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Gene Review

Mapk3  -  mitogen activated protein kinase 3

Rattus norvegicus

Synonyms: ERK-1, ERK1, ERT2, Erk-1, Erk1, ...
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Disease relevance of Mapk3


Psychiatry related information on Mapk3


High impact information on Mapk3

  • Interestingly, we find a Golgi-associated ERK, which we propose as the likely target for MEK1 in Golgi fragmentation [11].
  • Experiments with two subclones of C6 glioma cells in culture showed that cannabinoids signal apoptosis by a pathway involving cannabinoid receptors, sustained ceramide accumulation and Raf1/extracellular signal-regulated kinase activation [12].
  • The G betagamma-responsive ERK activation induced by H2O2 is independent of ligands binding to Gi-coupled receptors, but requires phosphatidylinositol-3-kinase and Src activation [13].
  • Previous studies showed that tyrosine kinases and small G proteins are involved in the activation of ERK by ROS; however, the initial target protein of ROS that leads to ERK activation remains unknown [13].
  • We conclude that G alpha(i) and G alpha(o) are critical targets of oxidative stress for activation of ERK [13].

Chemical compound and disease context of Mapk3


Biological context of Mapk3


Anatomical context of Mapk3

  • METHODS: We studied EGF-R levels, EGF-R phosphorylation levels, and ERK1 and ERK2 activity in normal and ulcerated rat gastric mucosa [1].
  • RESULTS: During the initial stages of healing (3 and 7 days), ulcerated mucosa showed significant increase (vs. controls) in protein tyrosine kinase activity, EGF-R levels (510% and 550%), EGF-R phosphorylation levels, ERK1 activity (430% and 880%), and ERK2 activity (550% and 990%) [1].
  • First, a biphasic MEK/ERK activation was evidenced in G(1) phase of hepatocytes from regenerating liver but not from sham-operated control animals [21].
  • Previously, we have observed that overexpression of either ERK1, MEK1, or a constitutively active truncated form of c-Raf-1 (BXB) is insufficient to activate AP-1 in REF52 fibroblasts [22].
  • To clarify the mechanisms responsible for the anchorage-dependent growth of astrocytes, the relationships between cell adhesion and ERK activation were investigated [23].

Associations of Mapk3 with chemical compounds

  • Tyrphostin A46 treatment significantly inhibited ulcer healing and reduced EGF-R levels, EGF-R phosphorylation, and ERK1 and ERK2 activity [1].
  • Specific inhibition of EGF-R function by either a dominant-negative EGF-R mutant or selective tyrphostin AG1478 completely abolished Ang II-induced ERK activation [24].
  • Interestingly, KN62, which interferes with calcium-calmodulin kinase (CaM-K) activity, leads to a reduction of glutamate-induced ERK activation and of CREB phosphorylation [25].
  • In this study, we found that endotoxin causes activation of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated protein kinase [ERK] 1 and 2, p38, and c-Jun NH2-terminal kinase [JNK]) and nuclear factor kappaB (NF-kappaB) and production of H(2)O(2) in culture-activated HSCs [26].
  • Similar to menadione, the polyunsaturated fatty acid (PUFA) arachidonic acid (AA) induced an increased activation of ERK1/2 in hepatocytes that overexpressed CYP2E1 [3].

Physical interactions of Mapk3

  • We observed that the majority of ERK1/2 activity induced by glucose remains in the cytoplasm and physically interacts with synapsin I, allowing phosphorylation of the substrate [27].
  • Corticotropin-releasing factor type 1 and type 2alpha receptors regulate phosphorylation of calcium/cyclic adenosine 3',5'-monophosphate response element-binding protein and activation of p42/p44 mitogen-activated protein kinase [28].
  • Recently, it was demonstrated that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958 produces a stronger activation of striatal extracellular signal-regulated kinase (ERK) 1/2 and cyclic AMP response element-binding protein (CREB) in FR relative to ad libitum (AL) fed rats [29].
  • We may conclude that GM1 and GM2 stimulate ERK1/2 via a pertussis toxin-sensitive G(i)-coupled receptor through a Raf-1 kinase-independent pathway [30].
  • PAK1 and ERK1/2 co-immunoprecipitated from rat aortic smooth muscle cells (SMC) plated on fibronectin, and the two proteins co-localized in membrane ruffles and adhesion complexes following PDGF-BB or sphingosine 1-phosphate treatment, respectively [31].

Enzymatic interactions of Mapk3

  • EGFR and phosphorylated ERK significantly declined from 5 to 20 weeks (P<0.05) [32].
  • By comparison, IGF-I increased the levels of the phosphorylated forms of ERK-1 and -2, and Akt/PKB [33].
  • Moreover, whereas Cpd 5 induced a striking translocation of phosphorylated ERK from cytosol to the nucleus, no significant nuclear translocation occurred after stimulation with EGF [34].
  • ET-1 caused interaction of caveolin-1 with phosphorylated ERK1/2 identified by coimmunoprecipitation [35].
  • The p44/42 MAP kinases were phosphorylated in cultured aortic smooth muscle cells and in physiologically contracted aortic vessels stimulated with angiotensin II and endothelin-1 for 5 min [36].

Regulatory relationships of Mapk3


Other interactions of Mapk3


Analytical, diagnostic and therapeutic context of Mapk3

  • Third, a correlation between the mid-late G(1) MEK/ERK activation in hepatocytes in vivo after partial hepatectomy and the mitogen-independent proliferation capacity of these cells in vitro was established [21].
  • Western blot analysis using anti-phospho-ERK antibodies along with an ERK kinase assay using the phosphorylated heat- and acid-stable protein (PHAS-1) substrate demonstrated that ERK activation peaked within 15 min after ONOO(-) treatment and was maximally activated with 100 micrometer ONOO(-) [45].
  • Electron microscopic immunohistochemistry revealed that ERK was mainly localized in the cytoplasm of clear zones in control osteoclasts, but apoptotic osteoclasts also showed immunoreactivity in clear zone-like structures in contact with osteoblast-lineage cells [46].
  • MATERIALS AND METHODS: Using a rat calvarial organ culture system, the inhibition of ERK phosphorylation by PD98059, a MAPK/ERK kinase 1 (MEK1) inhibitor, was assayed by immunoblotting [46].
  • The cellular localization of ERK was also determined by immunoelectron microscopy [46].


  1. Induction of mitogen-activated protein kinase signal transduction pathway during gastric ulcer healing in rats. Pai, R., Ohta, M., Itani, R.M., Sarfeh, I.J., Tarnawski, A.S. Gastroenterology (1998) [Pubmed]
  2. 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]
  3. CYP2E1 overexpression alters hepatocyte death from menadione and fatty acids by activation of ERK1/2 signaling. Schattenberg, J.M., Wang, Y., Rigoli, R.M., Koop, D.R., Czaja, M.J. Hepatology (2004) [Pubmed]
  4. Dissociation of p44 and p42 mitogen-activated protein kinase activation from receptor-induced hypertrophy in neonatal rat ventricular myocytes. Post, G.R., Goldstein, D., Thuerauf, D.J., Glembotski, C.C., Brown, J.H. J. Biol. Chem. (1996) [Pubmed]
  5. Activation of Go-coupled dopamine D2 receptors inhibits ERK1/ERK2 in pituitary cells. A key step in the transcriptional suppression of the prolactin gene. Liu, J.C., Baker, R.E., Sun, C., Sundmark, V.C., Elsholtz, H.P. J. Biol. Chem. (2002) [Pubmed]
  6. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease. Pei, J.J., Gong, C.X., An, W.L., Winblad, B., Cowburn, R.F., Grundke-Iqbal, I., Iqbal, K. Am. J. Pathol. (2003) [Pubmed]
  7. Activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats. Cao, J.L., He, J.H., Ding, H.L., Zeng, Y.M. Pain (2005) [Pubmed]
  8. Differential activation of c-Jun N-terminal protein kinase and p38 in rat hippocampus and cerebellum after electroconvulsive shock. Oh, S.W., Ahn, Y.M., Kang, U.G., Kim, Y.S., Park, J.B. Neurosci. Lett. (1999) [Pubmed]
  9. Sleep deprivation impairs spatial memory and decreases extracellular signal-regulated kinase phosphorylation in the hippocampus. Guan, Z., Peng, X., Fang, J. Brain Res. (2004) [Pubmed]
  10. Differential patterns of extracellular signal-regulated kinase-1 and -2 phosphorylation in rat limbic brain regions after short-term and long-term inhibitory avoidance learning. Chai, S.C., Holahan, M.R., Shyu, B.C., Wang, C.C. Neuroscience (2006) [Pubmed]
  11. Signaling via mitogen-activated protein kinase kinase (MEK1) is required for Golgi fragmentation during mitosis. Acharya, U., Mallabiabarrena, A., Acharya, J.K., Malhotra, V. Cell (1998) [Pubmed]
  12. Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Galve-Roperh, I., Sánchez, C., Cortés, M.L., del Pulgar, T.G., Izquierdo, M., Guzmán, M. Nat. Med. (2000) [Pubmed]
  13. G alpha(i) and G alpha(o) are target proteins of reactive oxygen species. Nishida, M., Maruyama, Y., Tanaka, R., Kontani, K., Nagao, T., Kurose, H. Nature (2000) [Pubmed]
  14. Extracellular signal-regulated kinase plays an essential role in hypertrophic agonists, endothelin-1 and phenylephrine-induced cardiomyocyte hypertrophy. Yue, T.L., Gu, J.L., Wang, C., Reith, A.D., Lee, J.C., Mirabile, R.C., Kreutz, R., Wang, Y., Maleeff, B., Parsons, A.A., Ohlstein, E.H. J. Biol. Chem. (2000) [Pubmed]
  15. Resveratrol suppresses angiotensin II-induced Akt/protein kinase B and p70 S6 kinase phosphorylation and subsequent hypertrophy in rat aortic smooth muscle cells. Haider, U.G., Sorescu, D., Griendling, K.K., Vollmar, A.M., Dirsch, V.M. Mol. Pharmacol. (2002) [Pubmed]
  16. Specific role of the extracellular signal-regulated kinase pathway in angiotensin II-induced cardiac hypertrophy in vitro. Aoki, H., Richmond, M., Izumo, S., Sadoshima, J. Biochem. J. (2000) [Pubmed]
  17. Activation of p42/p44 mitogen-activated protein kinase by angiotensin II, vasopressin, norepinephrine, and prostaglandin F2alpha in hepatocytes is sustained, and like the effect of epidermal growth factor, mediated through pertussis toxin-sensitive mechanisms. Melien, O., Thoresen, G.H., Sandnes, D., Ostby, E., Christoffersen, T. J. Cell. Physiol. (1998) [Pubmed]
  18. Androgens activate mitogen-activated protein kinase signaling: role in neuroprotection. Nguyen, T.V., Yao, M., Pike, C.J. J. Neurochem. (2005) [Pubmed]
  19. Rapid mitogen-activated protein kinase activation by transforming growth factor alpha in wounded rat intestinal epithelial cells. Göke, M., Kanai, M., Lynch-Devaney, K., Podolsky, D.K. Gastroenterology (1998) [Pubmed]
  20. Regulation of both apoptosis and cell survival by the v-Src oncoprotein. Johnson, D., Agochiya, M., Samejima, K., Earnshaw, W., Frame, M., Wyke, J. Cell Death Differ. (2000) [Pubmed]
  21. The mitogen-activated protein kinase kinase/extracellular signal-regulated kinase cascade activation is a key signalling pathway involved in the regulation of G(1) phase progression in proliferating hepatocytes. Talarmin, H., Rescan, C., Cariou, S., Glaise, D., Zanninelli, G., Bilodeau, M., Loyer, P., Guguen-Guillouzo, C., Baffet, G. Mol. Cell. Biol. (1999) [Pubmed]
  22. Simian virus 40 small t antigen cooperates with mitogen-activated kinases to stimulate AP-1 activity. Frost, J.A., Alberts, A.S., Sontag, E., Guan, K., Mumby, M.C., Feramisco, J.R. Mol. Cell. Biol. (1994) [Pubmed]
  23. Growth factor activity of endothelin-1 in primary astrocytes mediated by adhesion-dependent and -independent pathways. Cazaubon, S., Chaverot, N., Romero, I.A., Girault, J.A., Adamson, P., Strosberg, A.D., Couraud, P.O. J. Neurosci. (1997) [Pubmed]
  24. Angiotensin II type 1 receptor-induced extracellular signal-regulated protein kinase activation is mediated by Ca2+/calmodulin-dependent transactivation of epidermal growth factor receptor. Murasawa, S., Mori, Y., Nozawa, Y., Gotoh, N., Shibuya, M., Masaki, H., Maruyama, K., Tsutsumi, Y., Moriguchi, Y., Shibazaki, Y., Tanaka, Y., Iwasaka, T., Inada, M., Matsubara, H. Circ. Res. (1998) [Pubmed]
  25. Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Vanhoutte, P., Barnier, J.V., Guibert, B., Pagès, C., Besson, M.J., Hipskind, R.A., Caboche, J. Mol. Cell. Biol. (1999) [Pubmed]
  26. Mechanisms of endotoxin-induced NO, IL-6, and TNF-alpha production in activated rat hepatic stellate cells: role of p38 MAPK. Thirunavukkarasu, C., Watkins, S.C., Gandhi, C.R. Hepatology (2006) [Pubmed]
  27. Extracellularly regulated kinases 1/2 (p44/42 mitogen-activated protein kinases) phosphorylate synapsin I and regulate insulin secretion in the MIN6 beta-cell line and islets of Langerhans. Longuet, C., Broca, C., Costes, S., Hani, e.l. .H., Bataille, D., Dalle, S. Endocrinology (2005) [Pubmed]
  28. Corticotropin-releasing factor type 1 and type 2alpha receptors regulate phosphorylation of calcium/cyclic adenosine 3',5'-monophosphate response element-binding protein and activation of p42/p44 mitogen-activated protein kinase. Rossant, C.J., Pinnock, R.D., Hughes, J., Hall, M.D., McNulty, S. Endocrinology (1999) [Pubmed]
  29. Food restriction increases NMDA receptor-mediated calcium-calmodulin kinase II and NMDA receptor/extracellular signal-regulated kinase 1/2-mediated cyclic amp response element-binding protein phosphorylation in nucleus accumbens upon D-1 dopamine receptor stimulation in rats. Haberny, S.L., Carr, K.D. Neuroscience (2005) [Pubmed]
  30. Gangliosides GM1 and GM2 induce vascular smooth muscle cell proliferation via extracellular signal-regulated kinase 1/2 pathway. Gouni-Berthold, I., Seul, C., Ko, Y., Hescheler, J., Sachinidis, A. Hypertension (2001) [Pubmed]
  31. Adhesion stimulates direct PAK1/ERK2 association and leads to ERK-dependent PAK1 Thr212 phosphorylation. Sundberg-Smith, L.J., Doherty, J.T., Mack, C.P., Taylor, J.M. J. Biol. Chem. (2005) [Pubmed]
  32. Antisense to epidermal growth factor receptor prevents the development of left ventricular hypertrophy. Kagiyama, S., Qian, K., Kagiyama, T., Phillips, M.I. Hypertension (2003) [Pubmed]
  33. Inhibition of phosphatidylinositol 3-kinase and p70S6 kinase blocks osteogenic protein-1 induction of alkaline phosphatase activity in fetal rat calvaria cells. Shoba, L.N., Lee, J.C. J. Cell. Biochem. (2003) [Pubmed]
  34. Involvement of hepatocyte epidermal growth factor receptor mediated activation of mitogen-activated protein kinase signaling pathways in response to growth inhibition by a novel K vitamin. Wang, Z., Wang, M., Carr, B.I. J. Cell. Physiol. (2000) [Pubmed]
  35. Endothelin-1 activates mesangial cell ERK1/2 via EGF-receptor transactivation and caveolin-1 interaction. Hua, H., Munk, S., Whiteside, C.I. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  36. Involvement of p44/42 mitogen-activated protein kinases in regulating angiotensin II- and endothelin-1-induced contraction of rat thoracic aorta. Ishihata, A., Tasaki, K., Katano, Y. Eur. J. Pharmacol. (2002) [Pubmed]
  37. Inhibition of p38 mitogen-activated protein kinase augments progression of remnant kidney model by activating the ERK pathway. Ohashi, R., Nakagawa, T., Watanabe, S., Kanellis, J., Almirez, R.G., Schreiner, G.F., Johnson, R.J. Am. J. Pathol. (2004) [Pubmed]
  38. Mechanism in the sequential control of cell morphology and S phase entry by epidermal growth factor involves distinct MEK/ERK activations. Rescan, C., Coutant, A., Talarmin, H., Theret, N., Glaise, D., Guguen-Guillouzo, C., Baffet, G. Mol. Biol. Cell (2001) [Pubmed]
  39. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Traverse, S., Seedorf, K., Paterson, H., Marshall, C.J., Cohen, P., Ullrich, A. Curr. Biol. (1994) [Pubmed]
  40. Fibroblast growth factor-2 represses platelet-derived growth factor receptor-alpha (PDGFR-alpha) transcription via ERK1/2-dependent Sp1 phosphorylation and an atypical cis-acting element in the proximal PDGFR-alpha promoter. Bonello, M.R., Khachigian, L.M. J. Biol. Chem. (2004) [Pubmed]
  41. Epidermal growth factor-induced rapid retinoblastoma phosphorylation at Ser780 and Ser795 is mediated by ERK1/2 in small intestine epithelial cells. Guo, J., Sheng, G., Warner, B.W. J. Biol. Chem. (2005) [Pubmed]
  42. Disruption of Raf-1/heat shock protein 90 complex and Raf signaling by dexamethasone in mast cells. Cissel, D.S., Beaven, M.A. J. Biol. Chem. (2000) [Pubmed]
  43. Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. Cheng, Y., Zhizhin, I., Perlman, R.L., Mangoura, D. J. Biol. Chem. (2000) [Pubmed]
  44. A role for the extracellular signal-regulated kinase and p38 mitogen-activated protein kinases in interleukin-1 beta-stimulated delayed signal tranducer and activator of transcription 3 activation, atrial natriuretic factor expression, and cardiac myocyte morphology. Ng, D.C., Long, C.S., Bogoyevitch, M.A. J. Biol. Chem. (2001) [Pubmed]
  45. Peroxynitrite targets the epidermal growth factor receptor, Raf-1, and MEK independently to activate MAPK. Zhang, P., Wang, Y.Z., Kagan, E., Bonner, J.C. J. Biol. Chem. (2000) [Pubmed]
  46. Role of osteoclast extracellular signal-regulated kinase (ERK) in cell survival and maintenance of cell polarity. Nakamura, H., Hirata, A., Tsuji, T., Yamamoto, T. J. Bone Miner. Res. (2003) [Pubmed]
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