mitogen activated protein kinase 11


Summary: A 38-kDa mitogen-activated protein kinase that is expressed in a broad variety of cell types. It may play a role in regulating cell proliferation and TRANSCRIPTION FACTOR AP-1 dependent transcription.

Top Publications

  1. Jones N, Tyner K, Nibarger L, Stanley H, Cornelison D, Fedorov Y, et al. The p38alpha/beta MAPK functions as a molecular switch to activate the quiescent satellite cell. J Cell Biol. 2005;169:105-16 pubmed
    ..Activation of satellite cells and p38alpha/beta MAPKs occurs concomitantly, providing further support that these MAPKs function as a molecular switch for satellite cell activation. ..
  2. O Keefe S, Mudgett J, Cupo S, Parsons J, Chartrain N, Fitzgerald C, et al. Chemical genetics define the roles of p38alpha and p38beta in acute and chronic inflammation. J Biol Chem. 2007;282:34663-71 pubmed
    ..Similarly, p38beta knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38alpha isoform is necessary and sufficient for anti-inflammatory efficacy in vivo. ..
  3. Beardmore V, Hinton H, Eftychi C, Apostolaki M, Armaka M, Darragh J, et al. Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol. 2005;25:10454-64 pubmed
    ..Together these results suggest that p38alpha, and not p38beta, is the major p38 isoform involved in the immune response and that it would not be necessary to retain activity against p38beta during the development of p38 inhibitors. ..
  4. Lee M, Kong H, Cheong J. Regulation of activating transcription factor-2 in early stage of the adipocyte differentiation program. Biochem Biophys Res Commun. 2001;281:1241-7 pubmed
  5. Kenny T, Keen C, Jones P, Kung H, Schmitz H, Gershwin M. Pentameric procyanidins isolated from Theobroma cacao seeds selectively downregulate ErbB2 in human aortic endothelial cells. Exp Biol Med (Maywood). 2004;229:255-63 pubmed
    ..These results suggest specific dietary flavonoids are capable of selectively inhibiting ErbB2 and therefore may offer important insight into the design of therapeutic agents that target tumors overexpressing ErbB2. ..
  6. Bouchard V, Harnois C, Demers M, Thibodeau S, Laquerre V, Gauthier R, et al. B1 integrin/Fak/Src signaling in intestinal epithelial crypt cell survival: integration of complex regulatory mechanisms. Apoptosis. 2008;13:531-42 pubmed publisher
    ..Hence, beta1 integrin/Fak/Src signaling translates into integrated mediating functions of p38beta activation and regulation of Bcl-2 homologs by PI3-K/Akt-1 and MEK/Erk, consequently determining their requirement (or not) for survival. ..
  7. Jiang Y, Chen C, Li Z, Guo W, Gegner J, Lin S, et al. Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem. 1996;271:17920-6 pubmed
    ..The data reported here suggest that while closely related, p38beta and p38 may be regulated by differing mechanisms and may exert their actions on separate downstream targets. ..
  8. Lemieux K, Konrad D, Klip A, Marette A. The AMP-activated protein kinase activator AICAR does not induce GLUT4 translocation to transverse tubules but stimulates glucose uptake and p38 mitogen-activated protein kinases alpha and beta in skeletal muscle. FASEB J. 2003;17:1658-65 pubmed
  9. Hong S, Choi H, Park M, Kim Y, Choi Y, Kim H, et al. Activation and interaction of ATF2 with the coactivator ASC-2 are responsive for granulocytic differentiation by retinoic acid. J Biol Chem. 2004;279:16996-7003 pubmed

More Information


  1. Razandi M, Pedram A, Park S, Levin E. Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem. 2003;278:2701-12 pubmed
    ..The E domain is sufficient to enact these events, defining additional details of the important cross-talk between membrane ER and EGFR in breast cancer. ..
  2. Cao X, Rui L, Pennington P, Chlan Fourney J, Jiang Z, Wei Z, et al. Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity. J Neurochem. 2009;111:101-10 pubmed publisher
  3. Wong J, Campbell G, Spector S. Differential induction of interleukin-10 in monocytes by HIV-1 clade B and clade C Tat proteins. J Biol Chem. 2010;285:18319-25 pubmed publisher
    ..These findings provide further evidence that HIV-1 clades differ in their biological properties that may impact HIV-1 pathogenesis and disease progression. ..
  4. Frey M, Dise R, Edelblum K, Polk D. p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration. EMBO J. 2006;25:5683-92 pubmed
    ..Together these data position p38 as a modulator of ligand-stimulated EGFR processing and demonstrate that this processing has a profound impact on the cellular outcome of EGFR signaling. ..
  5. Lamalice L, Houle F, Huot J. Phosphorylation of Tyr1214 within VEGFR-2 triggers the recruitment of Nck and activation of Fyn leading to SAPK2/p38 activation and endothelial cell migration in response to VEGF. J Biol Chem. 2006;281:34009-20 pubmed
    ..In turn, this triggers the activation of the SAPK2/p38 MAP kinase module, and promotes stress fiber formation and endothelial cell migration. ..
  6. Meissner J, Chang K, Kubis H, Nebreda A, Gros G, Scheibe R. 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. J Biol Chem. 2007;282:7265-75 pubmed
    ..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. ..
  7. Kan W, Hsu J, Ba Z, Schwacha M, Chen J, Choudhry M, et al. p38 MAPK-dependent eNOS upregulation is critical for 17beta-estradiol-mediated cardioprotection following trauma-hemorrhage. Am J Physiol Heart Circ Physiol. 2008;294:H2627-36 pubmed publisher
    ..The salutary effects of E2 on cardiac functions and tissue protection following trauma-hemorrhage are mediated, in part, through activation of p38 MAPK and subsequent eNOS expression and phosphorylation. ..
  8. Harrington E, Smeglin A, Parks N, Newton J, Rounds S. Adenosine induces endothelial apoptosis by activating protein tyrosine phosphatase: a possible role of p38alpha. Am J Physiol Lung Cell Mol Physiol. 2000;279:L733-42 pubmed
    ..These results indicate that PTPase(s) plays an integral role in the induction of EC apoptosis upon exposure to homocysteine and/or adenosine, possibly by the attenuation of p38alpha activity...
  9. Knebel A, Haydon C, Morrice N, Cohen P. Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways. Biochem J. 2002;367:525-32 pubmed
    ..Since the phosphorylation of Ser-377 does not inhibit eEF2 kinase in vitro, our results suggest that anisomycin or TNF-alpha inhibit eEF2 kinase via the phosphorylation of Ser-359. ..
  10. Svensson C, Fitzsimmons B, Azizi S, Powell H, Hua X, Yaksh T. Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem. 2005;92:1508-20 pubmed
    ..Thus, spinal p38beta, probably in microglia, plays a significant role in spinal nociceptive processing and represents a potential target for pain therapy. ..
  11. Eckert R, Efimova T, Balasubramanian S, Crish J, Bone F, Dashti S. p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta. J Invest Dermatol. 2003;120:823-8 pubmed
    ..In this review, we discuss the role of the p38 alpha, p38 beta, and p38 gamma isoforms and then present recent findings that define a role for p38 delta as a regulator of differentiation-dependent gene expression in keratinocytes. ..
  12. Cross H, Li M, Petrich B, Murphy E, Wang Y, Steenbergen C. Effect of p38 MAP kinases on contractility and ischemic injury in intact heart. Acta Physiol Hung. 2009;96:307-23 pubmed publisher
    ..In summary, attenuated p38 activity led to increased myocardial contractility; specific isoforms of p38 and their sub-cellular localization may have different roles in modulating ischemic injury. ..
  13. Miller F, Fenart L, Landry V, Coisne C, Cecchelli R, Dehouck M, et al. The MAP kinase pathway mediates transcytosis induced by TNF-alpha in an in vitro blood-brain barrier model. Eur J Neurosci. 2005;22:835-44 pubmed
    ..These data suggest that the MAPK pathway is involved in the transcytosis regulation in endothelial cells from an in vitro BBB model. ..
  14. Rousseau S, Peggie M, Campbell D, Nebreda A, Cohen P. Nogo-B is a new physiological substrate for MAPKAP-K2. Biochem J. 2005;391:433-40 pubmed
    ..The anisomycin-induced phosphorylation of Ser107 in HeLa cells can be prevented by 'knockdown' of MAPKAP-K2 using siRNA (small interfering RNA). Taken together, our results identify Nogo-B as a new physiological substrate of MAPKAP-K2. ..
  15. Piao C, Yu Y, Han P, Lee J. Dynamic expression of p38beta MAPK in neurons and astrocytes after transient focal ischemia. Brain Res. 2003;976:120-4 pubmed
    ..The temporally and spatially regulated pattern of p38beta MAPK expression in the postischemic brain suggests distinct roles of p38beta MAPK in neuronal death and in the astrocyte activation. ..
  16. Sebe A, Leivonen S, Fintha A, Masszi A, Rosivall L, Kahari V, et al. Transforming growth factor-beta-induced alpha-smooth muscle cell actin expression in renal proximal tubular cells is regulated by p38beta mitogen-activated protein kinase, extracellular signal-regulated protein kinase1,2 and the Smad signalling durin. Nephrol Dial Transplant. 2008;23:1537-45 pubmed publisher
    ..TGFbeta-induced alphaSMA expression is regulated by the coordinated activation of a complex system of parallel MAPK and Smad signalling pathways in renal proximal tubular cells during epithelial-mesenchymal transdifferentiation. ..
  17. Rouget R, Auclair Y, Loignon M, Affar E, Drobetsky E. A sensitive flow cytometry-based nucleotide excision repair assay unexpectedly reveals that mitogen-activated protein kinase signaling does not regulate the removal of UV-induced DNA damage in human cells. J Biol Chem. 2008;283:5533-41 pubmed
    ..Our results provide solid evidence for the first time, in disaccord with a burgeoning perception, that mitogen-activated protein kinase signaling does not influence the efficiency of human global-genomic nucleotide excision repair. ..
  18. Lim S, Zou Y, Friedman E. The transcriptional activator Mirk/Dyrk1B is sequestered by p38alpha/beta MAP kinase. J Biol Chem. 2002;277:49438-45 pubmed
    ..These data suggest a novel cell cycle-dependent function for p38, suppression of the function of Mirk as a transcriptional activator only when cells are proliferating, and thus limiting Mirk function to growth-arrested cells. ..
  19. Arantes V, Reis M, Latorraca M, Ferreira F, Stoppiglia L, Carneiro E, et al. Palmitic acid increase levels of pancreatic duodenal homeobox-1 and p38/stress-activated protein kinase in islets from rats maintained on a low protein diet. Br J Nutr. 2006;96:1006-12 pubmed
  20. Dambach D. Potential adverse effects associated with inhibition of p38alpha/beta MAP kinases. Curr Top Med Chem. 2005;5:929-39 pubmed
  21. Schulz R, Gres P, Skyschally A, Duschin A, Belosjorow S, Konietzka I, et al. Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo. FASEB J. 2003;17:1355-7 pubmed
    ..We conclude that IP increases co-localization of protein kinases with Cx43 and preserves phosphorylation of Cx43 during ischemia. ..
  22. Cezar de Mello P, Nascimento Silva V, Villela C, Fierro I. Aspirin-triggered Lipoxin A4 inhibition of VEGF-induced endothelial cell migration involves actin polymerization and focal adhesion assembly. Oncogene. 2006;25:122-9 pubmed
  23. Bell C, Larivière N, Watson P, Watson A. Mitogen-activated protein kinase (MAPK) pathways mediate embryonic responses to culture medium osmolarity by regulating Aquaporin 3 and 9 expression and localization, as well as embryonic apoptosis. Hum Reprod. 2009;24:1373-86 pubmed publisher
    ..MAPK14/11 activation is a component of the rapid adaptive stress response mechanism that includes the effects of AQP mRNA expression and protein localization, whereas the MAPK8 pathway is a regulator of apoptosis. ..
  24. Silva G, Cunha A, Gregoire I, Seldon M, Soares M. The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform. J Immunol. 2006;177:1894-903 pubmed
    ..In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38alpha by the 26S proteasome and on the expression of p38beta. ..
  25. Rolli Derkinderen M, Machavoine F, Baraban J, Grolleau A, Beretta L, Dy M. ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1. J Biol Chem. 2003;278:18859-67 pubmed
    ..These data (i) are the first evidence of a new role of ERK and p38 on the translational machinery and (ii) demonstrate that 4E-BP1 is a new target for Egr-1. ..
  26. Park J, Kim Y, Yoo M. The role of p38b MAPK in age-related modulation of intestinal stem cell proliferation and differentiation in Drosophila. Aging (Albany NY). 2009;1:637-51 pubmed
    ..Taken together, our findings suggest that p38 MAPK plays a crucial role in the balance between ISC proliferation and proper differentiation in the adult Drosophila midgut. ..
  27. Wang H, Xu Q, Xiao F, Jiang Y, Wu Z. Involvement of the p38 mitogen-activated protein kinase alpha, beta, and gamma isoforms in myogenic differentiation. Mol Biol Cell. 2008;19:1519-28 pubmed publisher
    ..e., E2F2, cyclin D3, and WISP1) are found to be required for myogenin expression, which provides a molecular basis to explain why different p38 isoforms are required for myogenic differentiation. ..
  28. Ho D, Bardwell A, Abdollahi M, Bardwell L. A docking site in MKK4 mediates high affinity binding to JNK MAPKs and competes with similar docking sites in JNK substrates. J Biol Chem. 2003;278:32662-72 pubmed
    ..The MEK1 and MEK2 D-sites displayed a strong selectivity for their cognate MAPK (ERK2) versus a non-cognate MAPK (JNK). In contrast, the MKK4 D-site exhibited only limited selectivity for JNK versus ERK. ..
  29. Kim H, Wang X, Zhang J, Suh G, Benjamin I, Ryter S, et al. Heat shock protein-70 mediates the cytoprotective effect of carbon monoxide: involvement of p38 beta MAPK and heat shock factor-1. J Immunol. 2005;175:2622-9 pubmed
    ..These data provide a novel mechanism for the protective effects of CO and underscore a potential application of this gaseous molecule in anti-inflammatory therapies. ..
  30. Foschi M, Sorokin A, Pratt P, McGinty A, La Villa G, Franchi F, et al. PreproEndothelin-1 expression in human mesangial cells: evidence for a p38 mitogen-activated protein kinase/protein kinases-C-dependent mechanism. J Am Soc Nephrol. 2001;12:1137-50 pubmed
    ..In conclusion, human mesangial cell expression of preproET-1 may be increased potently in the presence of two common proinflammatory mediators, thereby providing a potential mechanism for ET-1 production in inflammatory renal disease. ..
  31. Van Laethem A, Van Kelst S, Lippens S, Declercq W, Vandenabeele P, Janssens S, et al. Activation of p38 MAPK is required for Bax translocation to mitochondria, cytochrome c release and apoptosis induced by UVB irradiation in human keratinocytes. FASEB J. 2004;18:1946-8 pubmed
  32. Jans R, Atanasova G, Jadot M, Poumay Y. Cholesterol depletion upregulates involucrin expression in epidermal keratinocytes through activation of p38. J Invest Dermatol. 2004;123:564-73 pubmed
  33. Guo Y, Kang B, Han J, Williamson J. p38beta MAP kinase protects rat mesangial cells from TNF-alpha-induced apoptosis. J Cell Biochem. 2001;82:556-65 pubmed
    ..While it is unclear whether p38beta regulates NF-kappaB transcription activity at other steps, it is apparent that p38beta does not affect TNF-alpha-induced NF-kappaB activation at the stage of nuclear translocation. ..
  34. Gabrys D, Greco O, Patel G, Prise K, Tozer G, Kanthou C. Radiation effects on the cytoskeleton of endothelial cells and endothelial monolayer permeability. Int J Radiat Oncol Biol Phys. 2007;69:1553-62 pubmed
    ..The results also suggest that the RhoA pathway might be a useful target for modulating the permeability and other effects of radiation for therapeutic gain. ..
  35. Ruiz Bonilla V, Perdiguero E, Gresh L, Serrano A, Zamora M, Sousa Victor P, et al. Efficient adult skeletal muscle regeneration in mice deficient in p38beta, p38gamma and p38delta MAP kinases. Cell Cycle. 2008;7:2208-14 pubmed
    ..This study constitutes the first analysis addressing the functionality of p38beta, p38gamma and p38delta in satellite cell-dependent adult muscle regeneration and growth. ..
  36. Esposito G, Prasad S, Rapacciuolo A, Mao L, Koch W, Rockman H. Cardiac overexpression of a G(q) inhibitor blocks induction of extracellular signal-regulated kinase and c-Jun NH(2)-terminal kinase activity in in vivo pressure overload. Circulation. 2001;103:1453-8 pubmed
  37. Ishii T, Sootome H, Toyoda H, Suda M, Noumi T, Yamashita K. Dual enzyme-linked immunosorbent assay system for detection of endogenous kinase activities of mitogen- and stress-activated protein kinase-1/2. Assay Drug Dev Technol. 2007;5:523-33 pubmed
    ..Our established system is applicable to inhibitor screening and drug discovery related to MSK1/MSK2. ..
  38. Hickson J, Fong B, Watson P, Watson A. PP2Cdelta (Ppm1d, WIP1), an endogenous inhibitor of p38 MAPK, is regulated along with Trp53 and Cdkn2a following p38 MAPK inhibition during mouse preimplantation development. Mol Reprod Dev. 2007;74:821-34 pubmed
    ..This study increases our understanding of the mechanisms controlling preimplantation development and of the interactions between preimplantation embryos and their culture environments. ..
  39. Zhu F, Zhang Y, Bode A, Dong Z. Involvement of ERKs and mitogen- and stress-activated protein kinase in UVC-induced phosphorylation of ATF2 in JB6 cells. Carcinogenesis. 2004;25:1847-52 pubmed
    ..Overall, our results reveal that MSK1 and ERKs, like p38 kinase and JNKs, are required for ATF2 phosphorylation (Thr71) in the UVC response. ..
  40. Pham H, Vincenti R, Slice L. COX-2 promoter activation by AT1R-Gq-PAK-p38beta signaling in intestinal epithelial cells. Biochim Biophys Acta. 2008;1779:408-13 pubmed publisher
    ..These data demonstrate that in IEC-18 cells, Ang II-dependent activation of the COX-2 promoter is mediated primarily through Gq/11 signaling via a PAK/MKK6/p38beta/CREB signaling cascade. ..
  41. Piao C, Che Y, Han P, Lee J. Delayed and differential induction of p38 MAPK isoforms in microglia and astrocytes in the brain after transient global ischemia. Brain Res Mol Brain Res. 2002;107:137-44 pubmed
  42. Johnstone E, Sibley C, Lowen B, Guilbert L. Epidermal growth factor stimulation of trophoblast differentiation requires MAPK11/14 (p38 MAP kinase) activation. Biol Reprod. 2005;73:1282-8 pubmed
  43. Dyson M, Thomson S, Inagaki M, Goto H, Arthur S, Nightingale K, et al. MAP kinase-mediated phosphorylation of distinct pools of histone H3 at S10 or S28 via mitogen- and stress-activated kinase 1/2. J Cell Sci. 2005;118:2247-59 pubmed
    ..These studies reveal a remarkable level of targeting of S10 and S28 phosphorylation to distinct H3 tails within chromatin in the interphase mouse nucleus. Possible models for such exquisite targeting are discussed. ..
  44. Sicard P, Clark J, Jacquet S, Mohammadi S, Arthur J, O Keefe S, et al. The activation of p38 alpha, and not p38 beta, mitogen-activated protein kinase is required for ischemic preconditioning. J Mol Cell Cardiol. 2010;48:1324-8 pubmed publisher
    ..Since p38 alpha is also the isoform that leads to lethal myocardial injury, it is unlikely that targeted therapeutic strategies to achieve isoform-selective inhibition will only prevent the harmful consequences of activation. ..
  45. Buee Scherrer V, Goedert M. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells. FEBS Lett. 2002;515:151-4 pubmed
    ..These findings indicate that the aberrant activation of SAP kinases, especially SAPK3/p38gamma and SAPK4/p38delta, could play an important role in the abnormal hyperphosphorylation of tau that is an invariant feature of the tauopathies. ..
  46. Camuzeaux B, Diring J, Hamard P, Oulad Abdelghani M, Donzeau M, Vigneron M, et al. p38beta2-mediated phosphorylation and sumoylation of ATF7 are mutually exclusive. J Mol Biol. 2008;384:980-91 pubmed publisher
    ..Our data therefore conclusively establish that sumoylation and phosphorylation of ATF7 are two antagonistic posttranslational modifications. ..
  47. Si H, Liu D. Isoflavone genistein protects human vascular endothelial cells against tumor necrosis factor-alpha-induced apoptosis through the p38beta mitogen-activated protein kinase. Apoptosis. 2009;14:66-76 pubmed publisher
    ..Preservation of the functional integrity of the endothelial monolayer may represent an important mechanism by which genistein exerts its vasculoprotective effect. ..
  48. Desbiens K, Deschesnes R, Labrie M, Desfosses Y, Lambert H, Landry J, et al. c-Myc potentiates the mitochondrial pathway of apoptosis by acting upstream of apoptosis signal-regulating kinase 1 (Ask1) in the p38 signalling cascade. Biochem J. 2003;372:631-41 pubmed
    ..The findings indicated that c-Myc potentiation of the mitochondrial pathway of apoptosis results, at least in part, from a sensitization of Ask1 activation, allowing DNA-damaging agents to induce in cascade Ask1, p38alpha and Bax. ..
  49. McClung J, Judge A, Powers S, Yan Z. p38 MAPK links oxidative stress to autophagy-related gene expression in cachectic muscle wasting. Am J Physiol Cell Physiol. 2010;298:C542-9 pubmed publisher
  50. Mahlknecht U, Will J, Varin A, Hoelzer D, Herbein G. Histone deacetylase 3, a class I histone deacetylase, suppresses MAPK11-mediated activating transcription factor-2 activation and represses TNF gene expression. J Immunol. 2004;173:3979-90 pubmed
  51. Huang H, Li Y, Chung M. Activin A induction of erythroid differentiation through MKK6-p38alpha/p38beta pathway is inhibited by follistatin. J Cell Physiol. 2010;223:687-94 pubmed publisher
    ..These results demonstrate that activin A induces erythroid differentiation of K562 cells through activation of MKK6-p38alpha/p38beta pathway and follistatin inhibits those effects. ..
  52. Park J, Kim Y, Kim J, Lee S, Park S, Yamaguchi M, et al. Regulation of the Drosophila p38b gene by transcription factor DREF in the adult midgut. Biochim Biophys Acta. 2010;1799:510-9 pubmed publisher
    ..Our results suggest that the D-p38b gene is regulated by the DREF pathway and that DREF is involved in the regulation of proliferation and differentiation of Drosophila ISCs and progenitors. ..