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Gene Review

Mapk3  -  mitogen-activated protein kinase 3

Mus musculus

Synonyms: ERK-1, ERT2, Erk-1, Erk1, Ert2, ...
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Disease relevance of Mapk3

  • Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling [1].
  • We have developed a gene expression-based imaging system that detects and quantifies MAPK activity in prostate cancer tumors implanted into severe combined immunodeficient mice [2].
  • Targeting Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase in the Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases [3].
  • Angiogenesis and signaling through the RAF/mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK cascade have been reported to play important roles in the development of hepatocellular carcinomas (HCC) [4].
  • Collectively, these data indicate that calcineurin hypertrophic signaling is interconnected with PKCalpha, theta, and JNK in the heart, while PKCepsilon, beta, lambda, p38, and ERK1/2 are not involved in calcineurin-mediated hypertrophy [5].
  • ERK1/2 signaling is not required for mediating physiologic or pathologic cardiac hypertrophy in vivo, although it does play a protective role in response to pathologic stimuli [6].

Psychiatry related information on Mapk3


High impact information on Mapk3

  • Early tyrosine phosphorylation, MAPK and AP-1 activation, and Ca2+ signaling were normal in mutant lymphocytes, but antigen receptor-induced NF-kappaB activation was absent [9].
  • Activation of the Ras/MAPK signaling cascade is essential for growth factor-induced cell proliferation and differentiation [10].
  • FRS2 functions as a lipid-anchored docking protein that targets signaling molecules to the plasma membrane in response to FGF stimulation to link receptor activation with the MAPK and other signaling pathways essential for cell growth and differentiation [10].
  • A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway [10].
  • PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways) [11].

Chemical compound and disease context of Mapk3


Biological context of Mapk3


Anatomical context of Mapk3


Associations of Mapk3 with chemical compounds


Physical interactions of Mapk3

  • The induction of AP-1 DNA binding activity by PG was also inhibited by these MAPK inhibitors [28].
  • Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma [29].
  • Blocking ERK1/2 activation with the upstream inhibitor U0126 (10 microm) enhanced H(2)O(2)-induced (100-300 microm range) neurotoxicity and inhibited H(2)O(2)-mediated phosphorylation of the cyclic AMP regulatory binding protein (CREB), suggesting that ERK1/2 signals to survival under these conditions [30].
  • This study investigated the participation of MAPK in the resumption of meiosis [germinal vesicle breakdown (GVB)] in oocytes and cumulus expansion using oocyte-cumulus cell complexes (OCC) from Mos-null mice (Mos(tm1Ev)/Mos(tm1Ev), hereafter Mos(-/-)) [31].
  • 6. These findings provide new evidence for a complex network of interacting pathways involving CDK/MAPK that control apoptosis downstream of KA receptor activation in excitotoxic neuronal cell death [32].

Enzymatic interactions of Mapk3


Co-localisations of Mapk3

  • Immunofluorescent antibody staining of the MBs that formed showed that MAPK p38 was colocalized with ubiquitin and p62 in the MBs [37].

Regulatory relationships of Mapk3

  • The results thus demonstrate a necessary role for PKC and p42 MAPK activation in 12-O-tetradecanoylphorbol-13-acetate induced mitogenesis and provide evidence for multiple PKC controls acting on this MAPK cascade [38].
  • MEK is a dual-specificity kinase that activates the extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinase upon agonist binding to receptors [39].
  • MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells [40].
  • Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkappaBalpha kinase-dependent nuclear factor kappaB-mediated promatrix metalloproteinase-9 activation [41].
  • Moreover, the Epo-induced activation of ERK1 and ERK2 was augmented and prolonged in cells inducibly overexpressing CrkL [42].

Other interactions of Mapk3


Analytical, diagnostic and therapeutic context of Mapk3

  • Western blots of tumor extracts showed that the elevated imaging signal in CWR22 xenografts correlated with elevated levels of phosphorylated extracellular signal-regulated kinase 1/2 but not p38 or c-Jun NH(2)-terminal kinase [2].
  • We measured MAPK activity in two well-characterized xenograft models, CWR22 and LAPC9 [2].
  • We report that ligation of microglial CD40 triggers activation of p44/42 mitogen-activated protein kinase (MAPK) [47].
  • IL-6 mRNA and protein were measured using real-time PCR and ELISA, and MAPK pathway activation was studied [48].
  • In summary, post-ischemic JNK and p38 (but not ERK1/2) activation was markedly reduced in a model of kidney ischemic preconditioning that was established in the mouse [49].


  1. Gene 33/RALT is induced by hypoxia in cardiomyocytes, where it promotes cell death by suppressing phosphatidylinositol 3-kinase and extracellular signal-regulated kinase survival signaling. Xu, D., Patten, R.D., Force, T., Kyriakis, J.M. Mol. Cell. Biol. (2006) [Pubmed]
  2. Imaging mitogen-activated protein kinase function in xenograft models of prostate cancer. Ilagan, R., Pottratz, J., Le, K., Zhang, L., Wong, S.G., Ayala, R., Iyer, M., Wu, L., Gambhir, S.S., Carey, M. Cancer Res. (2006) [Pubmed]
  3. Targeting Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase in the Mutant (V600E) B-Raf Signaling Cascade Effectively Inhibits Melanoma Lung Metastases. Sharma, A., Tran, M.A., Liang, S., Sharma, A.K., Amin, S., Smith, C.D., Dong, C., Robertson, G.P. Cancer Res. (2006) [Pubmed]
  4. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Liu, L., Cao, Y., Chen, C., Zhang, X., McNabola, A., Wilkie, D., Wilhelm, S., Lynch, M., Carter, C. Cancer Res. (2006) [Pubmed]
  5. Calcineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart. Cross-talk between cardiac hypertrophic signaling pathways. De Windt, L.J., Lim, H.W., Haq, S., Force, T., Molkentin, J.D. J. Biol. Chem. (2000) [Pubmed]
  6. Genetic inhibition of cardiac ERK1/2 promotes stress-induced apoptosis and heart failure but has no effect on hypertrophy in vivo. Purcell, N.H., Wilkins, B.J., York, A., Saba-El-Leil, M.K., Meloche, S., Robbins, J., Molkentin, J.D. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. Valjent, E., Corvol, J.C., Pages, C., Besson, M.J., Maldonado, R., Caboche, J. J. Neurosci. (2000) [Pubmed]
  8. Paradoxical striatal cellular signaling responses to psychostimulants in hyperactive mice. Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., Caron, M.G. J. Biol. Chem. (2006) [Pubmed]
  9. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Ruland, J., Duncan, G.S., Elia, A., del Barco Barrantes, I., Nguyen, L., Plyte, S., Millar, D.G., Bouchard, D., Wakeham, A., Ohashi, P.S., Mak, T.W. Cell (2001) [Pubmed]
  10. A lipid-anchored Grb2-binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Kouhara, H., Hadari, Y.R., Spivak-Kroizman, T., Schilling, J., Bar-Sagi, D., Lax, I., Schlessinger, J. Cell (1997) [Pubmed]
  11. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Takimoto, E., Champion, H.C., Li, M., Belardi, D., Ren, S., Rodriguez, E.R., Bedja, D., Gabrielson, K.L., Wang, Y., Kass, D.A. Nat. Med. (2005) [Pubmed]
  12. Yersinia enterocolitica promotes deactivation of macrophage mitogen-activated protein kinases extracellular signal-regulated kinase-1/2, p38, and c-Jun NH2-terminal kinase. Correlation with its inhibitory effect on tumor necrosis factor-alpha production. Ruckdeschel, K., Machold, J., Roggenkamp, A., Schubert, S., Pierre, J., Zumbihl, R., Liautard, J.P., Heesemann, J., Rouot, B. J. Biol. Chem. (1997) [Pubmed]
  13. Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Westermann, D., Rutschow, S., Van Linthout, S., Linderer, A., Bücker-Gärtner, C., Sobirey, M., Riad, A., Pauschinger, M., Schultheiss, H.P., Tschöpe, C. Diabetologia (2006) [Pubmed]
  14. Differential expression and/or activation of P38MAPK, erk1/2, and jnk during the initiation and progression of prostate cancer. Uzgare, A.R., Kaplan, P.J., Greenberg, N.M. Prostate (2003) [Pubmed]
  15. Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways. Ward, Y., Wang, W., Woodhouse, E., Linnoila, I., Liotta, L., Kelly, K. Mol. Cell. Biol. (2001) [Pubmed]
  16. Protective effects of sesamin and sesamolin on murine BV-2 microglia cell line under hypoxia. Hou, R.C., Wu, C.C., Yang, C.H., Jeng, K.C. Neurosci. Lett. (2004) [Pubmed]
  17. The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades: MSK1 as a potential histone H3/HMG-14 kinase. Thomson, S., Clayton, A.L., Hazzalin, C.A., Rose, S., Barratt, M.J., Mahadevan, L.C. EMBO J. (1999) [Pubmed]
  18. Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Murakami, S., Kan, M., McKeehan, W.L., de Crombrugghe, B. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  19. Confluence of vascular endothelial cells induces cell cycle exit by inhibiting p42/p44 mitogen-activated protein kinase activity. Viñals, F., Pouysségur, J. Mol. Cell. Biol. (1999) [Pubmed]
  20. Transactivation of Fra-1 and consequent activation of AP-1 occur extracellular signal-regulated kinase dependently. Young, M.R., Nair, R., Bucheimer, N., Tulsian, P., Brown, N., Chapp, C., Hsu, T.C., Colburn, N.H. Mol. Cell. Biol. (2002) [Pubmed]
  21. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Pagès, G., Guérin, S., Grall, D., Bonino, F., Smith, A., Anjuere, F., Auberger, P., Pouysségur, J. Science (1999) [Pubmed]
  22. Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Ishibe, S., Joly, D., Liu, Z.X., Cantley, L.G. Mol. Cell (2004) [Pubmed]
  23. Different protein tyrosine kinases are required for B cell antigen receptor-mediated activation of extracellular signal-regulated kinase, c-Jun NH2-terminal kinase 1, and p38 mitogen-activated protein kinase. Jiang, A., Craxton, A., Kurosaki, T., Clark, E.A. J. Exp. Med. (1998) [Pubmed]
  24. Cell type-specific activation of mitogen-activated protein kinases by CpG-DNA controls interleukin-12 release from antigen-presenting cells. Häcker, H., Mischak, H., Häcker, G., Eser, S., Prenzel, N., Ullrich, A., Wagner, H. EMBO J. (1999) [Pubmed]
  25. Src homology 2 domain-containing inositol-5-phosphatase 1 (SHIP1) negatively regulates TLR4-mediated LPS response primarily through a phosphatase activity- and PI-3K-independent mechanism. An, H., Xu, H., Zhang, M., Zhou, J., Feng, T., Qian, C., Qi, R., Cao, X. Blood (2005) [Pubmed]
  26. Extracellular signal-regulated kinase 1 interacts with and phosphorylates CdGAP at an important regulatory site. Tcherkezian, J., Danek, E.I., Jenna, S., Triki, I., Lamarche-Vane, N. Mol. Cell. Biol. (2005) [Pubmed]
  27. Bile acid regulation of C/EBPbeta, CREB, and c-Jun function, via the extracellular signal-regulated kinase and c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Qiao, L., Han, S.I., Fang, Y., Park, J.S., Gupta, S., Gilfor, D., Amorino, G., Valerie, K., Sealy, L., Engelhardt, J.F., Grant, S., Hylemon, P.B., Dent, P. Mol. Cell. Biol. (2003) [Pubmed]
  28. Activation of mitogen-activated protein kinases and AP-1 by polysaccharide isolated from the radix of Platycodon grandiflorum in RAW 264.7 cells. Yoon, Y.D., Kang, J.S., Han, S.B., Park, S.K., Lee, H.S., Kang, J.S., Kim, H.M. Int. Immunopharmacol. (2004) [Pubmed]
  29. Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma. Halupa, A., Chohan, M., Stickle, N.H., Beattie, B.K., Miller, B.A., Barber, D.L. Exp. Cell Res. (2005) [Pubmed]
  30. Hydrogen peroxide-mediated phosphorylation of ERK1/2, Akt/PKB and JNK in cortical neurones: dependence on Ca(2+) and PI3-kinase. Crossthwaite, A.J., Hasan, S., Williams, R.J. J. Neurochem. (2002) [Pubmed]
  31. Mitogen-activated protein kinase activity in cumulus cells is essential for gonadotropin-induced oocyte meiotic resumption and cumulus expansion in the mouse. Su, Y.Q., Wigglesworth, K., Pendola, F.L., O'Brien, M.J., Eppig, J.J. Endocrinology (2002) [Pubmed]
  32. Kainate receptor-mediated apoptosis in primary cultures of cerebellar granule cells is attenuated by mitogen-activated protein and cyclin-dependent kinase inhibitors. Giardina, S.F., Beart, P.M. Br. J. Pharmacol. (2002) [Pubmed]
  33. Inhibition of ligand-independent ERK1/2 activity in kidney proximal tubular cells deprived of soluble survival factors up-regulates Akt and prevents apoptosis. Sinha, D., Bannergee, S., Schwartz, J.H., Lieberthal, W., Levine, J.S. J. Biol. Chem. (2004) [Pubmed]
  34. Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Pouysségur, J., Lenormand, P. Eur. J. Biochem. (2003) [Pubmed]
  35. MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Brott, B.K., Alessandrini, A., Largaespada, D.A., Copeland, N.G., Jenkins, N.A., Crews, C.M., Erikson, R.L. Cell Growth Differ. (1993) [Pubmed]
  36. Age-related alteration in hepatic acyl-CoA: cholesterol acyltransferase and its relation to LDL receptor and MAPK. Bose, C., Bhuvaneswaran, C., Udupa, K.B. Mech. Ageing Dev. (2005) [Pubmed]
  37. Mallory body (cytokeratin aggresomes) formation is prevented in vitro by p38 inhibitor. Nan, L., Dedes, J., French, B.A., Bardag-Gorce, F., Li, J., Wu, Y., French, S.W. Exp. Mol. Pathol. (2006) [Pubmed]
  38. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Schönwasser, D.C., Marais, R.M., Marshall, C.J., Parker, P.J. Mol. Cell. Biol. (1998) [Pubmed]
  39. Mek2 is dispensable for mouse growth and development. Bélanger, L.F., Roy, S., Tremblay, M., Brott, B., Steff, A.M., Mourad, W., Hugo, P., Erikson, R., Charron, J. Mol. Cell. Biol. (2003) [Pubmed]
  40. MAPK mediation of hypertonicity-stimulated cyclooxygenase-2 expression in renal medullary collecting duct cells. Yang, T., Huang, Y., Heasley, L.E., Berl, T., Schnermann, J.B., Briggs, J.P. J. Biol. Chem. (2000) [Pubmed]
  41. Nuclear factor-inducing kinase plays a crucial role in osteopontin-induced MAPK/IkappaBalpha kinase-dependent nuclear factor kappaB-mediated promatrix metalloproteinase-9 activation. Rangaswami, H., Bulbule, A., Kundu, G.C. J. Biol. Chem. (2004) [Pubmed]
  42. CrkL mediates Ras-dependent activation of the Raf/ERK pathway through the guanine nucleotide exchange factor C3G in hematopoietic cells stimulated with erythropoietin or interleukin-3. Nosaka, Y., Arai, A., Miyasaka, N., Miura, O. J. Biol. Chem. (1999) [Pubmed]
  43. Survival function of ERK1/2 as IL-3-activated, staurosporine-resistant Bcl2 kinases. Deng, X., Ruvolo, P., Carr, B., May, W.S. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  44. Kinase suppressor of ras is necessary for tumor necrosis factor alpha activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in intestinal epithelial cells. Yan, F., Polk, D.B. Cancer Res. (2001) [Pubmed]
  45. Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development. Li, C., Scott, D.A., Hatch, E., Tian, X., Mansour, S.L. Development (2007) [Pubmed]
  46. Overexpression of protein kinase C isoforms protects RAW 264.7 macrophages from nitric oxide-induced apoptosis: involvement of c-Jun N-terminal kinase/stress-activated protein kinase, p38 kinase, and CPP-32 protease pathways. Jun, C.D., Oh, C.D., Kwak, H.J., Pae, H.O., Yoo, J.C., Choi, B.M., Chun, J.S., Park, R.K., Chung, H.T. J. Immunol. (1999) [Pubmed]
  47. Ligation of microglial CD40 results in p44/42 mitogen-activated protein kinase-dependent TNF-alpha production that is opposed by TGF-beta 1 and IL-10. Tan, J., Town, T., Saxe, M., Paris, D., Wu, Y., Mullan, M. J. Immunol. (1999) [Pubmed]
  48. Annexin 1 Negatively Regulates IL-6 Expression via Effects on p38 MAPK and MAPK Phosphatase-1. Yang, Y.H., Toh, M.L., Clyne, C.D., Leech, M., Aeberli, D., Xue, J., Dacumos, A., Sharma, L., Morand, E.F. J. Immunol. (2006) [Pubmed]
  49. Prevention of kidney ischemia/reperfusion-induced functional injury and JNK, p38, and MAPK kinase activation by remote ischemic pretreatment. Park, K.M., Chen, A., Bonventre, J.V. J. Biol. Chem. (2001) [Pubmed]
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