma

Van Allen, EM, Wagle, N, Sucker, A, Treacy, DJ, Johannessen, CM, Goetz, EM, Place, CS, Taylor-Weiner, A, Whittaker, S, Kryukov, GV, Hodis, E, Rosenberg, M, McKenna, A, Cibulskis, K, Farlow, D, Zimmer, L, Hillen, U, Gutzmer, R, Goldinger, SM, Ugurel, S, Gogas, HJ, Egberts, F, Berking, C, Trefzer, U, Loquai, C, Weide, B, Hassel, JC, Gabriel, SB, Carter, SL, Getz, G, Garraway, LA, Schadendorf, D, Dermatologic Cooperative Oncology Group of Germany (DeCOG), -

Cancer Discov 2014
25435214 Targeting RAS-ERK signalling in cancer: promises and challenges

Samatar, AA, Poulikakos, PI

Nat Rev Drug Discov 2014
22197931 Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma

Nikolaev, SI, 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, JS, Xenarios, I, Halazonetis, TD, Jongeneel, CV, Stevenson, BJ, Antonarakis, SE

Nat. Genet. 2011
23875798 The RASopathies

Rauen, KA

Annu Rev Genomics Hum Genet 2013
25182392 The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes

Bezniakow, N, Gos, M, Obersztyn, E

Dev Period Med 2014
25049390 Next-generation sequencing identifies rare variants associated with Noonan syndrome

Chen, PC, Yin, J, Yu, HW, Yuan, T, Fernandez, M, Yung, CK, Trinh, QM, Peltekova, VD, Reid, JG, Tworog-Dube, E, Morgan, MB, Muzny, DM, Stein, L, McPherson, JD, Roberts, AE, Gibbs, RA, Neel, BG, Kucherlapati, R

Proc. Natl. Acad. Sci. U.S.A. 2014
18413255 Biochemical characterization of novel germline BRAF and MEK mutations in cardio-facio-cutaneous syndrome

Rodriguez-Viciana, P, Rauen, KA

Meth. Enzymol. 2008
21383288 Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling

Wagle, N, Emery, C, Berger, MF, Davis, MJ, Sawyer, A, Pochanard, P, Kehoe, SM, Johannessen, CM, Macconaill, LE, Hahn, WC, Meyerson, M, Garraway, LA

J. Clin. Oncol. 2011
18060073 Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy

Estep, AL, Palmer, C, McCormick, F, Rauen, KA

PLoS ONE 2007
Catalyst Activity

protein serine/threonine kinase activity of MAP2K1 and MAP2K2 mutants [cytosol]

Functional status

Gain of function of MAP2K1 and MAP2K2 mutants [cytosol]

Disease Entity
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
cardiofaciocutaneous syndrome DOID:0060233 CFC syndrome, cardio-facial-cutaneous syndrome
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