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Gene Review

MAPK3  -  mitogen-activated protein kinase 3

Homo sapiens

Synonyms: ERK-1, ERK1, ERT2, Extracellular signal-regulated kinase 1, HS44KDAP, ...
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Disease relevance of MAPK3


Psychiatry related information on MAPK3


High impact information on MAPK3


Chemical compound and disease context of MAPK3


Biological context of MAPK3


Anatomical context of MAPK3


Associations of MAPK3 with chemical compounds

  • Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner [28].
  • By contrast, neither an ERK inhibitor (PD098059) nor p38 inhibitors (SB203580 and SB202190) had an effect on Bcl-2 phosphorylation [29].
  • ERK1/2 activation by dual efficacy ligands was not affected by ADP-ribosylation of Galphai and could be observed in S49-cyc- cells lacking Galphas indicating that, unlike the conventional agonist isoproterenol, these drugs induce ERK1/2 activation in a Gs/i-independent manner [30].
  • This phenomenon is not unique to beta2-adrenergic ligands because SR121463B, an inverse agonist on the V2 vasopressin receptor-stimulated adenylyl cyclase, recruited beta-arrestin and stimulated ERK1/2 [30].
  • Here we show that beta2AR ligands like ICI118551 and propranolol, which are inverse agonists for Gs-stimulated adenylyl cyclase, induce partial agonist responses for the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK) 1/2 thus behaving as dual efficacy ligands [30].
  • Using PKCdeltatyrosine mutants, we found that the phosphorylation of PKCdeltaon these tyrosine residues, but not on tyrosine 155, was also essential for the activation of Erk1/2 by etoposide [31].
  • The blocking of the NK-target conjugate by EDTA or anti-CD11a or/and anti-CD2 antibody decreased the phosphorylation of Erk1/2 and NK cell cytotoxicity [32].

Physical interactions of MAPK3

  • PLD2 co-immunoprecipitated with ERK1/2 and became phosphorylated on MAP kinase consensus sites in fMLP-stimulated cells [33].
  • We showed that ERK1 binds lyn only in IL-2 stimulated PMN, but not in unstimulated PMN [34].
  • A putative p53 binding site at -360 bp functioned as a major repressor of ERK1 promoter activity even in the absence of exogenous p53 expression [35].
  • Pair-wise binding studies using recombinant proteins demonstrated that ERK1 directly interacts with the C-terminal tail of occludin [36].
  • HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway [37].

Enzymatic interactions of MAPK3

  • We find that the JNKs are the predominant Elk-1 activation domain kinases in extracts of UV-irradiated cells and that immunopurified JNK1/2 phosphorylate Elk-1 on the same major sites recognized by ERK1/2, that potentiate its transcriptional activity [38].
  • These results indicate a ligand-stimulated negative regulatory feedback loop in which activated ERK1/2 phosphorylates FRS2 on serine/threonine residues thereby down-regulating its tyrosine phosphorylation [39].
  • Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action [40].
  • HVH1 selectively dephosphorylated threonine and tyrosine residues but not serine residues of the activated ERK1 [41].
  • Treatment of these cells with the MAPK kinase inhibitor PD98059 prior to infection blocked the increase in phosphorylated ERK1/2 seen with infection [42].

Co-localisations of MAPK3


Regulatory relationships of MAPK3

  • Consistent with this hypothesis, we find that inactivating mutations in the RSK1 kinase domains disrupted the mitogen-regulated dissociation of ERK1/2 in vivo [44].
  • PKCzeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines [45].
  • Treatment with anti-VEGF and anti-Flt1 antibodies inhibited ERK1/2 activation, down-regulated bcl-2, and reversed the hypoxia-mediated drug resistance to etoposide [14].
  • The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells [46].
  • EGCG inhibits epidermal growth factor-dependent activation of EGFR, and EGFR-dependent activation of the mitogen-activated protein kinases ERK1/2 [47].
  • ERK activation also promotes upregulated expression of EGFR ligands, promoting an autocrine growth loop critical for tumor growth [48].

Other interactions of MAPK3

  • Cell lines dependent on the activation of Tyr kinase mitogen receptor targets of the resorcylic acid lactones were unusually sensitive toward hypothemycin and showed the expected inhibition of kinase phosphorylation due to inhibition of the mitogen receptors and/or MEK1/2 and ERK1/2 [49].
  • Incubation of HUVEC with PD98059, which inhibits flow-mediated ERK1/2 activation, prevented flow from inhibiting cytokine activation of JNK [50].
  • The role of beta-arrestin was further confirmed by showing that transfection of beta-arrestin 2 in these knockout cells restored ICI118551 promoted ERK1/2 activation [30].
  • In contrast to EGF stimulation, VEGF stimulation of ERK1/2 phosphorylation was unaffected by dominant-negative Ras-N17 [51].
  • In this report we show that RSK1 and ERK1/2 form a complex in quiescent HEK293 cells that transiently dissociates upon mitogen stimulation [44].

Analytical, diagnostic and therapeutic context of MAPK3


  1. Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms. Yang, J., Price, M.A., Neudauer, C.L., Wilson, C., Ferrone, S., Xia, H., Iida, J., Simpson, M.A., McCarthy, J.B. J. Cell Biol. (2004) [Pubmed]
  2. 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]
  3. Cell-cycle-dependent activation of mitogen-activated protein kinase kinase (MEK-1/2) in myeloid leukemia cell lines and induction of growth inhibition and apoptosis by inhibitors of RAS signaling. Morgan, M.A., Dolp, O., Reuter, C.W. Blood (2001) [Pubmed]
  4. Decreased phosphorylation of protein kinase B and extracellular signal-regulated kinase in neutrophils from patients with myelodysplasia. Fuhler, G.M., Drayer, A.L., Vellenga, E. Blood (2003) [Pubmed]
  5. Death Receptor-3, a New E-Selectin Counter-Receptor that Confers Migration and Survival Advantages to Colon Carcinoma Cells by Triggering p38 and ERK MAPK Activation. Gout, S., Morin, C., Houle, F., Huot, J. Cancer Res. (2006) [Pubmed]
  6. Distribution, levels and phosphorylation of Raf-1 in Alzheimer's disease. Mei, M., Su, B., Harrison, K., Chao, M., Siedlak, S.L., Previll, L.A., Jackson, L., Cai, D.X., Zhu, X. J. Neurochem. (2006) [Pubmed]
  7. Cross talk between nitric oxide and ERK1/2 signaling pathway in the spinal cord mediates naloxone-precipitated withdrawal in morphine-dependent rats. Cao, J.L., Liu, H.L., Wang, J.K., Zeng, Y.M. Neuropharmacology (2006) [Pubmed]
  8. Early Activation of Extracellular Signal-Regulated Kinase Signaling Pathway in the Hippocampus is Required for Short-Term Memory Formation of a Fear-Motivated Learning. Igaz, L.M., Winograd, M., Cammarota, M., Izquierdo, L.A., Alonso, M., Izquierdo, I., Medina, J.H. Cell. Mol. Neurobiol. (2006) [Pubmed]
  9. An internally controlled peripheral biomarker for Alzheimer's disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin. Khan, T.K., Alkon, D.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  10. Reduced activation and expression of ERK1/2 MAP kinase in the post-mortem brain of depressed suicide subjects. Dwivedi, Y., Rizavi, H.S., Roberts, R.C., Conley, R.C., Tamminga, C.A., Pandey, G.N. J. Neurochem. (2001) [Pubmed]
  11. 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]
  12. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Ma, L., Chen, Z., Erdjument-Bromage, H., Tempst, P., Pandolfi, P.P. Cell (2005) [Pubmed]
  13. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Wang, H.G., Rapp, U.R., Reed, J.C. Cell (1996) [Pubmed]
  14. A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Das, B., Yeger, H., Tsuchida, R., Torkin, R., Gee, M.F., Thorner, P.S., Shibuya, M., Malkin, D., Baruchel, S. Cancer Res. (2005) [Pubmed]
  15. 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]
  16. Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells. Abiru, S., Nakao, K., Ichikawa, T., Migita, K., Shigeno, M., Sakamoto, M., Ishikawa, H., Hamasaki, K., Nakata, K., Eguchi, K. Hepatology (2002) [Pubmed]
  17. Mechanism of 17-beta-estradiol-induced Erk1/2 activation in breast cancer cells. A role for HER2 AND PKC-delta. Keshamouni, V.G., Mattingly, R.R., Reddy, K.B. J. Biol. Chem. (2002) [Pubmed]
  18. Integrin alpha2 and extracellular signal-regulated kinase are functionally linked in highly malignant autocrine transforming growth factor-alpha-driven colon cancer cells. Sawhney, R.S., Sharma, B., Humphrey, L.E., Brattain, M.G. J. Biol. Chem. (2003) [Pubmed]
  19. Exogenous nitric oxide stimulates cell proliferation via activation of a mitogen-activated protein kinase pathway in ovine fetoplacental artery endothelial cells. Zheng, J., Wen, Y., Austin, J.L., Chen, D.B. Biol. Reprod. (2006) [Pubmed]
  20. Characterization of human fetal osteoblasts by microarray analysis following stimulation with 58S bioactive gel-glass ionic dissolution products. Christodoulou, I., Buttery, L.D., Tai, G., Hench, L.L., Polak, J.M. Journal of biomedical materials research. Part B, Applied biomaterials. (2006) [Pubmed]
  21. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Lu, Z., Xu, S., Joazeiro, C., Cobb, M.H., Hunter, T. Mol. Cell (2002) [Pubmed]
  22. A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. Dang, P.M., Stensballe, A., Boussetta, T., Raad, H., Dewas, C., Kroviarski, Y., Hayem, G., Jensen, O.N., Gougerot-Pocidalo, M.A., El-Benna, J. J. Clin. Invest. (2006) [Pubmed]
  23. Clostridium difficile toxin B activates the EGF receptor and the ERK/MAP kinase pathway in human colonocytes. Na, X., Zhao, D., Koon, H.W., Kim, H., Husmark, J., Moyer, M.P., Pothoulakis, C., LaMont, J.T. Gastroenterology (2005) [Pubmed]
  24. 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]
  25. Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Knall, C., Worthen, G.S., Johnson, G.L. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  26. Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. Esnault, S., Malter, J.S. Blood (2002) [Pubmed]
  27. Protein kinase Czeta mediated Raf-1/extracellular-regulated kinase activation by daunorubicin. Mas, V.M., Hernandez, H., Plo, I., Bezombes, C., Maestre, N., Quillet-Mary, A., Filomenko, R., Demur, C., Jaffrézou, J.P., Laurent, G. Blood (2003) [Pubmed]
  28. Myosin light chain kinase functions downstream of Ras/ERK to promote migration of urokinase-type plasminogen activator-stimulated cells in an integrin-selective manner. Nguyen, D.H., Catling, A.D., Webb, D.J., Sankovic, M., Walker, L.A., Somlyo, A.V., Weber, M.J., Gonias, S.L. J. Cell Biol. (1999) [Pubmed]
  29. Deletion of the loop region of Bcl-2 completely blocks paclitaxel-induced apoptosis. Srivastava, R.K., Mi, Q.S., Hardwick, J.M., Longo, D.L. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  30. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Azzi, M., Charest, P.G., Angers, S., Rousseau, G., Kohout, T., Bouvier, M., Piñeyro, G. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  31. Phosphorylation of protein kinase Cdelta on distinct tyrosine residues induces sustained activation of Erk1/2 via down-regulation of MKP-1: role in the apoptotic effect of etoposide. Lomonaco, S.L., Kahana, S., Blass, M., Brody, Y., Okhrimenko, H., Xiang, C., Finniss, S., Blumberg, P.M., Lee, H.K., Brodie, C. J. Biol. Chem. (2008) [Pubmed]
  32. LFA-1 and CD2 synergize for the Erk1/2 activation in the Natural Killer (NK) cell immunological synapse. Zheng, X., Wang, Y., Wei, H., Sun, R., Tian, Z. J. Biol. Chem. (2009) [Pubmed]
  33. A role of p44/42 mitogen-activated protein kinases in formyl-peptide receptor-mediated phospholipase D activity and oxidant production. Paruch, S., El-Benna, J., Djerdjouri, B., Marullo, S., Périanin, A. FASEB J. (2006) [Pubmed]
  34. IL-2 induces the association of IL-2Rbeta, lyn, and MAP kinase ERK-1 in human neutrophils. Wei, S., Liu, J.H., Epling-Burnette, P.K., Jiang, K., Zhong, B., Elkabani, M.E., Pearson, E.W., Djeu, J.Y. Immunobiology (2000) [Pubmed]
  35. Regulation of ERK1 gene expression by coactivator proteins. Chu, B.Y., Tran, K., Ku, T.K., Crowe, D.L. Biochem. J. (2005) [Pubmed]
  36. MAPK interacts with occludin and mediates EGF-induced prevention of tight junction disruption by hydrogen peroxide. Basuroy, S., Seth, A., Elias, B., Naren, A.P., Rao, R. Biochem. J. (2006) [Pubmed]
  37. HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway. Serù, R., Mondola, P., Damiano, S., Svegliati, S., Agnese, S., Avvedimento, E.V., Santillo, M. J. Neurochem. (2004) [Pubmed]
  38. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. Cavigelli, M., Dolfi, F., Claret, F.X., Karin, M. EMBO J. (1995) [Pubmed]
  39. EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2. Wu, Y., Chen, Z., Ullrich, A. Biol. Chem. (2003) [Pubmed]
  40. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. Mannella, P., Brinton, R.D. J. Neurosci. (2006) [Pubmed]
  41. Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase. Zheng, C.F., Guan, K.L. J. Biol. Chem. (1993) [Pubmed]
  42. Trypanosoma cruzi infection activates extracellular signal-regulated kinase in cultured endothelial and smooth muscle cells. Mukherjee, S., Huang, H., Petkova, S.B., Albanese, C., Pestell, R.G., Braunstein, V.L., Christ, G.J., Wittner, M., Lisanti, M.P., Berman, J.W., Weiss, L.M., Tanowitz, H.B. Infect. Immun. (2004) [Pubmed]
  43. Decreased expression of caveolin-1 and altered regulation of mitogen-activated protein kinase in cultured bovine parathyroid cells and human parathyroid adenomas. Kifor, O., Kifor, I., Moore, F.D., Butters, R.R., Cantor, T., Gao, P., Brown, E.M. J. Clin. Endocrinol. Metab. (2003) [Pubmed]
  44. Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. Roux, P.P., Richards, S.A., Blenis, J. Mol. Cell. Biol. (2003) [Pubmed]
  45. Protein kinase C zeta mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase. Cohen, E.E., Lingen, M.W., Zhu, B., Zhu, H., Straza, M.W., Pierce, C., Martin, L.E., Rosner, M.R. Cancer Res. (2006) [Pubmed]
  46. The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. Dang, A., Frost, J.A., Cobb, M.H. J. Biol. Chem. (1998) [Pubmed]
  47. Epigallocatechin-3-gallate inhibits epidermal growth factor receptor signaling pathway. Evidence for direct inhibition of ERK1/2 and AKT kinases. Sah, J.F., Balasubramanian, S., Eckert, R.L., Rorke, E.A. J. Biol. Chem. (2004) [Pubmed]
  48. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Roberts, P.J., Der, C.J. Oncogene (2007) [Pubmed]
  49. Targeted covalent inactivation of protein kinases by resorcylic acid lactone polyketides. Schirmer, A., Kennedy, J., Murli, S., Reid, R., Santi, D.V. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  50. Fluid shear stress inhibits TNF-alpha activation of JNK but not ERK1/2 or p38 in human umbilical vein endothelial cells: Inhibitory crosstalk among MAPK family members. Surapisitchat, J., Hoefen, R.J., Pi, X., Yoshizumi, M., Yan, C., Berk, B.C. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  51. Sphingosine kinase mediates vascular endothelial growth factor-induced activation of ras and mitogen-activated protein kinases. Shu, X., Wu, W., Mosteller, R.D., Broek, D. Mol. Cell. Biol. (2002) [Pubmed]
  52. 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]
  53. Fc receptor gamma-chain activation via hOSCAR induces survival and maturation of dendritic cells and modulates Toll-like receptor responses. Merck, E., de Saint-Vis, B., Scuiller, M., Gaillard, C., Caux, C., Trinchieri, G., Bates, E.E. Blood (2005) [Pubmed]
  54. Loss of SMEK, a novel, conserved protein, suppresses MEK1 null cell polarity, chemotaxis, and gene expression defects. Mendoza, M.C., Du, F., Iranfar, N., Tang, N., Ma, H., Loomis, W.F., Firtel, R.A. Mol. Cell. Biol. (2005) [Pubmed]
  55. Sustained activation of the extracellular signal-regulated kinase pathway protects cells from photofrin-mediated photodynamic therapy. Tong, Z., Singh, G., Rainbow, A.J. Cancer Res. (2002) [Pubmed]
  56. Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes. Shakibaei, M., Schulze-Tanzil, G., de Souza, P., John, T., Rahmanzadeh, M., Rahmanzadeh, R., Merker, H.J. J. Biol. Chem. (2001) [Pubmed]
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