mitogen activated protein kinase 12


Summary: A 38-kDa mitogen-activated protein kinase found primarily in SKELETAL MUSCLE.

Top Publications

  1. Askari N, Diskin R, Avitzour M, Capone R, Livnah O, Engelberg D. Hyperactive variants of p38alpha induce, whereas hyperactive variants of p38gamma suppress, activating protein 1-mediated transcription. J Biol Chem. 2007;282:91-9 pubmed
    ..Thus, intrinsically active variants that are spontaneously active in vivo have been obtained for all p38 isoforms. These variants have disclosed different effects of each isoform on AP-1 activity. ..
  2. Kuma Y, Sabio G, Bain J, Shpiro N, Marquez R, Cuenda A. BIRB796 inhibits all p38 MAPK isoforms in vitro and in vivo. J Biol Chem. 2005;280:19472-9 pubmed
  3. Lechner C, Zahalka M, Giot J, Møller N, Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996;93:4355-9 pubmed
  4. Tortorella L, Lin C, Pilch P. ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle. Biochem Biophys Res Commun. 2003;306:163-8 pubmed
    ..These results delineate a distinct pattern of ERK6 expression in mature skeletal muscle cells and suggest a specific role for ERK6 in muscle development or muscle function. ..
  5. Sabio G, Arthur J, Kuma Y, Peggie M, Carr J, Murray Tait V, et al. p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005;24:1134-45 pubmed
    ..This is likely to regulate the integrity of intercellular-junctional complexes, and cell shape and volume in response to osmotic stress. ..
  6. Cuenda A, Cohen P. Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis. J Biol Chem. 1999;274:4341-6 pubmed
    ..These results show for the first time that SAPK2/p38 plays an essential role in C2C12 cell differentiation. ..
  7. 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 pubmed
    ..Transcripts encoding stress-activated protein kinase-3 are widely expressed, with high levels in skeletal muscle. ..
  8. Hasegawa M, Cuenda A, Spillantini M, Thomas G, Buee Scherrer V, Cohen P, et al. Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition. J Biol Chem. 1999;274:12626-31 pubmed
    ..Phosphorylation of a PDZ domain-containing protein by an associated protein kinase is a novel mechanism for determining both the localization and the substrate specificity of a protein kinase. ..
  9. 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. ..

More Information


  1. 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. ..
  2. Cuenda A, Cohen P, Buee Scherrer V, Goedert M. Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. 1997;16:295-305 pubmed
    ..Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3. ..
  3. Sudarshan C, Galon J, Zhou Y, O Shea J. TGF-beta does not inhibit IL-12- and IL-2-induced activation of Janus kinases and STATs. J Immunol. 1999;162:2974-81 pubmed
    ..Rather, our data suggest the existence of alternative mechanisms of inhibition by TGF-beta. ..
  4. Marinissen M, Chiariello M, Gutkind J. Regulation of gene expression by the small GTPase Rho through the ERK6 (p38 gamma) MAP kinase pathway. Genes Dev. 2001;15:535-53 pubmed
    ..Furthermore, we present evidence that RhoA, PKN, MKK3/MKK6, and ERK6 (p38 gamma) are components of a novel signal transduction pathway involved in the regulation of gene expression and cellular transformation. ..
  5. Duyndam M, van Dam H, Smits P, Verlaan M, van der Eb A, Zantema A. The N-terminal transactivation domain of ATF2 is a target for the co-operative activation of the c-jun promoter by p300 and 12S E1A. Oncogene. 1999;18:2311-21 pubmed
    ..These data indicate that E1A does not inhibit all transcription activation functions of p300, and, in fact, cooperates with p300 in the activation of the ATF2 N-terminus. ..
  6. Qi X, Tang J, Loesch M, Pohl N, Alkan S, Chen G. p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion. Cancer Res. 2006;66:7540-7 pubmed
    ..Selective targeting of p38gamma-dependent invasion pathways may be a novel strategy to control breast cancer progression. ..
  7. Seta K, Sadoshima J. What is the unique function of SAPK3/p38gamma in cardiac myocytes?. J Mol Cell Cardiol. 2002;34:597-600 pubmed
  8. Iñesta Vaquera F, Campbell D, Arthur J, Cuenda A. ERK5 pathway regulates the phosphorylation of tumour suppressor hDlg during mitosis. Biochem Biophys Res Commun. 2010;399:84-90 pubmed publisher
    ..This is likely to have important implications in the correct timely mitotic entry and mitosis progression. ..
  9. Bogoyevitch M, Court N. Counting on mitogen-activated protein kinases--ERKs 3, 4, 5, 6, 7 and 8. Cell Signal. 2004;16:1345-54 pubmed
    ..It is clear from these studies that these additional ERKs show similarities to ERK1 and ERK2, but with some interesting differences that challenge the paradigm of the archetypical ERK1/2 MAPK pathway. ..
  10. Gillespie M, Le Grand F, Scime A, Kuang S, von Maltzahn J, Seale V, et al. p38-{gamma}-dependent gene silencing restricts entry into the myogenic differentiation program. J Cell Biol. 2009;187:991-1005 pubmed publisher
    ..Together, these results establish a hitherto unappreciated and essential role for p38-gamma signaling in positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration. ..
  11. Borsch Haubold A, Ghomashchi F, Pasquet S, Goedert M, Cohen P, Gelb M, et al. Phosphorylation of cytosolic phospholipase A2 in platelets is mediated by multiple stress-activated protein kinase pathways. Eur J Biochem. 1999;265:195-203 pubmed
    ..Our data suggest that cPLA2 is a substrate for several SAPK cascades and that phosphorylation of cPLA2 augments arachidonic acid release. ..
  12. Perdiguero E, Ruiz Bonilla V, Serrano A, Munoz Canoves P. Genetic deficiency of p38alpha reveals its critical role in myoblast cell cycle exit: the p38alpha-JNK connection. Cell Cycle. 2007;6:1298-303 pubmed
    ..We discuss these findings in the context of the emerging crosstalk of p38 and JNK signaling pathways in controlling cell growth and differentiation. ..
  13. Ruiter G, Zerp S, Bartelink H, van Blitterswijk W, Verheij M. Anti-cancer alkyl-lysophospholipids inhibit the phosphatidylinositol 3-kinase-Akt/PKB survival pathway. Anticancer Drugs. 2003;14:167-73 pubmed
    ..Inhibition of the PI3K-Akt/PKB survival pathway represents a novel mode of action of ALPs that may significantly contribute to the induction of apoptosis...
  14. Courtney M, Coffey E. The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons. Eur J Neurosci. 1999;11:1073-84 pubmed
  15. Migheli A, Piva R, Atzori C, Troost D, Schiffer D. c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 1997;56:1314-22 pubmed
    ..These results support the view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses. ..
  16. Giasson B, Mushynski W. Aberrant stress-induced phosphorylation of perikaryal neurofilaments. J Biol Chem. 1996;271:30404-9 pubmed
    ..We propose that SAPKgamma, perhaps in concert with other SAPKs, is involved in the abnormal phosphorylation of perikaryal NFH. This finding could lead to new insights into the etiology of several neurological diseases. ..
  17. Hou S, Zhi H, Pohl N, Loesch M, Qi X, Li R, et al. PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction. Cancer Res. 2010;70:2901-10 pubmed publisher
    ..These results reveal a coordinative oncogenic activity of a MAPK with its specific phosphatase and suggest that PDZ-mediated p38gamma/PTPH1 complex may be a novel target for Ras-dependent malignancies. ..
  18. de Groot R, van Dijk T, Caldenhoven E, Coffer P, Raaijmakers J, Lammers J, et al. Activation of 12-O-tetradecanoylphorbol-13-acetate response element- and dyad symmetry element-dependent transcription by interleukin-5 is mediated by Jun N-terminal kinase/stress-activated protein kinase kinases. J Biol Chem. 1997;272:2319-25 pubmed
    ..Taken together, we show for the first time that IL-5 activates kinases of the JNK/SAPK family, and that this activation is linked to IL-5-induced TRE- and DSE-dependent transcription. ..
  19. Fearns C, Kline L, Gram H, Di Padova F, Zurini M, Han J, et al. Coordinate activation of endogenous p38alpha, beta, gamma, and delta by inflammatory stimuli. J Leukoc Biol. 2000;67:705-11 pubmed
    ..The kinetics of activation of each of the p38s were similar for each stimulus used, suggesting a common upstream activation pathway. Simultaneous activation of the p38s suggests that all four may be important in inflammation. ..
  20. Court N, Kuo I, Quigley O, Bogoyevitch M. Phosphorylation of the mitochondrial protein Sab by stress-activated protein kinase 3. Biochem Biophys Res Commun. 2004;319:130-7 pubmed
    ..Our results suggest that SAPK3 and JNK may share a common target at the mitochondria and provide new insights into the substrate recognition by SAPK3. ..
  21. Tosti E, Waldbaum L, Warshaw G, Gross E, Ruggieri R. The stress kinase MRK contributes to regulation of DNA damage checkpoints through a p38gamma-independent pathway. J Biol Chem. 2004;279:47652-60 pubmed
    ..Thus, in response to IR MRK controls two independent pathways: the Chk2-Cdc25A pathway leading to cell cycle arrest and the p38gamma MAPK pathway. ..
  22. Lovett F, Cosgrove R, Gonzalez I, Pell J. Essential role for p38alpha MAPK but not p38gamma MAPK in Igf2 expression and myoblast differentiation. Endocrinology. 2010;151:4368-80 pubmed publisher
  23. Hernandez Losa J, Parada Cobo C, Guinea Viniegra J, Sánchez Arévalo Lobo V, Ramon Y Cajal S, Sanchez Prieto R. Role of the p38 MAPK pathway in cisplatin-based therapy. Oncogene. 2003;22:3998-4006 pubmed
    ..Therefore, we conclude that the p38 MAPK pathway is a specific target for cisplatin-based therapy with clinical implications. ..
  24. 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. ..
  25. Ellinger Ziegelbauer H, Brown K, Kelly K, Siebenlist U. Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. J Biol Chem. 1997;272:2668-74 pubmed
    ..The ability of MEKK3 to simultaneously activate the SAPK and ERK pathways is remarkable, given that they have divergent roles in cellular homeostasis. ..
  26. Yin T, Sandhu G, Wolfgang C, Burrier A, Webb R, Rigel D, et al. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem. 1997;272:19943-50 pubmed
  27. Jenkins S, Zinnerman M, Garner C, Johnson G. Modulation of tau phosphorylation and intracellular localization by cellular stress. Biochem J. 2000;345 Pt 2:263-70 pubmed
  28. Goedert M, Hasegawa J, Craxton M, Leversha M, Clegg S. Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization. Genomics. 1997;41:501-2 pubmed
  29. Turner N, Lord C, Iorns E, Brough R, Swift S, Elliott R, et al. A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J. 2008;27:1368-77 pubmed publisher
    ..These results highlight the potential of synthetic lethal siRNA screens with chemical inhibitors to define new determinants of sensitivity and potential therapeutic targets. ..
  30. Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, et al. Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science. 1998;280:1262-5 pubmed
    ..Catalytic activation of MAP kinase phosphatases through substrate binding may regulate MAP kinase activation by a large number of receptor systems. ..
  31. Eyers P, Craxton M, Morrice N, Cohen P, Goedert M. Conversion of SB 203580-insensitive MAP kinase family members to drug-sensitive forms by a single amino-acid substitution. Chem Biol. 1998;5:321-8 pubmed
  32. Behrens A, Sibilia M, Wagner E. Amino-terminal phosphorylation of c-Jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet. 1999;21:326-9 pubmed
    ..Our results provide evidence that JNP is dispensable for mouse development, and identify c-Jun as the essential substrate of JNK signalling during kainate-induced neuronal apoptosis. ..
  33. Kimonides V, Spillantini M, Sofroniew M, Fawcett J, Herbert J. Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures. Neuroscience. 1999;89:429-36 pubmed
    ..This protective action may involve stress-activated protein kinase 3-related intracellular pathways, though direct evidence for this has still to be obtained. ..
  34. Sakabe K, Teramoto H, Zohar M, Behbahani B, Miyazaki H, Chikumi H, et al. Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38gamma-dependent signaling pathway. FEBS Lett. 2002;511:15-20 pubmed
    ..These findings suggest that this unique GTPase stimulates proliferative pathways distinct from those regulated by other Ras family members. ..
  35. Zhang J, Harrison J, Studzinski G. Isoforms of p38MAPK gamma and delta contribute to differentiation of human AML cells induced by 1,25-dihydroxyvitamin D?. Exp Cell Res. 2011;317:117-30 pubmed publisher
    ..This activation may result from the removal of feedback inhibition of an upstream regulator of those pathways, when p38MAPK alpha and beta are inhibited by SB. ..
  36. Fabre S, Reynaud C, Jalinot P. Identification of functional PDZ domain binding sites in several human proteins. Mol Biol Rep. 2000;27:217-24 pubmed
    ..The significance of the presence of a PDZ-BS in these various proteins is discussed with respect to their function. ..
  37. Court N, dos Remedios C, Cordell J, Bogoyevitch M. Cardiac expression and subcellular localization of the p38 mitogen-activated protein kinase member, stress-activated protein kinase-3 (SAPK3). J Mol Cell Cardiol. 2002;34:413-26 pubmed
    ..These differences between p38- alpha/ beta and SAPK3 probably reflect the specialized functions of SAPK3 and emphasize the need to evaluate SAPK3 upstream activators and downstream targets in the heart. ..
  38. Gum R, McLaughlin M, Kumar S, Wang Z, Bower M, Lee J, et al. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket. J Biol Chem. 1998;273:15605-10 pubmed
    ..These results indicate that these three amino acids can confer specificity and sensitivity to SB 203580 for at least two different classes of MAPKs. ..
  39. Abdollahi T, Robertson N, Abdollahi A, Litwack G. Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3. Cancer Res. 2003;63:4521-6 pubmed
    ..The data suggest a potentially important role of IL-8 in protecting ovarian cancer cells from TRAIL-mediated apoptosis and signify a new potential chemotherapeutic target to augment TRAIL therapy. ..
  40. Qi X, Pohl N, Loesch M, Hou S, Li R, Qin J, et al. p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007;282:31398-408 pubmed
    ..These results suggest that p38alpha may, upon phosphorylation, act as a gatekeeper of the p38 MAPK family to yield a coordinative biological response through disrupting its antagonistic p38gamma family protein. ..
  41. Knebel A, Morrice N, Cohen P. A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. EMBO J. 2001;20:4360-9 pubmed
    ..The phosphorylation of eEF2K at Ser359 was also induced by insulin-like growth factor-1. However, this was blocked by rapamycin, indicating that Ser359 is targeted by at least two signalling pathways. ..
  42. Franco D, Nojek I, Molinero L, Coso O, Costas M. Osmotic stress sensitizes naturally resistant cells to TNF-alpha-induced apoptosis. Cell Death Differ. 2002;9:1090-8 pubmed
    ..The inhibition of p38 kinase, also involved in NF-kappaB activation, significantly increases the effect of osmotic stress on TNF-alpha-induced cell death. ..
  43. Ambrose M, Ryan A, O Sullivan G, Dunne C, Barry O. Induction of apoptosis in renal cell carcinoma by reactive oxygen species: involvement of extracellular signal-regulated kinase 1/2, p38delta/gamma, cyclooxygenase-2 down-regulation, and translocation of apoptosis-inducing factor. Mol Pharmacol. 2006;69:1879-90 pubmed
    ..Our data provide a molecular basis for the anticancer activity of LY83583. ..
  44. ter Haar E, Coll J, Austen D, Hsiao H, Swenson L, Jain J. Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol. 2001;8:593-6 pubmed
    ..The structure explains the unique primed phosphorylation mechanism of GSK3beta and how GSK3beta relies on a phosphoserine in the substrate for the alignment of the beta- and alpha-helical domains. ..
  45. Lawler S, Cuenda A, Goedert M, Cohen P. SKK4, a novel activator of stress-activated protein kinase-1 (SAPK1/JNK). FEBS Lett. 1997;414:153-8 pubmed
    ..The identification of SKK4 explains why the major SAPK1/JNK activator detected in many mammalian cell extracts is chromatographically separable from SKK1/MKK4. ..
  46. 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 pubmed
    ..Unlike SAPK2a and SAPK2b, SAPK4 and SAPK3 were not inhibited by the drugs SB 203580 and SB 202190. Our results suggest that cellular functions previously attributed to SAPK1 and/or SAPK2 may be mediated by SAPK3 or SAPK4. ..
  47. Smith S, Fenwick P, Nicholson A, Kirschenbaum F, Finney Hayward T, Higgins L, et al. Inhibitory effect of p38 mitogen-activated protein kinase inhibitors on cytokine release from human macrophages. Br J Pharmacol. 2006;149:393-404 pubmed
    ..These effects are not due to lack of p38 activation or p38alpha expression in macrophages but may reflect differential effects on the stability of cytokine mRNA. ..
  48. May G, Funk M, Black E, Clark W, Hussain S, Woodgett J, et al. An oncogenic mutation uncouples the v-Jun oncoprotein from positive regulation by the SAPK/JNK pathway in vivo. Curr Biol. 1998;8:117-20 pubmed
  49. Lee J, Park J, Lee Y, Lee S, Han P. Distinct localization of SAPK isoforms in neurons of adult mouse brain implies multiple signaling modes of SAPK pathway. Brain Res Mol Brain Res. 1999;70:116-24 pubmed
    ..In addition, differential regional and subcellular localizations of SAPK isoforms allow us to speculate multiple signaling modes for SAPK activation in brain. ..
  50. Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P. p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. J Biol Chem. 2009;284:11237-46 pubmed publisher
  51. Faraone D, Aguzzi M, Toietta G, Facchiano A, Facchiano F, Magenta A, et al. Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo. Neoplasia. 2009;11:732-42 pubmed
    ..All together, these data demonstrate that PDGF-Ralpha strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control. ..
  52. Touyz R, Cruzado M, Tabet F, Yao G, Salomon S, Schiffrin E. Redox-dependent MAP kinase signaling by Ang II in vascular smooth muscle cells: role of receptor tyrosine kinase transactivation. Can J Physiol Pharmacol. 2003;81:159-67 pubmed
    ..These findings suggest that Ang II activates p38MAP kinase and ERK5 via redox-dependent cascades that are regulated by IGF-1R and EGFR transactivation. ERK1/2 regulation by Ang II is via redox-insensitive pathways. ..
  53. Court N, Ingley E, Klinken S, Bogoyevitch M. Outer membrane protein 25-a mitochondrial anchor and inhibitor of stress-activated protein kinase-3. Biochim Biophys Acta. 2005;1744:68-75 pubmed
    ..This is a new mechanism for the regulation of SAPK3 and suggests that its intracellular activity should not be solely assessed by its phosphorylation status. ..