mitogen activated protein kinase 13


Summary: A 38-kDa mitogen-activated protein kinase found expressed at high levels in LUNG; KIDNEY; TESTIS; PANCREAS; and SMALL INTESTINE. It may play a role in regulating functions such as CELL DIFFERENTIATION and APOPTOSIS of EPITHELIAL CELLS.

Top Publications

  1. Efimova T, Broome A, Eckert R. Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signal-regulated kinase 1/2 complex. Mol Cell Biol. 2004;24:8167-83 pubmed
    ..This regulation appears to be physiological, since H(2)O(2), a known inducer of keratinocyte apoptosis, promotes identical PKCdelta and p38delta-ERK1/2 activity changes, leading to similar morphological changes. ..
  2. Feijoo C, Campbell D, Jakes R, Goedert M, Cuenda A. Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. J Cell Sci. 2005;118:397-408 pubmed
    ..These findings suggest a role for Tau in the adaptative response of neurons to stress and indicate that SAPK4/p38delta and/or SAPK3/p38delta may contribute to the hyperphosphorylation of Tau in the human tauopathies. ..
  3. Clark A, Staniland A, Marchand F, Kaan T, McMahon S, Malcangio M. P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J Neurosci. 2010;30:573-82 pubmed publisher
    ..We suggest that CNS-penetrant P2X7 receptor antagonists, by targeting microglia in pain-enhanced response states, may be beneficial for the treatment of persistent pain. ..
  4. Tan F, Ooi A, Huang D, Wong J, Qian C, Chao C, et al. p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion. Int J Cancer. 2010;126:2353-61 pubmed publisher
    ..In summary, p38delta may serve as a novel diagnostic marker for CC and may also serve as a new target for molecular based therapy of this disease. ..
  5. Schindler E, Hindes A, Gribben E, Burns C, Yin Y, Lin M, et al. p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice. Cancer Res. 2009;69:4648-55 pubmed publisher
    ..These findings strongly suggest an in vivo role for p38delta in promoting cell proliferation and tumor development in epidermis and may have therapeutic implication for skin cancer. ..
  6. Sumara G, Formentini I, Collins S, Sumara I, Windak R, Bodenmiller B, et al. Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell. 2009;136:235-48 pubmed publisher
    ..In conclusion, the p38delta-PKD pathway integrates regulation of the insulin secretory capacity and survival of pancreatic beta cells, pointing to a pivotal role for this pathway in the development of overt diabetes mellitus. ..
  7. Diédhiou C, Popova O, Dietz K, Golldack D. The SNF1-type serine-threonine protein kinase SAPK4 regulates stress-responsive gene expression in rice. BMC Plant Biol. 2008;8:49 pubmed publisher
  8. 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. ..
  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. ..

More Information


  1. Balasubramanian S, Eckert R. Green tea polyphenol and curcumin inversely regulate human involucrin promoter activity via opposing effects on CCAAT/enhancer-binding protein function. J Biol Chem. 2004;279:24007-14 pubmed
    ..The observation that two antioxidants can produce opposite effects is an important consideration in the context of therapeutic antioxidant use. ..
  2. Yoshida H, Goedert M. Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope. J Neurochem. 2006;99:154-64 pubmed
    ..Phosphorylation by PKA and SAPK4/p38delta abolished the ability of tau to promote microtubule assembly, but failed to influence significantly the heparin-induced assembly of tau into filaments. ..
  3. 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. ..
  4. Schoorlemmer J, Goldfarb M. Fibroblast growth factor homologous factors and the islet brain-2 scaffold protein regulate activation of a stress-activated protein kinase. J Biol Chem. 2002;277:49111-9 pubmed
    ..These results support the existence of a signaling module in which IB2 scaffolds a MLK3/MKK/p38delta kinase cascade. FHFs aid in recruitment of p38 to IB2 and may serve as kinase substrates. ..
  5. 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. ..
  6. Herbison C, Sayer D, Bellgard M, Allcock R, Christiansen F, Price P. Structure and polymorphism of two stress-activated protein kinase genes centromeric of the MHC: SAPK2a and SAPK4. DNA Seq. 1999;10:229-43 pubmed
    ..This highlights the selective pressure placed on these genes to maintain their protein sequence, but does not favour a role in genetic regulation of disease or provide evidence of linkage disequilibrium with the MHC. ..
  7. 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
  8. Pani E, Ferrari S. p38MAPK delta controls c-Myb degradation in response to stress. Blood Cells Mol Dis. 2008;40:388-94 pubmed
    ..Particularly, mutation of Thr(354), Thr(486), Ser(556) and Thr(572) to Alanine conferred resistance to stress-induced degradation. The implications of c-Myb downregulation during inflammatory responses are discussed. ..
  9. 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. ..
  10. Zelenka M, Schäfers M, Sommer C. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain. 2005;116:257-63 pubmed
    ..The absence of corresponding morphological changes in nerves supports the concept of a functional effect of the cytokines at these doses. ..
  11. Adhikary G, Chew Y, Reece E, Eckert R. PKC-delta and -eta, MEKK-1, MEK-6, MEK-3, and p38-delta are essential mediators of the response of normal human epidermal keratinocytes to differentiating agents. J Invest Dermatol. 2010;130:2017-30 pubmed publisher
    ..These findings are informative as they suggest an essential role for selected PKC and MAPK cascade enzymes in mediating a range of end responses to a range of differentiation stimuli in keratinocytes. ..
  12. 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
  13. 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. ..
  14. Wang L, Ma R, Flavell R, Choi M. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells. J Biol Chem. 2002;277:47257-62 pubmed
    ..These data demonstrate that the MKK3 is a critical component of the TGF-beta1 signaling pathway, and its activation is required for subsequent p38alpha and p38delta MAPK activation and collagen stimulation by TGF-beta1. ..
  15. Eckert R, Crish J, Efimova T, Balasubramanian S. Antioxidants regulate normal human keratinocyte differentiation. Biochem Pharmacol. 2004;68:1125-31 pubmed
    ..Curcumin, for example, inhibits the differentiation-promoting activity of EGCG. This report discusses the mechanism of EGCG and curcumin action in regulating expression of involucrin, a marker of keratinocyte differentiation. ..
  16. Wang S, Huang Q, Guo X, Brunk U, Han J, Zhao K, et al. The P38alpha and P38delta MAP kinases may be gene therapy targets in the future treatment of severe burns. Shock. 2010;34:176-82 pubmed publisher
  17. Chakraborty S, Kang B, Huang F, Guo Y. Mouse embryonic stem cells lacking p38alpha and p38delta can differentiate to endothelial cells, smooth muscle cells, and epithelial cells. Differentiation. 2009;78:143-50 pubmed publisher
    ..Our results highlight the possibility that p38 MAP kinases may play less significant roles in ESC differentiation than in the regulation of cellular activities of fully differentiated somatic cells. ..
  18. Kraft C, Efimova T, Eckert R. Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. Arch Dermatol Res. 2007;299:71-83 pubmed
    ..Our data indicate that OA is an agent that regulates both keratinocyte differentiation and apoptosis, and that this regulation is mediated via activation of a PKCdelta/p38delta signaling cascade. ..
  19. Cuenda A, Nebreda A. p38delta and PKD1: kinase switches for insulin secretion. Cell. 2009;136:209-10 pubmed publisher
    ..In this issue, Sumara et al. (2009) report key roles for the protein kinases p38delta and PKD1 in the regulation of insulin secretion as well as in the survival of pancreatic beta cells. ..
  20. Zhou X, Ferraris J, Dmitrieva N, Liu Y, Burg M. MKP-1 inhibits high NaCl-induced activation of p38 but does not inhibit the activation of TonEBP/OREBP: opposite roles of p38alpha and p38delta. Proc Natl Acad Sci U S A. 2008;105:5620-5 pubmed publisher
  21. 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. ..
  22. 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. ..
  23. Wang L, Kwak J, Kim S, He Y, Choi M. Transforming growth factor-beta1 stimulates vascular endothelial growth factor 164 via mitogen-activated protein kinase kinase 3-p38alpha and p38delta mitogen-activated protein kinase-dependent pathway in murine mesangial cells. J Biol Chem. 2004;279:33213-9 pubmed
    ..Further, VEGF164 stimulates collagen and fibronectin expression in mesangial cells and thus in turn enhances TGF-beta1-induced extracellular matrix and may play an important role in progressive glomerular fibrosis. ..
  24. Ozawa S, Ito S, Kato Y, Kubota E, Hata R. Human p38 delta MAP kinase mediates UV irradiation induced up-regulation of the gene expression of chemokine BRAK/CXCL14. Biochem Biophys Res Commun. 2010;396:1060-4 pubmed publisher
    ..Taken together, the data indicate that the respective stress-dependent action of p38 isoforms is responsible for the up-regulation of the gene expression of the chemokine BRAK/CXCL14. ..
  25. 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. ..
  26. Gum R, Young P. Identification of two distinct regions of p38 MAPK required for substrate binding and phosphorylation. Biochem Biophys Res Commun. 1999;266:284-9 pubmed
    ..Hence, we show for the first time that MAPKs contain two distinct regions for recognizing and phosphorylating protein substrates. ..
  27. Schrum L, Black D, Iimuro Y, Rippe R, Brenner D, Behrns K. c-Jun does not mediate hepatocyte apoptosis following NFkappaB inhibition and partial hepatectomy. J Surg Res. 2000;88:142-9 pubmed
    ..4%) after PH. Hepatocyte apoptosis after NFkappaB inhibition and PH is not mediated by increased JNK activity or c-Jun. ..
  28. Smith E, Proud C. cdc2-cyclin B regulates eEF2 kinase activity in a cell cycle- and amino acid-dependent manner. EMBO J. 2008;27:1005-16 pubmed publisher
    ..These data closely match the control of Ser359 phosphorylation and indicate that cdc2 may be regulated by mTORC1. ..
  29. 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. ..
  30. Dong H, Tian Y, Xiang H, Tian X, Jin X. [The cellular location and significance of p38alpha/beta isoforms in the lumbar spinal cord of the bone cancer pain rats]. Zhonghua Yi Xue Za Zhi. 2007;87:53-7 pubmed
    ..Our studies indicate that p38alpha and p38beta are involved in the generation and maintenance of bone cancer pain states. p38alpha is predominantly expressed in neurons, while p38beta is expressed in microglia. ..
  31. 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
  32. Kitatani K, Sheldon K, Anelli V, Jenkins R, Sun Y, Grabowski G, et al. Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid. J Biol Chem. 2009;284:12979-88 pubmed publisher
    ..Furthermore, the p38delta isoform was identified as a novel and predominant target of ceramide signaling as well as a regulator of IL-6 biosynthesis. ..
  33. Efimova T, Broome A, Eckert R. A regulatory role for p38 delta MAPK in keratinocyte differentiation. Evidence for p38 delta-ERK1/2 complex formation. J Biol Chem. 2003;278:34277-85 pubmed
    ..These unique observations suggest that p38 delta is the major p38 isoform driving suprabasal hINV gene expression and that p38 delta directly regulates ERK1/2 activity via formation of a p38 delta-ERK1/2 complex. ..
  34. Kim S, Zhang Z, Hitomi E, Lee Y, Mukherjee A. Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL. Hum Mol Genet. 2006;15:1826-34 pubmed
    ..Our results provide insight into at least one of the molecular mechanisms of apoptosis in INCL and may allow the identification of potential targets for therapeutic intervention. ..
  35. 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. ..
  36. Efimova T. p38delta mitogen-activated protein kinase regulates skin homeostasis and tumorigenesis. Cell Cycle. 2010;9:498-05 pubmed
    ..We focus on function of p38delta in regulating of epidermal keratinocyte differentiation, apoptosis and skin tumor development. ..
  37. Wang D, Perides G, Liu Y. Vaccination alone or in combination with pyridostigmine promotes and prolongs activation of stress-activated kinases induced by stress in the mouse brain. J Neurochem. 2005;93:1010-20 pubmed
    ..Our current studies suggest that stress, vaccination, and PY may synergistically act on multiple stress-activated kinases in the brain to cause neurological impairments in GWI. ..
  38. 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. ..
  39. Kuchen S, Seemayer C, Rethage J, von Knoch R, Kuenzler P, Beat A, et al. The L1 retroelement-related p40 protein induces p38delta MAP kinase. Autoimmunity. 2004;37:57-65 pubmed
    ..The induction of p38delta appears to be mediated by an ORF1/p40-dependent process. This is the first indication of a p40 mediated transactivation. ..