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Gene Review

MAPK1  -  mitogen-activated protein kinase 1

Homo sapiens

Synonyms: ERK, ERK-2, ERK2, ERT1, Extracellular signal-regulated kinase 2, ...

Disease relevance of MAPK1


Psychiatry related information on MAPK1


High impact information on MAPK1

  • It is now clear that the plasma membrane does not represent the only platform for Ras/MAPK signaling [13].
  • Recent findings in B lymphocytes have clearly illustrated that these external inputs affect the magnitude and duration of the intracellular calcium response, which in turn contributes to differential triggering of the transcriptional regulators NF kappa B, JNK, NFAT, and ERK [14].
  • Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation [15].
  • In Saccharomyces cerevisiae, there are five MAPK pathways involved in mating, cell wall remodelling, nutrient deprivation, and responses to stress stimuli such as osmolarity changes [16].
  • In this review, we define all known MAPK module kinases from yeast to humans, what is known about their regulation, defined MAPK substrates, and the function of MAPK in cell physiology [16].

Chemical compound and disease context of MAPK1


Biological context of MAPK1


Anatomical context of MAPK1


Associations of MAPK1 with chemical compounds


Physical interactions of MAPK1

  • Myc-tagged cRaf-1, MEK1, and green fluorescent protein-tagged ERK2 coprecipitated with Flag-tagged beta-arrestin-2 from transfected COS-7 cells [40].
  • IQGAP1 binds ERK2 and modulates its activity [41].
  • MEKK1 binds raf-1 and the ERK2 cascade components [42].
  • Pyst2 binds p42 MAP kinase in vivo and both MAP kinase binding and substrate selectivity correlate with the ability of different recombinant MAP and SAP kinases to cause catalytic activation of the Pyst2 phosphatase in vitro [43].
  • We then identified two conserved hydrophobic residues on ERK2 that play roles in docking with MEK1 [44].

Enzymatic interactions of MAPK1


Regulatory relationships of MAPK1


Other interactions of MAPK1


Analytical, diagnostic and therapeutic context of MAPK1


  1. Systemic anthrax lethal toxin therapy produces regressions of subcutaneous human melanoma tumors in athymic nude mice. Abi-Habib, R.J., Singh, R., Leppla, S.H., Greene, J.J., Ding, Y., Berghuis, B., Duesbery, N.S., Frankel, A.E. Clin. Cancer Res. (2006) [Pubmed]
  2. Direct interaction of surfactant protein a with myometrial binding sites: signaling and modulation by bacterial lipopolysaccharide. Garcia-Verdugo, I., Leiber, D., Robin, P., Billon-Denis, E., Chaby, R., Tanfin, Z. Biol. Reprod. (2007) [Pubmed]
  3. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. MacDonald, T.J., Brown, K.M., LaFleur, B., Peterson, K., Lawlor, C., Chen, Y., Packer, R.J., Cogen, P., Stephan, D.A. Nat. Genet. (2001) [Pubmed]
  4. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Orth, K., Palmer, L.E., Bao, Z.Q., Stewart, S., Rudolph, A.E., Bliska, J.B., Dixon, J.E. Science (1999) [Pubmed]
  5. Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Zhu, J.H., Guo, F., Shelburne, J., Watkins, S., Chu, C.T. Brain. Pathol. (2003) [Pubmed]
  6. Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Zhu, J.H., Kulich, S.M., Oury, T.D., Chu, C.T. Am. J. Pathol. (2002) [Pubmed]
  7. Oncogenic B-RafV600E inhibits apoptosis and promotes ERK-dependent inactivation of Bad and Bim. Sheridan, C., Brumatti, G., Martin, S.J. J. Biol. Chem. (2008) [Pubmed]
  8. Phosphorylation of mitogen-activated protein kinase by one-trial and multi-trial classical conditioning. Crow, T., Xue-Bian, J.J., Siddiqi, V., Kang, Y., Neary, J.T. J. Neurosci. (1998) [Pubmed]
  9. Effects of the beta-amyloid and carboxyl-terminal fragment of Alzheimer's amyloid precursor protein on the production of the tumor necrosis factor-alpha and matrix metalloproteinase-9 by human monocytic THP-1. Chong, Y.H., Sung, J.H., Shin, S.A., Chung, J.H., Suh, Y.H. J. Biol. Chem. (2001) [Pubmed]
  10. Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Ferrer, I., Blanco, R., Carmona, M., Ribera, R., Goutan, E., Puig, B., Rey, M.J., Cardozo, A., Viñals, F., Ribalta, T. Brain Pathol. (2001) [Pubmed]
  11. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Rodriguez-Viciana, P., Tetsu, O., Tidyman, W.E., Estep, A.L., Conger, B.A., Cruz, M.S., McCormick, F., Rauen, K.A. Science (2006) [Pubmed]
  12. ERK2: a logical AND gate critical for drug-induced plasticity? Girault, J.A., Valjent, E., Caboche, J., Hervé, D. Current opinion in pharmacology (2007) [Pubmed]
  13. Compartmentalized ras/mapk signaling. Mor, A., Philips, M.R. Annu. Rev. Immunol. (2006) [Pubmed]
  14. Positive versus negative signaling by lymphocyte antigen receptors. Healy, J.I., Goodnow, C.C. Annu. Rev. Immunol. (1998) [Pubmed]
  15. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Kyriakis, J.M., Avruch, J. Physiol. Rev. (2001) [Pubmed]
  16. Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Widmann, C., Gibson, S., Jarpe, M.B., Johnson, G.L. Physiol. Rev. (1999) [Pubmed]
  17. Progesterone Receptors Upregulate Wnt-1 To Induce Epidermal Growth Factor Receptor Transactivation and c-Src-Dependent Sustained Activation of Erk1/2 Mitogen-Activated Protein Kinase in Breast Cancer Cells. Faivre, E.J., Lange, C.A. Mol. Cell. Biol. (2007) [Pubmed]
  18. Ras-associated protein-1 regulates extracellular signal-regulated kinase activation and migration in melanoma cells: two processes important to melanoma tumorigenesis and metastasis. Gao, L., Feng, Y., Bowers, R., Becker-Hapak, M., Gardner, J., Council, L., Linette, G., Zhao, H., Cornelius, L.A. Cancer Res. (2006) [Pubmed]
  19. SHP-2-dependent mitogen-activated protein kinase activation regulates EGFRvIII but not wild-type epidermal growth factor receptor phosphorylation and glioblastoma cell survival. Zhan, Y., O'Rourke, D.M. Cancer Res. (2004) [Pubmed]
  20. Pharmacologic mitogen-activated protein/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase inhibitors interact synergistically with STI571 to induce apoptosis in Bcr/Abl-expressing human leukemia cells. Yu, C., Krystal, G., Varticovksi, L., McKinstry, R., Rahmani, M., Dent, P., Grant, S. Cancer Res. (2002) [Pubmed]
  21. Blocking the Raf/MEK/ERK pathway sensitizes acute myelogenous leukemia cells to lovastatin-induced apoptosis. Wu, J., Wong, W.W., Khosravi, F., Minden, M.D., Penn, L.Z. Cancer Res. (2004) [Pubmed]
  22. Intensity-dependent activation of extracellular signal-regulated protein kinase 5 in sensory neurons contributes to pain hypersensitivity. Mizushima, T., Obata, K., Katsura, H., Sakurai, J., Kobayashi, K., Yamanaka, H., Dai, Y., Fukuoka, T., Mashimo, T., Noguchi, K. J. Pharmacol. Exp. Ther. (2007) [Pubmed]
  23. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Minden, A., Lin, A., Claret, F.X., Abo, A., Karin, M. Cell (1995) [Pubmed]
  24. Conserved docking site is essential for activation of mammalian MAP kinase kinases by specific MAP kinase kinase kinases. Takekawa, M., Tatebayashi, K., Saito, H. Mol. Cell (2005) [Pubmed]
  25. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. Sumimoto, H., Imabayashi, F., Iwata, T., Kawakami, Y. J. Exp. Med. (2006) [Pubmed]
  26. 6-Hydroxydopamine induces mitochondrial ERK activation. Kulich, S.M., Horbinski, C., Patel, M., Chu, C.T. Free. Radic. Biol. Med. (2007) [Pubmed]
  27. Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson's disease. Dagda, R.K., Zhu, J., Kulich, S.M., Chu, C.T. Autophagy. (2008) [Pubmed]
  28. Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Zhu, J.H., Horbinski, C., Guo, F., Watkins, S., Uchiyama, Y., Chu, C.T. Am. J. Pathol. (2007) [Pubmed]
  29. Regulation of Cdc25C by ERK-MAP Kinases during the G(2)/M Transition. Wang, R., He, G., Nelman-Gonzalez, M., Ashorn, C.L., Gallick, G.E., Stukenberg, P.T., Kirschner, M.W., Kuang, J. Cell (2007) [Pubmed]
  30. RAC1/P38 MAPK signaling pathway controls beta1 integrin-induced interleukin-8 production in human natural killer cells. Mainiero, F., Soriani, A., Strippoli, R., Jacobelli, J., Gismondi, A., Piccoli, M., Frati, L., Santoni, A. Immunity (2000) [Pubmed]
  31. Eosinophil adhesion under flow conditions activates mechanosensitive signaling pathways in human endothelial cells. Cuvelier, S.L., Paul, S., Shariat, N., Colarusso, P., Patel, K.D. J. Exp. Med. (2005) [Pubmed]
  32. Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades. Tong, Q., Booth, R.E., Worrell, R.T., Stockand, J.D. Am. J. Physiol. Renal Physiol. (2004) [Pubmed]
  33. Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Morrison, D.K., Davis, R.J. Annu. Rev. Cell Dev. Biol. (2003) [Pubmed]
  34. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Camps, M., Nichols, A., Gillieron, C., Antonsson, B., Muda, M., Chabert, C., Boschert, U., Arkinstall, S. Science (1998) [Pubmed]
  35. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Sasaki, A., Taketomi, T., Kato, R., Saeki, K., Nonami, A., Sasaki, M., Kuriyama, M., Saito, N., Shibuya, M., Yoshimura, A. Nat. Cell Biol. (2003) [Pubmed]
  36. Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. Nick, J.A., Avdi, N.J., Young, S.K., Lehman, L.A., McDonald, P.P., Frasch, S.C., Billstrom, M.A., Henson, P.M., Johnson, G.L., Worthen, G.S. J. Clin. Invest. (1999) [Pubmed]
  37. Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: implications for Parkinson's disease. Kulich, S.M., Chu, C.T. J. Neurochem. (2001) [Pubmed]
  38. Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins. Cindrova-Davies, T., Spasic-Boskovic, O., Jauniaux, E., Charnock-Jones, D.S., Burton, G.J. Am. J. Pathol. (2007) [Pubmed]
  39. Interaction between ERK and GSK3beta mediates basic fibroblast growth factor-induced apoptosis in SK-N-MC neuroblastoma cells. Ma, C., Bower, K.A., Chen, G., Shi, X., Ke, Z.J., Luo, J. J. Biol. Chem. (2008) [Pubmed]
  40. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Luttrell, L.M., Roudabush, F.L., Choy, E.W., Miller, W.E., Field, M.E., Pierce, K.L., Lefkowitz, R.J. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  41. IQGAP1 binds ERK2 and modulates its activity. Roy, M., Li, Z., Sacks, D.B. J. Biol. Chem. (2004) [Pubmed]
  42. MEKK1 binds raf-1 and the ERK2 cascade components. Karandikar, M., Xu, S., Cobb, M.H. J. Biol. Chem. (2000) [Pubmed]
  43. Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. Dowd, S., Sneddon, A.A., Keyse, S.M. J. Cell. Sci. (1998) [Pubmed]
  44. Hydrophobic as well as charged residues in both MEK1 and ERK2 are important for their proper docking. Xu Be, n.u.l.l., Stippec, S., Robinson, F.L., Cobb, M.H. J. Biol. Chem. (2001) [Pubmed]
  45. Mechanistic studies of the dual phosphorylation of mitogen-activated protein kinase. Ferrell, J.E., Bhatt, R.R. J. Biol. Chem. (1997) [Pubmed]
  46. Direct suppression of TCR-mediated activation of extracellular signal-regulated kinase by leukocyte protein tyrosine phosphatase, a tyrosine-specific phosphatase. Oh-hora, M., Ogata, M., Mori, Y., Adachi, M., Imai, K., Kosugi, A., Hamaoka, T. J. Immunol. (1999) [Pubmed]
  47. Retinoic acid increases amount of phosphorylated RAF; ectopic expression of cFMS reveals that retinoic acid-induced differentiation is more strongly dependent on ERK2 signaling than induced GO arrest is. Yen, A., Varvayanis, S. In Vitro Cell. Dev. Biol. Anim. (2000) [Pubmed]
  48. Selective activation of the mitogen-activated protein kinase subgroups c-Jun NH2 terminal kinase and p38 by IL-1 and TNF in human articular chondrocytes. Geng, Y., Valbracht, J., Lotz, M. J. Clin. Invest. (1996) [Pubmed]
  49. Extracellular signal-regulated kinases modulate capacitation of human spermatozoa. Luconi, M., Barni, T., Vannelli, G.B., Krausz, C., Marra, F., Benedetti, P.A., Evangelista, V., Francavilla, S., Properzi, G., Forti, G., Baldi, E. Biol. Reprod. (1998) [Pubmed]
  50. Epidermal growth factor receptor and protein kinase C signaling to ERK2: spatiotemporal regulation of ERK2 by dual specificity phosphatases. Caunt, C.J., Rivers, C.A., Conway-Campbell, B.L., Norman, M.R., McArdle, C.A. J. Biol. Chem. (2008) [Pubmed]
  51. De novo expression of vascular endothelial growth factor in human pancreatic cancer: evidence for an autocrine mitogenic loop. von Marschall, Z., Cramer, T., Höcker, M., Burde, R., Plath, T., Schirner, M., Heidenreich, R., Breier, G., Riecken, E.O., Wiedenmann, B., Rosewicz, S. Gastroenterology (2000) [Pubmed]
  52. Activation of apoptosis signal-regulating kinase 1 (ASK1) by tumor necrosis factor receptor-associated factor 2 requires prior dissociation of the ASK1 inhibitor thioredoxin. Liu, H., Nishitoh, H., Ichijo, H., Kyriakis, J.M. Mol. Cell. Biol. (2000) [Pubmed]
  53. Signal transduction pathways involved in soluble fractalkine-induced monocytic cell adhesion. Cambien, B., Pomeranz, M., Schmid-Antomarchi, H., Millet, M.A., Breittmayer, V., Rossi, B., Schmid-Alliana, A. Blood (2001) [Pubmed]
  54. The activation of the c-Jun N-terminal kinase and p38 mitogen-activated protein kinase signaling pathways protects HeLa cells from apoptosis following photodynamic therapy with hypericin. Assefa, Z., Vantieghem, A., Declercq, W., Vandenabeele, P., Vandenheede, J.R., Merlevede, W., de Witte, P., Agostinis, P. J. Biol. Chem. (1999) [Pubmed]
  55. Fibronectin fragments and blocking antibodies to alpha2beta1 and alpha5beta1 integrins stimulate mitogen-activated protein kinase signaling and increase collagenase 3 (matrix metalloproteinase 13) production by human articular chondrocytes. Forsyth, C.B., Pulai, J., Loeser, R.F. Arthritis Rheum. (2002) [Pubmed]
  56. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Kato, S., Endoh, H., Masuhiro, Y., Kitamoto, T., Uchiyama, S., Sasaki, H., Masushige, S., Gotoh, Y., Nishida, E., Kawashima, H., Metzger, D., Chambon, P. Science (1995) [Pubmed]
  57. Parallel signal processing among mammalian MAPKs. Cano, E., Mahadevan, L.C. Trends Biochem. Sci. (1995) [Pubmed]
  58. Sustained activation of Ras/Raf/mitogen-activated protein kinase cascade by the tumor suppressor p53. Lee, S.W., Fang, L., Igarashi, M., Ouchi, T., Lu, K.P., Aaronson, S.A. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  59. Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis. Franklin, C.C., Srikanth, S., Kraft, A.S. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  60. Cyclooxygenase-2 inhibitor (SC-236) suppresses activator protein-1 through c-Jun NH2-terminal kinase. Wong, B.C., Jiang, X.H., Lin, M.C., Tu, S.P., Cui, J.T., Jiang, S.H., Wong, W.M., Yuen, M.F., Lam, S.K., Kung, H.F. Gastroenterology (2004) [Pubmed]
  61. Fractalkine-mediated signals regulate cell-survival and immune-modulatory responses in intestinal epithelial cells. Brand, S., Sakaguchi, T., Gu, X., Colgan, S.P., Reinecker, H.C. Gastroenterology (2002) [Pubmed]
  62. Acid exposure activates the mitogen-activated protein kinase pathways in Barrett's esophagus. Souza, R.F., Shewmake, K., Terada, L.S., Spechler, S.J. Gastroenterology (2002) [Pubmed]
  63. Optimizing immunotherapy in multiple myeloma: restoring the function of patients' monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells. Wang, S., Hong, S., Yang, J., Qian, J., Zhang, X., Shpall, E., Kwak, L.W., Yi, Q. Blood (2006) [Pubmed]
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