MAPK1 explained

Mitogen-activated protein kinase 1 (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.^[1]

Function

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene.^[2] MAPK1 contains multiple amino acid sites that are phosphorylated and ubiquitinated.^[3]

Interactions

MAPK1 has been shown to interact with:

• ADAM17,^[4]
• CIITA,^[5]
• DUSP1,^{[6] [7]}
• DUSP3,^[8]
• ELK1,^[9]
• FHL2,^[10]
• HDAC4,^[11]
• MAP2K1,^{[12] [13] [14] [15] [16]}
• MAP3K1^[17]
• MAPK14,^{[18] [19]}
• MKNK1,^[20]
• MKNK2,^{[20] [21]}
• Myc,^{[22] [23] [24]}
• NEK2,^[25]
• PEA15,^[26]
• PTPN7,^{[27] [28]}
• Phosphatidylethanolamine binding protein 1,^[13]
• RPS6KA1,^[29]
• RPS6KA2,^[30]
• RPS6KA3,^{[31] [32]}
• SORBS3,^[33]
• STAT5A,^{[34] [35]}
• TNIP1,^[36]
• TOB1,^[37]
• TSC2,^[38]
• UBR5,^[29] and
• VAV1.^{[39] [40]}

Clinical significance

Mutations in MAPK1 are implicated in many types of cancer.^[41]

See also

• Extracellular signal-regulated kinases

Further reading

• Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Watanabe A, Titani K, Ihara Y . Hyperphosphorylation of tau in PHF . Neurobiol. Aging . 16 . 3 . 365–71; discussion 371–80 . 1995 . 7566346 . 10.1016/0197-4580(95)00027-C . 22471158 .
• Jeong Y, Du R, Zhu X, etal. . Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1 . J Leukoc Biol . 95 . 4 . 651–9 . 2014 . 24374966 . 10.1189/jlb.1013565. 40126163 .
• Davis RJ . Transcriptional regulation by MAP kinases . Mol. Reprod. Dev. . 42 . 4 . 459–67 . 1995 . 8607977 . 10.1002/mrd.1080420414 . 12842112 .
• Peruzzi F, Gordon J, Darbinian N, Amini S . Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway . J. Neurovirol. . 8 Suppl 2 . 2 . 91–6 . 2002 . 12491158 . 10.1080/13550280290167885 .
• Greenway AL, Holloway G, McPhee DA, Ellis P, Cornall A, Lidman M . HIV-1 Nef control of cell signalling molecules: multiple strategies to promote virus replication . J. Biosci. . 28 . 3 . 323–35 . 2003 . 12734410 . 10.1007/BF02970151 . 33749514 .
• Meloche S, Pouysségur J . The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition . Oncogene . 26 . 22 . 3227–39 . 2007 . 17496918 . 10.1038/sj.onc.1210414 . 2245848 .

External links

• MAP Kinase Resource .

Notes and References

1. Owaki H, Makar R, Boulton TG, Cobb MH, Geppert TD . Extracellular signal-regulated kinases in T cells: characterization of human ERK1 and ERK2 cDNAs . Biochem. Biophys. Res. Commun. . 182 . 3 . 1416–22 . February 1992 . 1540184 . 10.1016/0006-291X(92)91891-S .
2. Web site: Entrez Gene: MAPK1 mitogen-activated protein kinase 1.
3. Web site: ERK2 (human). 2020-10-31. www.phosphosite.org.
4. Díaz-Rodríguez E, Montero JC, Esparís-Ogando A, Yuste L, Pandiella A . Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding . Mol. Biol. Cell . 13 . 6 . 2031–44 . June 2002 . 12058067 . 117622 . 10.1091/mbc.01-11-0561 .
5. Voong LN, Slater AR, Kratovac S, Cressman DE . Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator . J. Biol. Chem. . 283 . 14 . 9031–9 . April 2008 . 18245089 . 2431044 . 10.1074/jbc.M706487200 . free .
6. Slack DN, Seternes OM, Gabrielsen M, Keyse SM . Distinct binding determinants for ERK2/p38alpha and JNK map kinases mediate catalytic activation and substrate selectivity of map kinase phosphatase-1 . J. Biol. Chem. . 276 . 19 . 16491–500 . May 2001 . 11278799 . 10.1074/jbc.M010966200 . free .
7. Calvisi DF, Pinna F, Meloni F, Ladu S, Pellegrino R, Sini M, Daino L, Simile MM, De Miglio MR, Virdis P, Frau M, Tomasi ML, Seddaiu MA, Muroni MR, Feo F, Pascale RM . Dual-specificity phosphatase 1 ubiquitination in extracellular signal-regulated kinase-mediated control of growth in human hepatocellular carcinoma . Cancer Res. . 68 . 11 . 4192–200 . June 2008 . 18519678 . 10.1158/0008-5472.CAN-07-6157 . free .
8. Todd JL, Tanner KG, Denu JM . Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway . J. Biol. Chem. . 274 . 19 . 13271–80 . May 1999 . 10224087 . 10.1074/jbc.274.19.13271. free .
9. Cano E, Hazzalin CA, Kardalinou E, Buckle RS, Mahadevan LC . Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction . J. Cell Sci. . 108 . 11. 3599–609 . November 1995 . 10.1242/jcs.108.11.3599 . 8586671 .
10. Purcell NH, Darwis D, Bueno OF, Müller JM, Schüle R, Molkentin JD . Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes . Mol. Cell. Biol. . 24 . 3 . 1081–95 . February 2004 . 14729955 . 321437 . 10.1128/mcb.24.3.1081-1095.2004.
11. Zhou X, Richon VM, Wang AH, Yang XJ, Rifkind RA, Marks PA . Histone deacetylase 4 associates with extracellular signal-regulated kinases 1 and 2, and its cellular localization is regulated by oncogenic Ras . Proc. Natl. Acad. Sci. U.S.A. . 97 . 26 . 14329–33 . December 2000 . 11114188 . 18918 . 10.1073/pnas.250494697 . 2000PNAS...9714329Z . free .
12. Robinson FL, Whitehurst AW, Raman M, Cobb MH . Identification of novel point mutations in ERK2 that selectively disrupt binding to MEK1 . J. Biol. Chem. . 277 . 17 . 14844–52 . April 2002 . 11823456 . 10.1074/jbc.M107776200 . free .
13. Yeung K, Janosch P, McFerran B, Rose DW, Mischak H, Sedivy JM, Kolch W . Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein . Mol. Cell. Biol. . 20 . 9 . 3079–85 . May 2000 . 10757792 . 85596 . 10.1128/mcb.20.9.3079-3085.2000.
14. Wunderlich W, Fialka I, Teis D, Alpi A, Pfeifer A, Parton RG, Lottspeich F, Huber LA . A novel 14-kilodalton protein interacts with the mitogen-activated protein kinase scaffold mp1 on a late endosomal/lysosomal compartment . J. Cell Biol. . 152 . 4 . 765–76 . February 2001 . 11266467 . 2195784 . 10.1083/jcb.152.4.765.
15. Stippec S, Robinson FL, Cobb MH . Hydrophobic as well as charged residues in both MEK1 and ERK2 are important for their proper docking . J. Biol. Chem. . 276 . 28 . 26509–15 . July 2001 . 11352917 . 10.1074/jbc.M102769200 . free .
16. Chen Z, Cobb MH . Regulation of stress-responsive mitogen-activated protein (MAP) kinase pathways by TAO2 . J. Biol. Chem. . 276 . 19 . 16070–5 . May 2001 . 11279118 . 10.1074/jbc.M100681200 . free .
17. Karandikar M, Xu S, Cobb MH . MEKK1 binds raf-1 and the ERK2 cascade components . J. Biol. Chem. . 275 . 51 . 40120–7 . December 2000 . 10969079 . 10.1074/jbc.M005926200 . free .
18. Sanz-Moreno V, Casar B, Crespo P . p38alpha isoform Mxi2 binds to extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase and regulates its nuclear activity by sustaining its phosphorylation levels . Mol. Cell. Biol. . 23 . 9 . 3079–90 . May 2003 . 12697810 . 153192 . 10.1128/mcb.23.9.3079-3090.2003.
19. Tanoue T, Maeda R, Adachi M, Nishida E . Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions . EMBO J. . 20 . 3 . 466–79 . February 2001 . 11157753 . 133461 . 10.1093/emboj/20.3.466 .
20. Waskiewicz AJ, Flynn A, Proud CG, Cooper JA . Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2 . EMBO J. . 16 . 8 . 1909–20 . April 1997 . 9155017 . 1169794 . 10.1093/emboj/16.8.1909 .
21. Scheper GC, Parra JL, Wilson M, Van Kollenburg B, Vertegaal AC, Han ZG, Proud CG . The N and C termini of the splice variants of the human mitogen-activated protein kinase-interacting kinase Mnk2 determine activity and localization . Mol. Cell. Biol. . 23 . 16 . 5692–705 . August 2003 . 12897141 . 166352 . 10.1128/mcb.23.16.5692-5705.2003.
22. Jin Z, Gao F, Flagg T, Deng X . Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation . J. Biol. Chem. . 279 . 38 . 40209–19 . September 2004 . 15210690 . 10.1074/jbc.M404056200 . free .
23. Gupta S, Davis RJ . MAP kinase binds to the NH2-terminal activation domain of c-Myc . FEBS Lett. . 353 . 3 . 281–5 . October 1994 . 7957875 . 10.1016/0014-5793(94)01052-8. 45404088 . free . 1994FEBSL.353..281G .
24. Tournier C, Whitmarsh AJ, Cavanagh J, Barrett T, Davis RJ . Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase . Proc. Natl. Acad. Sci. U.S.A. . 94 . 14 . 7337–42 . July 1997 . 9207092 . 23822 . 10.1073/pnas.94.14.7337. 1997PNAS...94.7337T . free .
25. Lou Y, Xie W, Zhang DF, Yao JH, Luo ZF, Wang YZ, Shi YY, Yao XB . Nek2A specifies the centrosomal localization of Erk2 . Biochem. Biophys. Res. Commun. . 321 . 2 . 495–501 . August 2004 . 15358203 . 10.1016/j.bbrc.2004.06.171 .
26. Formstecher E, Ramos JW, Fauquet M, Calderwood DA, Hsieh JC, Canton B, Nguyen XT, Barnier JV, Camonis J, Ginsberg MH, Chneiweiss H . PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase . Dev. Cell . 1 . 2 . 239–50 . August 2001 . 11702783 . 10.1016/s1534-5807(01)00035-1. free .
27. Pettiford SM, Herbst R . The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP . Oncogene . 19 . 7 . 858–69 . February 2000 . 10702794 . 10.1038/sj.onc.1203408 . 24843974 .
28. Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T . Inhibition of T cell signaling by mitogen-activated protein kinase-targeted hematopoietic tyrosine phosphatase (HePTP) . J. Biol. Chem. . 274 . 17 . 11693–700 . April 1999 . 10206983 . 10.1074/jbc.274.17.11693. free .
29. Eblen ST, Kumar NV, Shah K, Henderson MJ, Watts CK, Shokat KM, Weber MJ . Identification of novel ERK2 substrates through use of an engineered kinase and ATP analogs . J. Biol. Chem. . 278 . 17 . 14926–35 . April 2003 . 12594221 . 10.1074/jbc.M300485200 . free .
30. Roux PP, Richards SA, Blenis J . Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity . Mol. Cell. Biol. . 23 . 14 . 4796–804 . July 2003 . 12832467 . 162206 . 10.1128/mcb.23.14.4796-4804.2003.
31. Smith JA, Poteet-Smith CE, Malarkey K, Sturgill TW . Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo . J. Biol. Chem. . 274 . 5 . 2893–8 . January 1999 . 9915826 . 10.1074/jbc.274.5.2893. free .
32. Zhao Y, Bjorbaek C, Moller DE . Regulation and interaction of pp90(rsk) isoforms with mitogen-activated protein kinases . J. Biol. Chem. . 271 . 47 . 29773–9 . November 1996 . 8939914 . 10.1074/jbc.271.47.29773. free.
33. Mitsushima M, Suwa A, Amachi T, Ueda K, Kioka N . Extracellular signal-regulated kinase activated by epidermal growth factor and cell adhesion interacts with and phosphorylates vinexin . J. Biol. Chem. . 279 . 33 . 34570–7 . August 2004 . 15184391 . 10.1074/jbc.M402304200 . free .
34. Pircher TJ, Petersen H, Gustafsson JA, Haldosén LA . Extracellular signal-regulated kinase (ERK) interacts with signal transducer and activator of transcription (STAT) 5a . Mol. Endocrinol. . 13 . 4 . 555–65 . April 1999 . 10194762 . 10.1210/mend.13.4.0263 . free .
35. Dinerstein-Cali H, Ferrag F, Kayser C, Kelly PA, Postel-Vinay M . Growth hormone (GH) induces the formation of protein complexes involving Stat5, Erk2, Shc and serine phosphorylated proteins . Mol. Cell. Endocrinol. . 166 . 2 . 89–99 . August 2000 . 10996427 . 10.1016/s0303-7207(00)00277-x. 45725648 .
36. Zhang S, Fukushi M, Hashimoto S, Gao C, Huang L, Fukuyo Y, Nakajima T, Amagasa T, Enomoto S, Koike K, Miura O, Yamamoto N, Tsuchida N . A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling . Biochem. Biophys. Res. Commun. . 297 . 1 . 17–23 . September 2002 . 12220502 . 10.1016/s0006-291x(02)02086-7.
37. Maekawa M, Nishida E, Tanoue T . Identification of the Anti-proliferative protein Tob as a MAPK substrate . J. Biol. Chem. . 277 . 40 . 37783–7 . October 2002 . 12151396 . 10.1074/jbc.M204506200 . free .
38. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP . Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis . Cell . 121 . 2 . 179–93 . April 2005 . 15851026 . 10.1016/j.cell.2005.02.031 . 18663447 . free .
39. Song JS, Gomez J, Stancato LF, Rivera J . Association of a p95 Vav-containing signaling complex with the FcepsilonRI gamma chain in the RBL-2H3 mast cell line. Evidence for a constitutive in vivo association of Vav with Grb2, Raf-1, and ERK2 in an active complex . J. Biol. Chem. . 271 . 43 . 26962–70 . October 1996 . 8900182 . 10.1074/jbc.271.43.26962. free .
40. Lee IS, Liu Y, Narazaki M, Hibi M, Kishimoto T, Taga T . Vav is associated with signal transducing molecules gp130, Grb2 and Erk2, and is tyrosine phosphorylated in response to interleukin-6 . FEBS Lett. . 401 . 2–3 . 133–7 . January 1997 . 9013873 . 10.1016/s0014-5793(96)01456-1. 32632406 . free . 1997FEBSL.401..133L .
41. Web site: Expression of MAPK1 in cancer - Summary - The Human Protein Atlas. www.proteinatlas.org.