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MAPK14  -  mitogen-activated protein kinase 14

Homo sapiens

Synonyms: CSAID-binding protein, CSBP, CSBP1, CSBP2, CSPB1, ...
 
 
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Disease relevance of MAPK14

  • Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase [1].
  • Our results demonstrate that complementary activities of PKA, p38 and MK2 tip the transport balance of adenovirus towards the nucleus and thus enhance infection [2].
  • Epstein-Barr virus (EBV)-transformed lymphocytes natively expressing the most common of these variants (Gly56Ala) exhibited a similar loss of 5-HT uptake stimulation by PKG/p38 MAPK activators [3].
  • Hepatitis B virus X protein (pX) activates p38 MAP kinase and JNK pathways and, in response to weak apoptotic signals, sensitizes hepatocytes to apoptosis [4].
  • Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines [5].
 

Psychiatry related information on MAPK14

 

High impact information on MAPK14

  • p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci [10].
  • Inactivation of p38 MAPK (the product of Mapk14) in vivo by gene targeting or by PPM1D overexpression expedited tumor formation after injection of mouse embryo fibroblasts (MEFs) expressing E1A+Ras into nude mice [11].
  • The stress-responsive p38 and JNK MAPK pathways regulate cell cycle and apoptosis [12].
  • We propose that regulation of Cdc25B phosphorylation by p38 is a critical event for initiating the G2/M checkpoint after ultraviolet radiation [13].
  • Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications [14].
 

Chemical compound and disease context of MAPK14

 

Biological context of MAPK14

  • One means of understanding the role of p38 in these responses is to identify proteins with functions regulated by p38-catalysed phosphorylation [20].
  • The relationship between colonocyte apoptosis and p38/p53-dependent pathways was studied in intact mice [1].
  • These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism [21].
  • Taken together, these results demonstrate an interaction between IFN-gamma signaling and the p38 pathway that leads to increased transcriptional activation by STAT1 independently of phosphorylation at Ser-727 [22].
  • Conversely, cells of a proliferative phenotype display antiapoptotic NF-kappaB responses that antagonize c-Jun N-terminal kinase and p38 mitogen-activated protein kinase stress kinase effects [23].
 

Anatomical context of MAPK14

  • Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells [24].
  • Further, MNK1 was activated upon stimulation of HeLa cells with 12-O-tetradecanoylphorbol-13-acetate, fetal calf serum, anisomycin, UV irradiation, tumor necrosis factor-alpha, interleukin-1beta, or osmotic shock, and the activation by these stimuli was differentially inhibited by the MEK inhibitor PD098059 or the p38 MAP kinase inhibitor SB202190 [25].
  • However, under our assay conditions, SAPKK3 was the major activator of RK/p38 detected in extracts prepared from stress- or interleukin-1-stimulated epithelial (KB) cells, from bacterial lipopolysaccharide and tumour necrosis factor alpha-stimulated THP1 monocytes or from rabbit skeletal muscle [24].
  • Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation [26].
  • Employing hepatocyte cell lines expressing pX, which was regulated by tetracycline, we investigated the mechanism of apoptosis by p38 MAP kinase and JNK pathway activation [4].
 

Associations of MAPK14 with chemical compounds

  • SB203580, a specific inhibitor of p38, was found to inhibit ISGF3 formation but had no apparent effects on signal transducer and activator of transcription (STAT)1 homodimer formation [27].
  • We have identified and cloned a novel serine/ threonine kinase, p38-regulated/activated protein kinase (PRAK) [28].
  • Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase [3].
  • In addition, antioxidants significantly attenuated 3,3'-diindolylmethane-induced activation of p38 and JNK and induction of p21, indicating that oxidative stress is the major trigger of these events [29].
  • The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells [30].
 

Physical interactions of MAPK14

  • MKP-7 binds to and inactivates p38 alpha and -beta, but not gamma or delta [31].
  • Mxi2 in yeast interacts with Max and with the C terminus of c-Myc [32].
  • Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b [33].
  • Stimulation through modified CD40 containing increased numbers of TRAF6-binding sites in the cytoplasmic tails showed a dose-dependent increase in the activation of p38 kinase and more pronounced osteoclastogenesis [34].
  • These results show that E2-p38 is the form of E2 that interacts with PKR in the cytosol and may contribute to the resistance of HCV to IFN-alpha [35].
 

Enzymatic interactions of MAPK14

 

Regulatory relationships of MAPK14

 

Other interactions of MAPK14

  • Regulation of the MEF2 family of transcription factors by p38 [36].
  • These results show that p38 alpha plays an important role in some, but not all, CD28-dependent cellular responses [40].
  • Using a catalytically inactive mutant (D168A) of human CSBP2 as the bait in a yeast two-hybrid screen, we have identified and cloned a novel kinase which shares approximately 70% amino acid identity to mitogen-activated protein kinase-activated protein kinase (MAPKAP kinase)-2, and thus was designated MAPKAP kinase-3 [41].
  • H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells [45].
  • Here we report that the Rac-MAPK kinase (MKK)3/6-p38 pathway is a unique signaling pathway activated by H-Ras, leading to the invasive/migrative phenotype [45].
 

Analytical, diagnostic and therapeutic context of MAPK14

References

  1. Clostridium difficile toxin A-induced colonocyte apoptosis involves p53-dependent p21(WAF1/CIP1) induction via p38 mitogen-activated protein kinase. Kim, H., Kokkotou, E., Na, X., Rhee, S.H., Moyer, M.P., Pothoulakis, C., Lamont, J.T. Gastroenterology (2005) [Pubmed]
  2. Adenovirus-activated PKA and p38/MAPK pathways boost microtubule-mediated nuclear targeting of virus. Suomalainen, M., Nakano, M.Y., Boucke, K., Keller, S., Greber, U.F. EMBO J. (2001) [Pubmed]
  3. Human serotonin transporter variants display altered sensitivity to protein kinase G and p38 mitogen-activated protein kinase. Prasad, H.C., Zhu, C.B., McCauley, J.L., Samuvel, D.J., Ramamoorthy, S., Shelton, R.C., Hewlett, W.A., Sutcliffe, J.S., Blakely, R.D. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  4. Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor (TNF) receptor 1/TNF-alpha expression. Wang, W.H., Grégori, G., Hullinger, R.L., Andrisani, O.M. Mol. Cell. Biol. (2004) [Pubmed]
  5. Protein kinase A gating of a pseudopodial-located RhoA/ROCK/p38/NHE1 signal module regulates invasion in breast cancer cell lines. Cardone, R.A., Bagorda, A., Bellizzi, A., Busco, G., Guerra, L., Paradiso, A., Casavola, V., Zaccolo, M., Reshkin, S.J. Mol. Biol. Cell (2005) [Pubmed]
  6. Role of p38 and p44/42 mitogen-activated protein kinases in microglia. Koistinaho, M., Koistinaho, J. Glia (2002) [Pubmed]
  7. Active stress kinase p38 enhances and perpetuates abnormal tau phosphorylation and deposition in Pick's disease. Puig, B., Vinals, F., Ferrer, I. Acta Neuropathol. (2004) [Pubmed]
  8. HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway. Missé, D., Esteve, P.O., Renneboog, B., Vidal, M., Cerutti, M., St Pierre, Y., Yssel, H., Parmentier, M., Veas, F. Blood (2001) [Pubmed]
  9. Herpes simplex virus type 1 blocks the apoptotic host cell defense mechanisms that target Bcl-2 and manipulates activation of p38 mitogen-activated protein kinase to improve viral replication. Zachos, G., Koffa, M., Preston, C.M., Clements, J.B., Conner, J. J. Virol. (2001) [Pubmed]
  10. p38 pathway targets SWI-SNF chromatin-remodeling complex to muscle-specific loci. Simone, C., Forcales, S.V., Hill, D.A., Imbalzano, A.N., Latella, L., Puri, P.L. Nat. Genet. (2004) [Pubmed]
  11. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Bulavin, D.V., Demidov, O.N., Saito, S., Kauraniemi, P., Phillips, C., Amundson, S.A., Ambrosino, C., Sauter, G., Nebreda, A.R., Anderson, C.W., Kallioniemi, A., Fornace, A.J., Appella, E. Nat. Genet. (2002) [Pubmed]
  12. A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK. Takekawa, M., Saito, H. Cell (1998) [Pubmed]
  13. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Bulavin, D.V., Higashimoto, Y., Popoff, I.J., Gaarde, W.A., Basrur, V., Potapova, O., Appella, E., Fornace, A.J. Nature (2001) [Pubmed]
  14. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Evans, J.L., Goldfine, I.D., Maddux, B.A., Grodsky, G.M. Endocr. Rev. (2002) [Pubmed]
  15. Activation of the HIV-1 long terminal repeat by cytokines and environmental stress requires an active CSBP/p38 MAP kinase. Kumar, S., Orsini, M.J., Lee, J.C., McDonnell, P.C., Debouck, C., Young, P.R. J. Biol. Chem. (1996) [Pubmed]
  16. Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines. Liem, A.A., Appleyard, M.V., O'Neill, M.A., Hupp, T.R., Chamberlain, M.P., Thompson, A.M. Br. J. Cancer (2003) [Pubmed]
  17. Mxi2, a splice variant of p38 stress-activated kinase, is a distal nephron protein regulated with kidney ischemia. Faccio, L., Chen, A., Fusco, C., Martinotti, S., Bonventre, J.V., Zervos, A.S. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  18. Activation of p38 and N-acetylcysteine-sensitive c-Jun NH2-terminal kinase signaling cascades is required for induction of apoptosis in Parkinson's disease cybrids. Onyango, I.G., Tuttle, J.B., Bennett, J.P. Mol. Cell. Neurosci. (2005) [Pubmed]
  19. Interleukin-8 secretion from Mycobacterium tuberculosis-infected monocytes is regulated by protein tyrosine kinases but not by ERK1/2 or p38 mitogen-activated protein kinases. Ameixa, C., Friedland, J.S. Infect. Immun. (2002) [Pubmed]
  20. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation. Han, J., Jiang, Y., Li, Z., Kravchenko, V.V., Ulevitch, R.J. Nature (1997) [Pubmed]
  21. The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism. Winzen, R., Kracht, M., Ritter, B., Wilhelm, A., Chen, C.Y., Shyu, A.B., Müller, M., Gaestel, M., Resch, K., Holtmann, H. EMBO J. (1999) [Pubmed]
  22. p38 MAPK enhances STAT1-dependent transcription independently of Ser-727 phosphorylation. Ramsauer, K., Sadzak, I., Porras, A., Pilz, A., Nebreda, A.R., Decker, T., Kovarik, P. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  23. Switching leukemia cell phenotype between life and death. Tucker, S.J., Rae, C., Littlejohn, A.F., Paul, A., MacEwan, D.J. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  24. Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. Cuenda, A., Alonso, G., Morrice, N., Jones, M., Meier, R., Cohen, P., Nebreda, A.R. EMBO J. (1996) [Pubmed]
  25. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. Fukunaga, R., Hunter, T. EMBO J. (1997) [Pubmed]
  26. Regulation of the maintenance of peripheral T-cell anergy by TAB1-mediated p38 alpha activation. Ohkusu-Tsukada, K., Tominaga, N., Udono, H., Yui, K. Mol. Cell. Biol. (2004) [Pubmed]
  27. p38 MAP kinase is required for STAT1 serine phosphorylation and transcriptional activation induced by interferons. Goh, K.C., Haque, S.J., Williams, B.R. EMBO J. (1999) [Pubmed]
  28. PRAK, a novel protein kinase regulated by the p38 MAP kinase. New, L., Jiang, Y., Zhao, M., Liu, K., Zhu, W., Flood, L.J., Kato, Y., Parry, G.C., Han, J. EMBO J. (1998) [Pubmed]
  29. 3,3'-Diindolylmethane is a novel mitochondrial H(+)-ATP synthase inhibitor that can induce p21(Cip1/Waf1) expression by induction of oxidative stress in human breast cancer cells. Gong, Y., Sohn, H., Xue, L., Firestone, G.L., Bjeldanes, L.F. Cancer Res. (2006) [Pubmed]
  30. The p38/reactivating kinase mitogen-activated protein kinase cascade mediates the activation of the transcription factor insulin upstream factor 1 and insulin gene transcription by high glucose in pancreatic beta-cells. Macfarlane, W.M., Smith, S.B., James, R.F., Clifton, A.D., Doza, Y.N., Cohen, P., Docherty, K. J. Biol. Chem. (1997) [Pubmed]
  31. A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. Tanoue, T., Yamamoto, T., Maeda, R., Nishida, E. J. Biol. Chem. (2001) [Pubmed]
  32. Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Zervos, A.S., Faccio, L., Gatto, J.P., Kyriakis, J.M., Brent, R. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  33. Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Chang, C.I., Xu, B.E., Akella, R., Cobb, M.H., Goldsmith, E.J. Mol. Cell (2002) [Pubmed]
  34. Strength of TRAF6 signalling determines osteoclastogenesis. Kadono, Y., Okada, F., Perchonock, C., Jang, H.D., Lee, S.Y., Kim, N., Choi, Y. EMBO Rep. (2005) [Pubmed]
  35. Detection of a novel unglycosylated form of hepatitis C virus E2 envelope protein that is located in the cytosol and interacts with PKR. Pavio, N., Taylor, D.R., Lai, M.M. J. Virol. (2002) [Pubmed]
  36. Regulation of the MEF2 family of transcription factors by p38. Zhao, M., New, L., Kravchenko, V.V., Kato, Y., Gram, H., di Padova, F., Olson, E.N., Ulevitch, R.J., Han, J. Mol. Cell. Biol. (1999) [Pubmed]
  37. Ischemic preconditioning: from adenosine receptor to KATP channel. Cohen, M.V., Baines, C.P., Downey, J.M. Annu. Rev. Physiol. (2000) [Pubmed]
  38. Type II keratins are phosphorylated on a unique motif during stress and mitosis in tissues and cultured cells. Toivola, D.M., Zhou, Q., English, L.S., Omary, M.B. Mol. Biol. Cell (2002) [Pubmed]
  39. Phosphorylation motifs regulating the stability and function of myocyte enhancer factor 2A. Cox, D.M., Du, M., Marback, M., Yang, E.C., Chan, J., Siu, K.W., McDermott, J.C. J. Biol. Chem. (2003) [Pubmed]
  40. p38 alpha mitogen-activated protein kinase is activated by CD28-mediated signaling and is required for IL-4 production by human CD4+CD45RO+ T cells and Th2 effector cells. Schafer, P.H., Wadsworth, S.A., Wang, L., Siekierka, J.J. J. Immunol. (1999) [Pubmed]
  41. Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. McLaughlin, M.M., Kumar, S., McDonnell, P.C., Van Horn, S., Lee, J.C., Livi, G.P., Young, P.R. J. Biol. Chem. (1996) [Pubmed]
  42. Activation of discoidin domain receptor 1 facilitates the maturation of human monocyte-derived dendritic cells through the TNF receptor associated factor 6/TGF-beta-activated protein kinase 1 binding protein 1 beta/p38 alpha mitogen-activated protein kinase signaling cascade. Matsuyama, W., Faure, M., Yoshimura, T. J. Immunol. (2003) [Pubmed]
  43. MAPK p38 regulates transcriptional activity of NF-kappaB in primary human astrocytes via acetylation of p65. Saha, R.N., Jana, M., Pahan, K. J. Immunol. (2007) [Pubmed]
  44. The p38 mitogen-activated protein kinase augments nucleotide excision repair by mediating DDB2 degradation and chromatin relaxation. Zhao, Q., Barakat, B.M., Qin, S., Ray, A., El-Mahdy, M.A., Wani, G., Arafa, E.S., Mir, S.N., Wang, Q.E., Wani, A.A. J. Biol. Chem. (2008) [Pubmed]
  45. H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. Shin, I., Kim, S., Song, H., Kim, H.R., Moon, A. J. Biol. Chem. (2005) [Pubmed]
  46. 15-deoxy-Delta12,14-prostaglandin J2 inhibits IFN-inducible protein 10/CXC chemokine ligand 10 expression in human microglia: mechanisms and implications. Si, Q., Zhao, M.L., Morgan, A.C., Brosnan, C.F., Lee, S.C. J. Immunol. (2004) [Pubmed]
  47. TNF receptor-associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion, and Ig production following ligation of CD40 on human B cells. Grammer, A.C., Swantek, J.L., McFarland, R.D., Miura, Y., Geppert, T., Lipsky, P.E. J. Immunol. (1998) [Pubmed]
  48. p38 and ERK1/2 coordinate cellular migration and proliferation in epithelial wound healing: evidence of cross-talk activation between MAP kinase cascades. Sharma, G.D., He, J., Bazan, H.E. J. Biol. Chem. (2003) [Pubmed]
  49. Molecular cloning and characterization of a novel p38 mitogen-activated protein kinase. Wang, X.S., Diener, K., Manthey, C.L., Wang, S., Rosenzweig, B., Bray, J., Delaney, J., Cole, C.N., Chan-Hui, P.Y., Mantlo, N., Lichenstein, H.S., Zukowski, M., Yao, Z. J. Biol. Chem. (1997) [Pubmed]
  50. Stress-induced stimulation of early growth response gene-1 by p38/stress-activated protein kinase 2 is mediated by a cAMP-responsive promoter element in a MAPKAP kinase 2-independent manner. Rolli, M., Kotlyarov, A., Sakamoto, K.M., Gaestel, M., Neininger, A. J. Biol. Chem. (1999) [Pubmed]
 
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