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Gene Review

Mapk14  -  mitogen-activated protein kinase 14

Mus musculus

Synonyms: CRK1, CSBP2, Crk1, Csbp1, Csbp2, ...
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Disease relevance of Mapk14


Psychiatry related information on Mapk14


High impact information on Mapk14


Chemical compound and disease context of Mapk14


Biological context of Mapk14


Anatomical context of Mapk14

  • 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 [20].
  • Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling [2].
  • We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen-presenting cells and CD4(+) T cells [21].
  • Here we report that Mkk3 gene disruption caused a selective defect in the response of fibroblasts to the proinflammatory cytokine tumor necrosis factor, including reduced p38 MAP kinase activation and cytokine expression [22].
  • Partial inhibition of p38 MAPK impaired CD4(-)CD8(-) thymocyte development and T-cell proliferation, but not positive selection [23].

Associations of Mapk14 with chemical compounds


Physical interactions of Mapk14


Enzymatic interactions of Mapk14

  • Closer examination indicates that E47 is phosphorylated in vitro by p38, and deletion analysis predicts that the critical amino acid(s) phosphorylated by p38 lie outside of the minimal transcriptional activation domains [35].
  • T cells have an alternative pathway in which T cell receptor-activated tyrosine kinase Zap70 phosphorylates p38 on Tyr323 [36].
  • KSRP phosphorylated by p38 displays compromised binding to ARE-containing transcripts and fails to promote their rapid decay, although it retains the ability to interact with the mRNA degradation machinery [37].
  • This suggests that crk1 can be phosphorylated by a kinase other than p210bcr-abl and that crk1 may have a role in signaling by thrombopoietin [38].
  • Furthermore, pretreatment with oxymatrine significantly alleviated oleic acid-induced lung injury accompanied by reduction of lung index and wet-to-dry weight ratio, decreases in serum TNF-alpha level and inhibition of phosphorylated p38 MAPK [39].

Regulatory relationships of Mapk14

  • We show that MKK3 and MKK6are essential for tumor necrosis factor-stimulated p38 MAPK activation [40].
  • Apoptosis signal-regulating kinase 1 (ASK1) is an evolutionarily conserved mitogen-activated protein 3-kinase that activates both Jnk and p38 mitogen-activated protein kinases [16].
  • Our results indicate that this Gadd45/p38 pathway plays an important role in preventing oncogene-induced growth at least in part by regulating the p53 tumor suppressor [41].
  • Akt2 promoter activity and protein levels were regulated by p38 activation, thus providing a mechanism for communication [18].
  • We show that calcineurin promotes down-regulation of p38 MAPK activity and enhances expression of the dual specificity phosphatase MAPK phosphatase-1 (MKP-1) [4].
  • Inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells [42].
  • Wnt3a activates ERK and p38 in mesenchymal C3H10T1/2 cells by a low-density lipoprotein-receptor-related protein-5/6-independent mechanism [43].
  • Overexpression of wild-type, kinase-dead, caspase recruitment domain-deleted, or kinase-dead and caspase recruitment domain-deleted forms of RIP2 had no effect on the activating dual phosphorylation of p38 MAPK during simulated ischemia [44].

Other interactions of Mapk14

  • A discrete region of 40 residues located in the amono-terminal p38MAPK lobe directed the specificity of response to extracellular signals, whereas the p44MAPK chimera, expressed in vivo, redirected stress signals into early mitogenic responses, demonstrating the functional independence of these domains [45].
  • We have investigated several candidate pathways implicated in the regulation of p21 expression, and observed increased activity of the stress kinase p38 in regenerating livers of c-jun (Deltali*) mice [46].
  • To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we examined the effect of disruption of the murine Mkk3, Mkk4, and Mkk6 genes on the p38 MAPK signaling pathway [40].
  • Therefore, our study provides in vivo evidence for the role of p38 in endochondral ossification and suggests that Sox9 is a likely downstream target of the p38 MAPK pathway [47].
  • MNNG was found to induce the activation of JNK/SAPK and p38 mitogen-activated protein kinases (MAPKs) [26].
  • Taken together, the data indicate that p38alpha/beta MAPKs-mediated coactivator recruitment at a proximal MEF-2 site is important for MyHCIId/x gene regulation in skeletal muscle [48].
  • We also observed that TRAF2 and TAK1 were essential for RIG-I-mediated activation of p38 MAPK [49].

Analytical, diagnostic and therapeutic context of Mapk14


  1. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. Warny, M., Keates, A.C., Keates, S., Castagliuolo, I., Zacks, J.K., Aboudola, S., Qamar, A., Pothoulakis, C., LaMont, J.T., Kelly, C.P. J. Clin. Invest. (2000) [Pubmed]
  2. Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling. Braz, J.C., Bueno, O.F., Liang, Q., Wilkins, B.J., Dai, Y.S., Parsons, S., Braunwart, J., Glascock, B.J., Klevitsky, R., Kimball, T.F., Hewett, T.E., Molkentin, J.D. J. Clin. Invest. (2003) [Pubmed]
  3. 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]
  4. Calcineurin enhances MAPK phosphatase-1 expression and p38 MAPK inactivation in cardiac myocytes. Lim, H.W., New, L., Han, J., Molkentin, J.D. J. Biol. Chem. (2001) [Pubmed]
  5. Biphasic activation of p38MAPK suggests that apoptosis is a downstream event in pemphigus acantholysis. Lee, H.E., Berkowitz, P., Jolly, P.S., Diaz, L.A., Chua, M.P., Rubenstein, D.S. J. Biol. Chem. (2009) [Pubmed]
  6. Modulation of the JNK and p38 pathways by cdk5 protein kinase in a transgenic mouse model of Alzheimer's disease. Otth, C., Mendoza-Naranjo, A., Mujica, L., Zambrano, A., Concha, I.I., Maccioni, R.B. Neuroreport (2003) [Pubmed]
  7. Attenuation of fasting-induced phosphorylation of mitogen-activated protein kinases (ERK/p38) in the mouse hypothalamus in response to refeeding. Ueyama, E., Morikawa, Y., Yasuda, T., Senba, E. Neurosci. Lett. (2004) [Pubmed]
  8. PRAK Is Essential for ras-Induced Senescence and Tumor Suppression. Sun, P., Yoshizuka, N., New, L., Moser, B.A., Li, Y., Liao, R., Xie, C., Chen, J., Deng, Q., Yamout, M., Dong, M.Q., Frangou, C.G., Yates, J.R., Wright, P.E., Han, J. Cell (2007) [Pubmed]
  9. p38 and a p38-interacting protein are critical for downregulation of E-cadherin during mouse gastrulation. Zohn, I.E., Li, Y., Skolnik, E.Y., Anderson, K.V., Han, J., Niswander, L. Cell (2006) [Pubmed]
  10. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Bulavin, D.V., Phillips, C., Nannenga, B., Timofeev, O., Donehower, L.A., Anderson, C.W., Appella, E., Fornace, A.J. Nat. Genet. (2004) [Pubmed]
  11. Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. Kim, M.J., Park, B.J., Kang, Y.S., Kim, H.J., Park, J.H., Kang, J.W., Lee, S.W., Han, J.M., Lee, H.W., Kim, S. Nat. Genet. (2003) [Pubmed]
  12. 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]
  13. Role of p38 mitogen-activated protein kinase activation in podocyte injury and proteinuria in experimental nephrotic syndrome. Koshikawa, M., Mukoyama, M., Mori, K., Suganami, T., Sawai, K., Yoshioka, T., Nagae, T., Yokoi, H., Kawachi, H., Shimizu, F., Sugawara, A., Nakao, K. J. Am. Soc. Nephrol. (2005) [Pubmed]
  14. Inhibition of p38 mitogen-activated protein kinase reduces TNF-induced activation of NF-kappaB, elicits caspase activity, and enhances cytotoxicity. Lüschen, S., Scherer, G., Ussat, S., Ungefroren, H., Adam-Klages, S. Exp. Cell Res. (2004) [Pubmed]
  15. Differential regulation of p38 mitogen-activated protein kinase mediates gender-dependent catecholamine-induced hypertrophy. Dash, R., Schmidt, A.G., Pathak, A., Gerst, M.J., Biniakiewicz, D., Kadambi, V.J., Hoit, B.D., Abraham, W.T., Kranias, E.G. Cardiovasc. Res. (2003) [Pubmed]
  16. ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity. Matsuzawa, A., Saegusa, K., Noguchi, T., Sadamitsu, C., Nishitoh, H., Nagai, S., Koyasu, S., Matsumoto, K., Takeda, K., Ichijo, H. Nat. Immunol. (2005) [Pubmed]
  17. E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle-specific gene transcription. Lluís, F., Ballestar, E., Suelves, M., Esteller, M., Muñoz-Cánoves, P. EMBO J. (2005) [Pubmed]
  18. Akt2, a novel functional link between p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase pathways in myogenesis. Gonzalez, I., Tripathi, G., Carter, E.J., Cobb, L.J., Salih, D.A., Lovett, F.A., Holding, C., Pell, J.M. Mol. Cell. Biol. (2004) [Pubmed]
  19. The death domain kinase RIP1 is essential for tumor necrosis factor alpha signaling to p38 mitogen-activated protein kinase. Lee, T.H., Huang, Q., Oikemus, S., Shank, J., Ventura, J.J., Cusson, N., Vaillancourt, R.R., Su, B., Davis, R.J., Kelliher, M.A. Mol. Cell. Biol. (2003) [Pubmed]
  20. 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]
  21. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. Lu, H.T., Yang, D.D., Wysk, M., Gatti, E., Mellman, I., Davis, R.J., Flavell, R.A. EMBO J. (1999) [Pubmed]
  22. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Wysk, M., Yang, D.D., Lu, H.T., Flavell, R.A., Davis, R.J. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  23. Involvement of p38 mitogen-activated protein kinase in different stages of thymocyte development. Hsu, S.C., Wu, C.C., Han, J., Lai, M.Z. Blood (2003) [Pubmed]
  24. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. Brouard, S., Otterbein, L.E., Anrather, J., Tobiasch, E., Bach, F.H., Choi, A.M., Soares, M.P. J. Exp. Med. (2000) [Pubmed]
  25. 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]
  26. The cJun N-terminal kinase (JNK) signaling pathway mediates induction of urokinase-type plasminogen activator (uPA) by the alkylating agent MNNG. Parra, M., Lluís, F., Miralles, F., Caelles, C., Muñoz-Cánoves, P. Blood (2000) [Pubmed]
  27. Mechanism of Action of Sulforaphane: Inhibition of p38 Mitogen-Activated Protein Kinase Isoforms Contributing to the Induction of Antioxidant Response Element-Mediated Heme Oxygenase-1 in Human Hepatoma HepG2 Cells. Keum, Y.S., Yu, S., Chang, P.P., Yuan, X., Kim, J.H., Xu, C., Han, J., Agarwal, A., Kong, A.N. Cancer Res. (2006) [Pubmed]
  28. The role of mitogen-activated protein kinase phosphatase-1 in the response of alveolar macrophages to lipopolysaccharide: attenuation of proinflammatory cytokine biosynthesis via feedback control of p38. Zhao, Q., Shepherd, E.G., Manson, M.E., Nelin, L.D., Sorokin, A., Liu, Y. J. Biol. Chem. (2005) [Pubmed]
  29. Mitogen-activated protein kinase p38 regulates the Wnt/cyclic GMP/Ca2+ non-canonical pathway. Ma, L., Wang, H.Y. J. Biol. Chem. (2007) [Pubmed]
  30. Transforming growth factor-beta-activated protein kinase 1-binding protein (TAB)-1alpha, but not TAB1beta, mediates cytokine-induced p38 mitogen-activated protein kinase phosphorylation and cell death in insulin-producing cells. Makeeva, N., Roomans, G.M., Myers, J.W., Welsh, N. Endocrinology (2008) [Pubmed]
  31. SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. Barancík, M., Bohácová, V., Kvackajová, J., Hudecová, S., Krizanová, O., Breier, A. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. (2001) [Pubmed]
  32. Distinct cellular functions of MK2. Kotlyarov, A., Yannoni, Y., Fritz, S., Laass, K., Telliez, J.B., Pitman, D., Lin, L.L., Gaestel, M. Mol. Cell. Biol. (2002) [Pubmed]
  33. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. She, Q.B., Bode, A.M., Ma, W.Y., Chen, N.Y., Dong, Z. Cancer Res. (2001) [Pubmed]
  34. The p38 MAPK pathway is involved in the IL-2 induction of TNF-beta gene via the EBS element. Xu, W., Yan, M., Lu, L., Sun, L., Theze, J., Zheng, Z., Liu, X. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  35. MEKK1 signaling through p38 leads to transcriptional inactivation of E47 and repression of skeletal myogenesis. Page, J.L., Wang, X., Sordillo, L.M., Johnson, S.E. J. Biol. Chem. (2004) [Pubmed]
  36. The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway. Salvador, J.M., Mittelstadt, P.R., Belova, G.I., Fornace, A.J., Ashwell, J.D. Nat. Immunol. (2005) [Pubmed]
  37. p38-dependent phosphorylation of the mRNA decay-promoting factor KSRP controls the stability of select myogenic transcripts. Briata, P., Forcales, S.V., Ponassi, M., Corte, G., Chen, C.Y., Karin, M., Puri, P.L., Gherzi, R. Mol. Cell (2005) [Pubmed]
  38. Crkl is constitutively tyrosine phosphorylated in platelets from chronic myelogenous leukemia patients and inducibly phosphorylated in normal platelets stimulated by thrombopoietin. Oda, A., Miyakawa, Y., Druker, B.J., Ishida, A., Ozaki, K., Ohashi, H., Wakui, M., Handa, M., Watanabe, K., Okamoto, S., Ikeda, Y. Blood (1996) [Pubmed]
  39. Attenuation of acute lung injury in mice by oxymatrine is associated with inhibition of phosphorylated p38 mitogen-activated protein kinase. Xu, G.L., Yao, L., Rao, S.Y., Gong, Z.N., Zhang, S.Q., Yu, S.Q. Journal of ethnopharmacology. (2005) [Pubmed]
  40. Mechanism of p38 MAP kinase activation in vivo. Brancho, D., Tanaka, N., Jaeschke, A., Ventura, J.J., Kelkar, N., Tanaka, Y., Kyuuma, M., Takeshita, T., Flavell, R.A., Davis, R.J. Genes Dev. (2003) [Pubmed]
  41. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Bulavin, D.V., Kovalsky, O., Hollander, M.C., Fornace, A.J. Mol. Cell. Biol. (2003) [Pubmed]
  42. p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Hui, L., Bakiri, L., Mairhorfer, A., Schweifer, N., Haslinger, C., Kenner, L., Komnenovic, V., Scheuch, H., Beug, H., Wagner, E.F. Nat. Genet. (2007) [Pubmed]
  43. Essential role of Wnt3a-mediated activation of mitogen-activated protein kinase p38 for the stimulation of alkaline phosphatase activity and matrix mineralization in C3H10T1/2 mesenchymal cells. Caverzasio, J., Manen, D. Endocrinology (2007) [Pubmed]
  44. The role of RIP2 in p38 MAPK activation in the stressed heart. Jacquet, S., Nishino, Y., Kumphune, S., Sicard, P., Clark, J.E., Kobayashi, K.S., Flavell, R.A., Eickhoff, J., Cotten, M., Marber, M.S. J. Biol. Chem. (2008) [Pubmed]
  45. Identification of MAP kinase domains by redirecting stress signals into growth factor responses. Brunet, A., Pouysségur, J. Science (1996) [Pubmed]
  46. c-Jun/AP-1 controls liver regeneration by repressing p53/p21 and p38 MAPK activity. Stepniak, E., Ricci, R., Eferl, R., Sumara, G., Sumara, I., Rath, M., Hui, L., Wagner, E.F. Genes Dev. (2006) [Pubmed]
  47. Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. Zhang, R., Murakami, S., Coustry, F., Wang, Y., de Crombrugghe, B. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  48. The p38alpha/beta mitogen-activated protein kinases mediate recruitment of CREB-binding protein to preserve fast myosin heavy chain IId/x gene activity in myotubes. Meissner, J.D., Chang, K.C., Kubis, H.P., Nebreda, A.R., Gros, G., Scheibe, R.J. J. Biol. Chem. (2007) [Pubmed]
  49. RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1. Mikkelsen, S.S., Jensen, S.B., Chiliveru, S., Melchjorsen, J., Julkunen, I., Gaestel, M., Arthur, J.S., Flavell, R.A., Ghosh, S., Paludan, S.R. J. Biol. Chem. (2009) [Pubmed]
  50. Hepatic ischemic preconditioning in mice is associated with activation of NF-kappaB, p38 kinase, and cell cycle entry. Teoh, N., Dela Pena, A., Farrell, G. Hepatology (2002) [Pubmed]
  51. P38 and activating transcription factor-2 involvement in osteoblast osmotic response to elevated extracellular glucose. Zayzafoon, M., Botolin, S., McCabe, L.R. J. Biol. Chem. (2002) [Pubmed]
  52. MAPK-activated Protein Kinase-2 (MK2)-mediated Formation and Phosphorylation-regulated Dissociation of the Signal Complex Consisting of p38, MK2, Akt, and Hsp27. Zheng, C., Lin, Z., Zhao, Z.J., Yang, Y., Niu, H., Shen, X. J. Biol. Chem. (2006) [Pubmed]
  53. Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G1/S through a mechanism requiring p38/RK. Molnár, A., Theodoras, A.M., Zon, L.I., Kyriakis, J.M. J. Biol. Chem. (1997) [Pubmed]
  54. p38 Mitogen-activated protein kinase contributes to autoimmune renal injury in MRL-Fas lpr mice. Iwata, Y., Wada, T., Furuichi, K., Sakai, N., Matsushima, K., Yokoyama, H., Kobayashi, K. J. Am. Soc. Nephrol. (2003) [Pubmed]
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