MAPK13 (mitogen-activated protein kinase 13)

2009-12-01   Maria Isabel Cerezo-Guisado , Ana Cuenda 

Centro Nacional de Biotecnologia-CSIC, Department of Immunology, Oncology, Madrid, Spain


Atlas Image
MAPK13 genomic context (chromosome 6, location 6p21.31).


Atlas Image
Genomic organization of MAPK13 gene on chromosome 6p21.31. The boxes indicate coding regions (exon 1-12) of the gene.


The MAPK13 entire gene spans 9.58 Kb on the short arm of chromosome 6. It contains 12 exons.


The MAPK13 gene encodes a 365 amino-acid protein of about 40 KDa. No splice variants have been reported.


No human or mouse pseudogene known.



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.
Atlas Image
Schematic representation of the p38delta (MAPK13) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif containing the regulatory phosphorylation residues.


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).


p38delta (MAPK13) mRNA is widely expressed with high levels of expression in testes, pancreas, kidney and small intestine.


p38delta (MAPK13) localizes to the cytoplasm and nucleus of cultured cells.


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).


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

Entity name
Skin cancer
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).
Entity name
p38delta may serve as a diagnostic marker for expression cholangiocarcinoma (CC), since its expression is upregulated in CC relative to 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).
Entity name
Malignant Pleural Mesothelioma
MAPK13 gene is hypermethylated in Malignant Pleural Mesothelioma (MPM) cell lines (Goto et al., 2009).
Entity name
Alzheimer disease
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 Alzheimers 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 Alzheimers disease (Goedert et al., 1997b; Feijoo et al., 2005).
Entity name
Diabetes type 2 (diabetes mellitus)
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).


Pubmed IDLast YearTitleAuthors
116984152002Green 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 et al
90291501997Activation 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 et al
174817472007p38 MAP-kinases pathway regulation, function and role in human diseases.Cuenda A et al
153134092004Antioxidants regulate normal human keratinocyte differentiation.Eckert RL et al
127135882003p38 Mitogen-activated protein kinases on the body surface--a function for p38 delta.Eckert RL et al
153400772004Protein 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 et al
156321082005Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule assembly.Feijoo C et al
92187981997Activation 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 et al
91995041997Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases.Goedert M et al
198876242009Epigenetic profiles distinguish malignant pleural mesothelioma from lung adenocarcinoma.Goto Y et al
106205032000Modulation of tau phosphorylation and intracellular localization by cellular stress.Jenkins SM et al
156567982005The mitogen-activated protein kinases p38 and ERK1/2 are increased in lesional psoriatic skin.Johansen C et al
121716002002Stress-induced regulation of eukaryotic elongation factor 2 kinase by SB 203580-sensitive and -insensitive pathways.Knebel A et al
115003632001A novel method to identify protein kinase substrates: eEF2 kinase is phosphorylated and inhibited by SAPK4/p38delta.Knebel A et al
172561482007Activation of PKCdelta and p38delta MAPK during okadaic acid dependent keratinocyte apoptosis.Kraft CA et al
97312151998Identification of stathmin as a novel substrate for p38 delta.Parker CG et al
200042422010Differential activation of p38MAPK isoforms by MKK6 and MKK3.Remy G et al
194580682009p38delta Mitogen-activated protein kinase is essential for skin tumor development in mice.Schindler EM et al
191352402009Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis.Sumara G et al
198169392010p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion.Tan FL et al
196290692009Signal integration by JNK and p38 MAPK pathways in cancer development.Wagner EF et al
168793172006Melatonin arrests peroxynitrite-induced tau hyperphosphorylation and the overactivation of protein kinases in rat brain.Yin J et al
169872432006Sequential 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 et al
116772592001Activation of MKK6, an upstream activator of p38, in Alzheimer's disease.Zhu X et al

Other Information

Locus ID:

NCBI: 5603
MIM: 602899
HGNC: 6875
Ensembl: ENSG00000156711


dbSNP: 5603
ClinVar: 5603
TCGA: ENSG00000156711


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
VEGF signaling pathwayKEGGko04370
Toll-like receptor signaling pathwayKEGGko04620
T cell receptor signaling pathwayKEGGko04660
Fc epsilon RI signaling pathwayKEGGko04664
Leukocyte transendothelial migrationKEGGko04670
GnRH signaling pathwayKEGGko04912
Progesterone-mediated oocyte maturationKEGGko04914
Amyotrophic lateral sclerosis (ALS)KEGGko05014
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
MAPK signaling pathwayKEGGhsa04010
VEGF signaling pathwayKEGGhsa04370
Toll-like receptor signaling pathwayKEGGhsa04620
T cell receptor signaling pathwayKEGGhsa04660
Fc epsilon RI signaling pathwayKEGGhsa04664
Leukocyte transendothelial migrationKEGGhsa04670
GnRH signaling pathwayKEGGhsa04912
Amyotrophic lateral sclerosis (ALS)KEGGhsa05014
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
Progesterone-mediated oocyte maturationKEGGhsa04914
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Salmonella infectionKEGGko05132
Salmonella infectionKEGGhsa05132
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Retrograde endocannabinoid signalingKEGGhsa04723
Retrograde endocannabinoid signalingKEGGko04723
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
FoxO signaling pathwayKEGGhsa04068
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Platelet activationKEGGhsa04611
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
MAPK (p38) signalingKEGGhsa_M00689
MAPK (p38) signalingKEGGM00689
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
NOD1/2 Signaling PathwayREACTOMER-HSA-168638
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
p38MAPK eventsREACTOMER-HSA-171007
Signaling by VEGFREACTOMER-HSA-194138
Cell-Cell communicationREACTOMER-HSA-1500931
DSCAM interactionsREACTOMER-HSA-376172
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Endocrine resistanceKEGGko01522
Endocrine resistanceKEGGhsa01522
Th1 and Th2 cell differentiationKEGGko04658
Th1 and Th2 cell differentiationKEGGhsa04658
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
IL-17 signaling pathwayKEGGko04657
Fluid shear stress and atherosclerosisKEGGko05418
IL-17 signaling pathwayKEGGhsa04657
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
231871302012IL-13-induced airway mucus production is attenuated by MAPK13 inhibition.78
128107192003A regulatory role for p38 delta MAPK in keratinocyte differentiation. Evidence for p38 delta-ERK1/2 complex formation.50
166448702006Endoplasmic reticulum stress-induced caspase-4 activation mediates apoptosis and neurodegeneration in INCL.44
237986822013An unbiased approach to identifying tau kinases that phosphorylate tau at sites associated with Alzheimer disease.36
153400772004Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signal-regulated kinase 1/2 complex.35
120800772002Novel protein kinase C isoforms regulate human keratinocyte differentiation by activating a p38 delta mitogen-activated protein kinase cascade that targets CCAAT/enhancer-binding protein alpha.34
183676662008MKP-1 inhibits high NaCl-induced activation of p38 but does not inhibit the activation of TonEBP/OREBP: opposite roles of p38alpha and p38delta.26
198169392010p38delta/MAPK13 as a diagnostic marker for cholangiocarcinoma and its involvement in cell motility and invasion.23
124828582003Evidence for a role of p38 kinase in hypoxia-inducible factor 1-independent induction of vascular endothelial growth factor expression by sodium arsenite.20


Maria Isabel Cerezo-Guisado ; Ana Cuenda

MAPK13 (mitogen-activated protein kinase 13)

Atlas Genet Cytogenet Oncol Haematol. 2009-12-01

Online version: