Note | p38delta (MAPK13), also known as Stress-activated protein kinase 4 (SAPK4) belongs to the p38 subfamily of MAPKs. The p38MAPK subfamily is composed by four members encoded by different genes, which share high sequence homologues and are designated as p38alpha (MAPK14, or SAPK2a), p38beta (MAPK11 or SAPK2b), p38gamma (MAPK12 or SAPK3) and p38delta (MAPK13 or SAPK4). They are about 60% identical in their amino acid sequence but differ in their expression patterns, substrate specificities and sensitivities to chemical inhibitors (Iñesta-Vaquera et al., 2008). All p38 MAPKs are strongly activated in vivo by environmental stresses and inflammatory cytokines, and less by serum and growth factors. |
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| Schematic representation of the p38delta (MAPK13) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif containing the regulatory phosphorylation residues. |
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Description | p38delta (MAPK13) is a Serine/Threonine protein kinase of 365 amino acids with a predicted molecular mass of 40 kDa. It possesses the conserved amino acid domains (I-XI) characteristic of protein kinases (Goedert et al., 1997). The Thr180 and Tyr182 residues in subdomain VIII are in an equivalent position to the TXY sequence in known MAPKs. The activation of p38delta (MAPK13) occurs via dual phosphorilation of its TGY motif, in the activation loop, by MKK3 and MKK6, although it is preferentially activated by MKK3 in mouse embryonic fibroblasts (Remy et al., 2009). |
Expression | p38delta (MAPK13) mRNA is widely expressed with high levels of expression in testes, pancreas, kidney and small intestine. |
Localisation | p38delta (MAPK13) localizes to the cytoplasm and nucleus of cultured cells. |
Function | p38delta (MAPK13) phosphorylates typical p38 MAPK substrates such as the transcription factors ATF2, Elk-1 or SAP1. However, it cannot phosphorylate MAPKAPK2 or MAPKAPK3, which are good substrates for other p38 MAPK isoforms (Cuenda et al., 1997; Goedert et al., 1997). p38delta possibly plays a role in cytoskeleton regulation as it has been reported to phosphorylate the cytoplasmic protein stathmin, which has been linked to regulation of microtubule dynamics (Parker et al., 1998). Microtubule-associated protein Tau is another protein substrate of p38delta (Goedert et al., 1997; Feijoo et al., 2005; Yoshida and Goedert, 2006). In addition p38delta plays a role in the regulation of protein translation by phosphorylating and inactivating the eukaryotic elongation factor 2 (eEF2) kinase (Knebel et al., 2001; Knebel et al., 2002). p38delta also plays a key role in the regulation of insulin secretion as well as in the survival of pancreatic beta cells, since p38delta catalyzes an inhibitory phosphorylation of the protein kinase D1 (PDK1), which controls insuline exocytosis in pancreatic beta cells (Sumara et al., 2009). p38delta has been suggested to play an important role in inducing keratinocyte differentiation by regulating the expression of involucrin, which is a protein expressed during keratinocyte differentiation (Eckert et al., 2003). Activation of exogenously expressed p38delta by differentiation-inducing agents such as a bioactive green tea polyphenol (EGCG), okadaic acid (OA) or the phorbol ester TPA, correlated with increased involucrin promoter activity in keratinocytes via increased activity at AP1, Sp1 and C/EBP sites (Balasubramanian et al., 2002; Efimova et al., 2003). The mechanisms by which p38delta may regulates keratinocyte differentiation is still unknown, although it has been reported that in keratinocytes expressing exogenous p38delta this forms a complex with ERK1/ERK2 (Efimova et al., 2003; Eckert et al., 2004). Additional data supporting the idea that p38delta may play a role in keratinocyte differentiation come from a study carried out in lesional psoriasis skin (Johansen et al., 2005). It has been shown that the activity of p38alpha, p38beta and p38delta are augmented in lesional psoriasis skin compared with nonlesional psoriasis skin (Johansen et al., 2005). Alternatively, it has been also claimed that p38delta may have a dual role in keratinocytes contributing not only to the differentiation process, but also to their apoptosis in a PKCdelta dependent manner, and in response to OA or H2O2 (Efimova et al., 2004; Kraft et al., 2007). |
Homology | p38delta (MAPK13) shows 70% identity with p38gamma (MAPK12), 60% sequence identity with p38alpha (MAPK14) and p38beta (MAPK11), 45% identity with HOG1 from S. cerevisiae, 47% identity with human SAP kinase-1 (JNK1) and 42% identity with p42 MAPkinase (ERK2). |
Green tea polyphenol stimulates a Ras, MEKK1, MEK3, and p38 cascade to increase activator protein 1 factor-dependent involucrin gene expression in normal human keratinocytes. |
Balasubramanian S, Efimova T, Eckert RL. |
J Biol Chem. 2002 Jan 18;277(3):1828-36. Epub 2001 Nov 6. |
PMID 11698415 |
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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). |
Cuenda A, Cohen P, Buee-Scherrer V, Goedert M. |
EMBO J. 1997 Jan 15;16(2):295-305. |
PMID 9029150 |
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p38 MAP-kinases pathway regulation, function and role in human diseases. |
Cuenda A, Rousseau S. |
Biochim Biophys Acta. 2007 Aug;1773(8):1358-75. Epub 2007 Mar 24. (REVIEW) |
PMID 17481747 |
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Antioxidants regulate normal human keratinocyte differentiation. |
Eckert RL, Crish JF, Efimova T, Balasubramanian S. |
Biochem Pharmacol. 2004 Sep 15;68(6):1125-31. |
PMID 15313409 |
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p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta. |
Eckert RL, Efimova T, Balasubramanian S, Crish JF, Bone F, Dashti S. |
J Invest Dermatol. 2003 May;120(5):823-8. (REVIEW) |
PMID 12713588 |
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Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signal-regulated kinase 1/2 complex. |
Efimova T, Broome AM, Eckert RL. |
Mol Cell Biol. 2004 Sep;24(18):8167-83. |
PMID 15340077 |
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Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly. |
Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A. |
J Cell Sci. 2005 Jan 15;118(Pt 2):397-408. Epub 2005 Jan 4. |
PMID 15632108 |
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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. |
Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. |
EMBO J. 1997a Jun 16;16(12):3563-71. |
PMID 9218798 |
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Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. |
Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. |
FEBS Lett. 1997b Jun 2;409(1):57-62. |
PMID 9199504 |
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Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. |
Goto Y, Shinjo K, Kondo Y, Shen L, Toyota M, Suzuki H, Gao W, An B, Fujii M, Murakami H, Osada H, Taniguchi T, Usami N, Kondo M, Hasegawa Y, Shimokata K, Matsuo K, Hida T, Fujimoto N, Kishimoto T, Issa JP, Sekido Y. |
Cancer Res. 2009 Dec 1;69(23):9073-82. Epub 2009 Nov 3. |
PMID 19887624 |
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Alternative p38MAPK pathways. Stress activated protein kinases. |
Inesta-Vaquera F., Sabio G., Kuma Y, Cuenda A |
Topics in Current Genetics. Springer-Verlag Berlin Heidelberg (DOI 10-1007/978-3-540-75569-2) 2008; 20:17-26 |
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Modulation of tau phosphorylation and intracellular localization by cellular stress. |
Jenkins SM, Zinnerman M, Garner C, Johnson GV. |
Biochem J. 2000 Jan 15;345 Pt 2:263-70. |
PMID 10620503 |
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The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin. |
Johansen C, Kragballe K, Westergaard M, Henningsen J, Kristiansen K, Iversen L. |
Br J Dermatol. 2005 Jan;152(1):37-42. |
PMID 15656798 |
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Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways. |
Knebel A, Haydon CE, Morrice N, Cohen P. |
Biochem J. 2002 Oct 15;367(Pt 2):525-32. |
PMID 12171600 |
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A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta. |
Knebel A, Morrice N, Cohen P. |
EMBO J. 2001 Aug 15;20(16):4360-9. |
PMID 11500363 |
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Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. |
Kraft CA, Efimova T, Eckert RL. |
Arch Dermatol Res. 2007 May;299(2):71-83. Epub 2007 Jan 26. |
PMID 17256148 |
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Identification of stathmin as a novel substrate for p38 delta. |
Parker CG, Hunt J, Diener K, McGinley M, Soriano B, Keesler GA, Bray J, Yao Z, Wang XS, Kohno T, Lichenstein HS. |
Biochem Biophys Res Commun. 1998 Aug 28;249(3):791-6. |
PMID 9731215 |
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Differential activation of p38MAPK isoforms by MKK6 and MKK3. |
Remy G, Risco AM, Inesta-Vaquera FA, Gonzalez-Teran B, Sabio G, Davis RJ, Cuenda A. |
Cell Signal. 2009 Dec 11. [Epub ahead of print] |
PMID 20004242 |
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p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice. |
Schindler EM, Hindes A, Gribben EL, Burns CJ, Yin Y, Lin MH, Owen RJ, Longmore GD, Kissling GE, Arthur JS, Efimova T. |
Cancer Res. 2009 Jun 1;69(11):4648-55. Epub 2009 May 19. |
PMID 19458068 |
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Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. |
Sumara G, Formentini I, Collins S, Sumara I, Windak R, Bodenmiller B, Ramracheya R, Caille D, Jiang H, Platt KA, Meda P, Aebersold R, Rorsman P, Ricci R. |
Cell. 2009 Jan 23;136(2):235-48. Epub 2009 Jan 8. |
PMID 19135240 |
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p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion. |
Tan FL, Ooi A, Huang D, Wong JC, Qian CN, Chao C, Ooi L, Tan YM, Chung A, Cheow PC, Zhang Z, Petillo D, Yang XJ, Teh BT. |
Int J Cancer. 2009 Oct 8. [Epub ahead of print] |
PMID 19816939 |
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Signal integration by JNK and p38 MAPK pathways in cancer development. |
Wagner EF, Nebreda AR. |
Nat Rev Cancer. 2009 Aug;9(8):537-49. (REVIEW) |
PMID 19629069 |
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Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain. |
Yin J, Liu YH, Xu YF, Zhang YJ, Chen JG, Shu BH, Wang JZ. |
J Pineal Res. 2006 Sep;41(2):124-9. |
PMID 16879317 |
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Sequential phosphorylation of tau protein by cAMP-dependent protein kinase and SAPK4/p38delta or JNK2 in the presence of heparin generates the AT100 epitope. |
Yoshida H, Goedert M. |
J Neurochem. 2006 Oct;99(1):154-64. |
PMID 16987243 |
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Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. |
Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H, Shimohama S, Perry G, Smith MA. |
J Neurochem. 2001 Oct;79(2):311-8. |
PMID 11677259 |
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