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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review MAPK13 (mitogen-activated protein kinase 13) Maria Isabel Cerezo-Guisado, Ana Cuenda Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (MICG, AC) Published in Atlas Database: December 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK13ID41291ch6p21.html DOI: 10.4267/2042/44858 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Other names: MGC99536; p38delta HGNC (Hugo): MAPK13 Location: 6p21.31 Protein PRKM13; SAPK4; 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. DNA/RNA Description The MAPK13 entire gene spans 9.58 kb on the short arm of chromosome 6. It contains 12 exons. Transcription The MAPK13 gene encodes a 365 amino-acid protein of about 40 kDa. No splice variants have been reported. Pseudogene No human or mouse pseudogene known. MAPK13 genomic context (chromosome 6, location 6p21.31). Genomic organization of MAPK13 gene on chromosome 6p21.31. The boxes indicate coding regions (exon 1-12) of the gene. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 911 MAPK13 (mitogen-activated protein kinase 13) Cerezo-Guisado MI, Cuenda A Schematic representation of the p38delta (MAPK13) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif containing the regulatory phosphorylation residues. 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). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 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). Implicated in Skin cancer Oncogenesis It has been suggested that p38delta functions as positive regulator of skin tumorogenesis by promoting cell proliferation and tumor development in epidermis (Schindler et al., 2009). Cholangiocarcinoma Oncogenesis p38delta may serve as a diagnostic marker for expression cholangiocarcinoma (CC), since its expression is upregulated in CC relative to 912 MAPK13 (mitogen-activated protein kinase 13) Cerezo-Guisado MI, Cuenda A Jenkins SM, Zinnerman M, Garner C, Johnson GV. Modulation of tau phosphorylation and intracellular localization by cellular stress. Biochem J. 2000 Jan 15;345 Pt 2:263-70 hepatocellularcarcinoma (HCC) and to normal biliary tract tissue (Li-Sher et al., 2009). It has been suggested that p38delta is important for motility and invasion of CC cells (Li-Sher et al., 2009). 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 Aug 15;20(16):4360-9 Malignant Pleural Mesothelioma Oncogenesis MAPK13 gene is hypermethylated in Malignant Pleural Mesothelioma (MPM) cell lines (Goto et al., 2009). Zhu X, Rottkamp CA, Hartzler A, Sun Z, Takeda A, Boux H, Shimohama S, Perry G, Smith MA. Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. J Neurochem. 2001 Oct;79(2):311-8 Alzheimer disease Balasubramanian S, Efimova T, Eckert RL. 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. J Biol Chem. 2002 Jan 18;277(3):1828-36 Note The protein Tau is a good in vitro substrate for the p38 isoforms p38delta and p38gamma, and its phosphorylation by these two enzymes results in a reduction in its ability to promote microtubule assembly (Goedert et al., 1997b; Feijoo et al., 2005). Moreover, overexpression of p38gamma in neuroblastoma, induces Tau phosphorylation which correlates with a decrease on Tau associated to the cytoskeleton and an increase of soluble Tau (Jenkins et al., 2000). It has been reported as well that p38delta is the major Tau kinase in neuroblastoma in response to osmotic shock (Feijoo et al., 2005) and that the p38MAPK activator, MKK6, has also been found to be active in neurodegenerative diseases (Zhu et al., 2001). Moreover, oxidant agents implicated in Alzheimer's disease can cause hyperphosphorylation in rat brain and also induce the activation of p38delta, indicating that this kinase may be involved in Tau phosphorylation (Yin et al., 2006). On the other hand, it has been shown using phosphospecific antibodies that p38MAPKs phosphorylate Tau on residues phosphorylated in a Tau obtained from patients suffering Alzheimer's disease (Goedert et al., 1997b; Feijoo et al., 2005). Knebel A, Haydon CE, Morrice N, Cohen P. Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways. Biochem J. 2002 Oct 15;367(Pt 2):525-32 Eckert RL, Efimova T, Balasubramanian S, Crish JF, Bone F, Dashti S. p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta. J Invest Dermatol. 2003 May;120(5):823-8 Efimova T, Broome AM, Eckert RL. A regulatory role for p38 delta MAPK in keratinocyte differentiation. Evidence for p38 delta-ERK1/2 complex formation. J Biol Chem. 2003 Sep 5;278(36):34277-85 Eckert RL, Crish JF, Efimova T, Balasubramanian S. Antioxidants regulate normal human keratinocyte differentiation. Biochem Pharmacol. 2004 Sep 15;68(6):112531 Efimova T, Broome AM, Eckert RL. Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signalregulated kinase 1/2 complex. Mol Cell Biol. 2004 Sep;24(18):8167-83 Feijoo C, Campbell DG, 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 Jan 15;118(Pt 2):397-408 Diabetes type 2 (diabetes mellitus) Note p38delta plays a key role in the regulation of insulin secretion as well as in the survival of pancreatic beta cells (Sumara et al., 2009). Johansen C, Kragballe K, Westergaard M, Henningsen J, Kristiansen K, Iversen L. The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin. Br J Dermatol. 2005 Jan;152(1):37-42 References Yin J, Liu YH, Xu YF, Zhang YJ, Chen JG, Shu BH, Wang JZ. Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain. J Pineal Res. 2006 Sep;41(2):124-9 Cuenda A, Cohen P, Buée-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 Jan 15;16(2):295-305 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 Oct;99(1):154-64 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 Jun 16;16(12):3563-71 Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007 Aug;1773(8):1358-75 Kraft CA, Efimova T, Eckert RL. Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis. Arch Dermatol Res. 2007 May;299(2):71-83 Goedert M, Hasegawa M, Jakes R, Lawler S, Cuenda A, Cohen P. Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases. FEBS Lett. 1997 Jun 2;409(1):57-62 Inesta-Vaquera F., Sabio G., Kuma Y, Cuenda A. Alternative p38MAPK pathways. Stress activated protein kinases. Topics in Current Genetics. Springer-Verlag Berlin Heidelberg (DOI 10-1007/978-3-540-75569-2) 2008; 20:17-26 Parker CG, Hunt J, Diener K, McGinley M, Soriano B, Keesler GA, Bray J, Yao Z, Wang XS, Kohno T, Lichenstein HS. Identification of stathmin as a novel substrate for p38 delta. Biochem Biophys Res Commun. 1998 Aug 28;249(3):791-6 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) 913 MAPK13 (mitogen-activated protein kinase 13) 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. Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma. Cancer Res. 2009 Dec 1;69(23):9073-82 Schindler EM, Hindes A, Gribben EL, Burns CJ, Yin Y, Lin MH, Owen RJ, Longmore GD, Kissling GE, Arthur JS, Efimova T. p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice. Cancer Res. 2009 Jun 1;69(11):4648-55 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. Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell. 2009 Jan 23;136(2):235-48 Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10) Cerezo-Guisado MI, Cuenda A Wagner EF, Nebreda AR. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009 Aug;9(8):537-49 Remy G, Risco AM, Iñesta-Vaquera FA, González-Terán B, Sabio G, Davis RJ, Cuenda A. Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cell Signal. 2010 Apr;22(4):660-7 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. p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion. Int J Cancer. 2010 May 15;126(10):2353-61 This article should be referenced as such: Cerezo-Guisado MI, Cuenda A. MAPK13 (mitogen-activated protein kinase 13). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(10):911-914. 914