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p38 MAPK Family

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Encyclopedia of Signaling Molecules

Synonyms

p38α: Crk1; Csbp1; CSBP2; Mapk14; Mitogen activated protein kinase 14; Mxi2; p38; p38 alpha Map kinase; p38 alpha MAP kinase; p38 alpha MAPK; p38-alpha; p38a; p38alpha; p38alpha MAPK; PRKM14; PRKM15

p38β: Mapk11; Mitogen-activated protein kinase 11; p38 beta MAP kinase; p38 beta Map kinase; p38 beta MAPK; p38-2; p38B; p38beta; p38beta MAPK; P38BETA2; Prkm11; Protein kinase, mitogen activated kinase, 11; SAPK2; SAPK2B

p38δ: Mapk13; MAPK13; Mitogen-activated protein kinase 13; p38 delta Map kinase; p38 delta MAP kinase; p38 delta MAPK; p38d; p38delta; p38delta MAPK; PRKM13; SAPK4; Serk4

p38γ: ERK6; Mapk12; Mitogen-activated protein kinase 12; p38 gamma MAP kinase; p38 gamma Map kinase; p38 gamma MAPK; p38g; p38gamma; p38gamma MAPK; Prkm12; SAPK-3; SAPK3; Stress-activated protein kinase 3

Historical Background: The p38 MAPK Family of Stress Response Signaling

The biological transduction of physiological and environmental signals involves highly specific protein-protein...

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References

  • Allen M, Svensson L, Roach M, Hambor J, McNeish J, Gabel CA. Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J Exp Med. 2000;191:859–70.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bendotti C, Bao Cutrona M, Cheroni C, Grignaschi G, Lo Coco D, Peviani M, Tortarolo M, Veglianese P, Zennaro E. Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase. Neurodegener Dis. 2005;2:128–34.

    Article  CAS  PubMed  Google Scholar 

  • Ben-Levy R, Hooper S, Wilson R, Paterson HF, Marshall CJ. Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol. 1998;8:1049–57.

    Article  CAS  PubMed  Google Scholar 

  • Bredeson S, Papaconstantinou J, Deford JH, Kechichian T, Syed TA, Saade GR, Menon R. HMGB1 promotes a p38MAPK associated non-infectious inflammatory response pathway in human fetal membranes. PLoS One. 2014;9:e113799.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Brobey RK, German D, Sonsalla PK, Gurnani P, Pastor J, Hsieh CC, Papaconstantinou J, Foster PP, Kuro-o M, Rosenblatt KP. Klotho protects dopaminergic neuron oxidant-induced degeneration by modulating ASK1 and p38 MAPK signaling pathways. PLoS One. 2015;10:e0139914.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cardier JE, Erickson-Miller CL. Fas (CD95)- and tumor necrosis factor-mediated apoptosis in liver endothelial cells: role of caspase-3 and the p38 MAPK. Microvasc Res. 2002;63:10–8.

    Article  CAS  PubMed  Google Scholar 

  • Chang CI, Xu BE, Akella R, Cobb MH, Goldsmith EJ. Crystal structures of MAP kinase p38 complexed to the docking sites on its nuclear substrate MEF2A and activator MKK3b. Mol Cell. 2002;9:1241–9.

    Article  CAS  PubMed  Google Scholar 

  • Conrad PW, Rust RT, Han J, Millhorn DE, Beitner-Johnson D. Selective activation of p38alpha and p38gamma by hypoxia. Role in regulation of cyclin D1 by hypoxia in PC12 cells. J Biol Chem. 1999;274:23570–6.

    Article  CAS  PubMed  Google Scholar 

  • Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Biochem J. 2010;429:403–17.

    Article  CAS  PubMed  Google Scholar 

  • Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773:1358–75.

    Article  CAS  PubMed  Google Scholar 

  • Engel K, Schultz H, Martin F, Kotlyarov A, Plath K, Hahn M, Heinemann U, Gaestel M. Constitutive activation of mitogen-activated protein kinase-activated protein kinase 2 by mutation of phosphorylation sites and an A-helix motif. J Biol Chem. 1995;270:27213–21.

    Article  CAS  PubMed  Google Scholar 

  • Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998;273:1741–8.

    Article  CAS  PubMed  Google Scholar 

  • Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30:1536–48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Gavin AC, Nebreda AR. A MAP kinase docking site is required for phosphorylation and activation of p90(rsk)/MAPKAP kinase-1. Curr Biol. 1999;9:281–4.

    Article  CAS  PubMed  Google Scholar 

  • Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997;16:3563–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Goldsmith EJ. Three-dimensional docking in the MAPK p38alpha. Sci Signal. 2011;4:pe47.

    Article  CAS  PubMed  Google Scholar 

  • Goldsmith EJ, Akella R, Min X, Zhou T, Humphreys JM. Substrate and docking interactions in serine/threonine protein kinases. Chem Rev. 2007;107:5065–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Guo YL, Kang B, Han J, Williamson JR. p38beta MAP kinase protects rat mesangial cells from TNF-alpha-induced apoptosis. J Cell Biochem. 2001;82:556–65.

    Article  CAS  PubMed  Google Scholar 

  • Haq R, Brenton JD, Takahashi M, Finan D, Finkielsztein A, Damaraju S, Rottapel R, Zanke B. Constitutive p38HOG mitogen-activated protein kinase activation induces permanent cell cycle arrest and senescence. Cancer Res. 2002;62:5076–82.

    PubMed  CAS  Google Scholar 

  • Hsieh CC, Papaconstantinou J. The effect of aging on p38 signaling pathway activity in the mouse liver and in response to ROS generated by 3-nitropropionic acid. Mech Ageing Dev. 2002;123:1423–35.

    Article  CAS  PubMed  Google Scholar 

  • Hsieh CC, Papaconstantinou J. Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice. FASEB J. 2006;20:259–68.

    Article  PubMed  CAS  Google Scholar 

  • Hsieh CC, Rosenblatt JI, Papaconstantinou J. Age-associated changes in SAPK/JNK and p38 MAPK signaling in response to the generation of ROS by 3-nitropropionic acid. Mech Ageing Dev. 2003;124:733–46.

    Article  CAS  PubMed  Google Scholar 

  • Humphreys JM, Piala AT, Akella R, He H, Goldsmith EJ. Precisely ordered phosphorylation reactions in the p38 mitogen-activated protein (MAP) kinase cascade. J Biol Chem. 2013;288:23322–30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Hutter D, Chen P, Barnes J, Liu Y. The carboxyterminal domains of MKP-1 and MKP-2 have inhibitory effects on their phosphtase activity. Mol Cell Biochem. 2002;233:107–17.

    Article  CAS  PubMed  Google Scholar 

  • Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells. 2003;8:131–44.

    Article  CAS  PubMed  Google Scholar 

  • Jeong HJ, Lee HJ, Vuong TA, Choi KS, Choi D, Koo SH, Cho SC, Cho H, Kang JS. Prmt7 deficiency causes reduced skeletal muscle oxidative metabolism and age-related obesity. Diabetes. 2016;65:1868–82.

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Chen C, Li Z, Guo W, Gegner JA, Lin S, Han J. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996;271:17920–6.

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y, Gram H, Zhao M, New L, Gu J, Feng L, Di Padova F, Ulevitch RJ, Han J. Characterization of the structure and function of the fourth member of p38 group mitogen-activated protein kinases, p38delta. J Biol Chem. 1997;272:30122–8.

    Article  CAS  PubMed  Google Scholar 

  • Keyse SM. Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr Opin Cell Biol. 2000;12:186–92.

    Article  CAS  PubMed  Google Scholar 

  • Kim DH, Feinbaum R, Alloing G, Emerson FE, Garsin DA, Inoue H, Tanaka-Hino M, Hisamoto N, Matsumoto K, Tan MW, et al. A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science. 2002;297:623–6.

    Article  CAS  PubMed  Google Scholar 

  • Kompa AR, See F, Lewis DA, Adrahtas A, Cantwell DM, Wang BH, Krum H. Long-term but not short-term p38 mitogen-activated protein kinase inhibition improves cardiac function and reduces cardiac remodeling post-myocardial infarction. J Pharmacol Exp Ther. 2008;325:741–50.

    Article  CAS  PubMed  Google Scholar 

  • Lechner C, Zahalka MA, Giot JF, Moller NP, Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996;93:4355–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Lee JC, Kassis S, Kumar S, Badger A, Adams JL. p38 mitogen-activated protein kinase inhibitors – mechanisms and therapeutic potentials. Pharmacol Ther. 1999;82:389–97.

    Article  CAS  PubMed  Google Scholar 

  • Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL, Reid MB. TNF-alpha acts via p38 MAPK to stimulate expression of the ubiquitin ligase atrogin1/MAFbx in skeletal muscle. FASEB J. 2005;19:362–70.

    Article  PubMed  CAS  Google Scholar 

  • Mertens S, Craxton M, Goedert M. SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett. 1996;383:273–6.

    Article  CAS  PubMed  Google Scholar 

  • Muda M, Theodosiou A, Gillieron C, Smith A, Chabert C, Camps M, Boschert U, Rodrigues N, Davies K, Ashworth A, et al. The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. J Biol Chem. 1998;273:9323–9.

    Article  CAS  PubMed  Google Scholar 

  • Munoz L, Ammit AJ. Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology. 2010;58:561–8.

    Article  CAS  PubMed  Google Scholar 

  • Munoz L, Ralay Ranaivo H, Roy SM, Hu W, Craft JM, McNamara LK, Chico LW, Van Eldik LJ, Watterson DM. A novel p38 alpha MAPK inhibitor suppresses brain proinflammatory cytokine up-regulation and attenuates synaptic dysfunction and behavioral deficits in an Alzheimer’s disease mouse model. J Neuroinflammation. 2007;4:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12:1–13.

    Article  CAS  PubMed  Google Scholar 

  • Papaconstantinou J, Hsieh CC. Activation of senescence and aging characteristics by mitochondrially generated ROS: how are they linked? Cell Cycle. 2010;9:3831–3.

    Article  PubMed  CAS  Google Scholar 

  • Papaconstantinou J, Wang CZ, Zhang M, Yang S, Deford J, Bulavin DV, Ansari NH. Attenuation of p38alpha MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells. Aging. 2015;7:718–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Park JM, Greten FR, Li ZW, Karin M. Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition. Science. 2002;297:2048–51.

    Article  CAS  PubMed  Google Scholar 

  • Peifer C, Abadleh M, Bischof J, Hauser D, Schattel V, Hirner H, Knippschild U, Laufer S. 3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38alpha mitogen activated protein kinase and casein kinase 1delta. J Med Chem. 2009;52:7618–30.

    Article  CAS  PubMed  Google Scholar 

  • Perdiguero E, Ruiz-Bonilla V, Gresh L, Hui L, Ballestar E, Sousa-Victor P, Baeza-Raja B, Jardi M, Bosch-Comas A, Esteller M, et al. Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation. EMBO J. 2007;26:1245–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Piala AT, Humphreys JM, Goldsmith EJ. MAP kinase modules: the excursion model and the steps that count. Biophys J. 2014;107:2006–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Sabio G, Arthur JS, Kuma Y, Peggie M, Carr J, Murray-Tait V, Centeno F, Goedert M, Morrice NA, Cuenda A. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005;24:1134–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Saurin AT, Martin JL, Heads RJ, Foley C, Mockridge JW, Wright MJ, Wang Y, Marber MS. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB J. 2000;14:2237–46.

    Article  CAS  PubMed  Google Scholar 

  • Stein B, Yang MX, Young DB, Janknecht R, Hunter T, Murray BW, Barbosa MS. p38-2, a novel mitogen-activated protein kinase with distinct properties. J Biol Chem. 1997;272:19509–17.

    Article  CAS  PubMed  Google Scholar 

  • Suh Y. Age-specific changes in expression, activity, and activation of the c-Jun NH(2)-terminal kinase and p38 mitogen-activated protein kinases by methyl methanesulfonate in rats. Mech Ageing Dev. 2001;122:1797–811.

    Article  CAS  PubMed  Google Scholar 

  • Sy JC, Seshadri G, Yang SC, Brown M, Oh T, Dikalov S, Murthy N, Davis ME. Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nat Mater. 2008;7:863–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tanoue T, Maeda R, Adachi M, Nishida E. Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions. EMBO J. 2001;20:466–79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wang Y, Huang S, Sah VP, Ross Jr J, Brown JH, Han J, Chien KR. Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. J Biol Chem. 1998;273:2161–8.

    Article  CAS  PubMed  Google Scholar 

  • Wang ZC, Lu H, Zhou Q, Yu SM, Mao YL, Zhang HJ, Zhang PC, Yan WJ. MiR-451 inhibits synovial fibroblasts proliferation and inflammatory cytokines secretion in rheumatoid arthritis through mediating p38MAPK signaling pathway. Int J Clin Exp Pathol. 2015;8:14562–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  • Wei YH, Lu CY, Lee HC, Pang CY, Ma YS. Oxidative damage and mutation to mitochondrial DNA and age-dependent decline of mitochondrial respiratory function. Ann N Y Acad Sci. 1998;854:155–70.

    Article  PubMed  CAS  Google Scholar 

  • Wong ES, Le Guezennec X, Demidov ON, Marshall NT, Wang ST, Krishnamurthy J, Sharpless NE, Dunn NR, Bulavin DV. p38MAPK controls expression of multiple cell cycle inhibitors and islet proliferation with advancing age. Dev Cell. 2009;17:142–9.

    Article  PubMed  CAS  Google Scholar 

  • Yang SH, Whitmarsh AJ, Davis RJ, Sharrocks AD. Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. EMBO J. 1998;17:1740–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yang SH, Galanis A, Sharrocks AD. Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol Cell Biol. 1999;19:4028–38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zer C, Sachs G, Shin JM. Identification of genomic targets downstream of p38 mitogen-activated protein kinase pathway mediating tumor necrosis factor-alpha signaling. Physiol Genomics. 2007;31:343–51.

    Article  PubMed  CAS  Google Scholar 

  • Zhou B, Wu L, Shen K, Zhang J, Lawrence DS, Zhang ZY. Multiple regions of MAP kinase phosphatase 3 are involved in its recognition and activation by ERK2. J Biol Chem. 2001;276:6506–15.

    Article  PubMed  CAS  Google Scholar 

  • Zhou T, Sun L, Humphreys J, Goldsmith EJ. Docking interactions induce exposure of activation loop in the MAP kinase ERK2. Structure. 2006;14:1011–9.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Human Biological Chemistry and Genetics, The University of Texas Medical Branch, Galveston, TX, 77555-0643, USA

    John Papaconstantinou

  2. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX, 77555-0643, USA

    John Papaconstantinou, Ching-Chyuan Hsieh & James H. DeFord

Authors
  1. John Papaconstantinou
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  2. Ching-Chyuan Hsieh
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  3. James H. DeFord
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Correspondence to John Papaconstantinou .

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Editors and Affiliations

  1. Department of Molecular Science and Technology, Ajou University, Suwon, Korea

    Sangdun Choi

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Papaconstantinou, J., Hsieh, CC., DeFord, J.H. (2018). p38 MAPK Family. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_221

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