MAPK12 (mitogen-activated protein kinase 12)

2010-01-01   Maria Isabel Cerezo-Guisado , Ana Cuenda 

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


Atlas Image
MAPK12 genomic context (Chromosome 22, location 22q13.33).


Atlas Image
Genomic organization of MAPK12 gene on chromosome 22q13.33. The boxes indicate coding regions (exon 1-12) of the gene.


The MAPK12 entire gene spans 8.46 kb on the long arm of chromosome 22. It contains 12 exons.


The MAPK12 gene encodes a 367 amino-acid protein of about 42 kDa. MAPK12 mRNA is 1457 bp. No splice variants have been reported.


No human or mouse pseudogene known.



p38gamma (MAPK12), also known as Stress-activated protein kinase 3 (SAPK3) belongs to the p38 subfamily of MAPKs. The p38MAPK subfamily is composed by four members encoded by different genes, which share high sequence homologies 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 expresion 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 p38gamma (MAPK12) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif containing the regulatory phosphorylation residues. p38gamma (MAPK12) possesses at the C-terminal a sequence that binds to PDZ domain of several proteins.


p38gamma (MAPK12) is a Serine/Threonine protein kinase of 367 amino acids with a predicted molecular mass of 42 kDa. It possesses the conserved amino acid domains (I-XI) characteristic of protein kinases (Mertens et al., 1996). The Thr183 and Tyr185 residues in subdomain VIII are in an equivalent position to the TXY sequence in known MAPKs. The activation of p38gamma (MAPK12) occurs via dual phosphorylation of its TGY motif, in the activation loop, by MKK3 and MKK6 (Cuenda et al., 1997; Goedert et al., 1997).


p38gamma (MAPK12) mRNA is widely expressed with high levels of expression in skeletal muscle.


p38gamma (MAPK12) localizes to the cytoplasm and nucleus of cultured cells.


p38gamma (MAPK12) regulates many cellular functions by phosphorylating several proteins. A feature that makes p38gamma unique among the p38 MAPKs is its short C-terminal sequence -KETXL, an amino acid sequence ideal for binding PDZ domains in proteins. SAPK3/p38gamma binds to a variety of these proteins, such as alpha1-syntrophin, SAP90/PSD95 and SAP97/hDlg, and under stress conditions is able to phosphorylate them and modulate their activity (Hasegawa et al., 1999; Sabio et al., 2004; Sabio et al., 2005). These proteins are scaffold proteins usually targeted to the plasma membrane cytoskeleton at specialised sites such as the neuromuscular junction and gap junctions through protein-protein interactions. In the case of SAP97/hDlg its phosphorylation by SAPK3/p38gamma provided a mechanism of dissociating SAP97/hDlg from the cytoskeleton (Sabio et al., 2005). p38gamma can also phosphorylate 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). Another p38gamma substrates that do not require PDZ domain binding interactions are the mitochondrial protein Sab (Court et al., 2004) and the microtubule-associated protein Tau (Feijoo et al., 2005).
Since p38gamma expression is very high in skeletal muscle in comparison to other tissues, it is not surprising that it may play a fundamental role in skeletal muscle differentiation. Thus, p38gamma protein level increases when myoblast differentiate into myotubes endogenous (Tortorella et al., 2003; Cuenda and Cohen, 1999). Moreover, it has been shown that over-expression of p38gamma in skeletal muscle cells leads to differentiation from myoblast to myotubes, and that a dominant-negative mutant of p38gamma prevented this differentiation process (Lechner et al., 1996). Recently, Gillespie et al. (2009) reported that p38gamma phosphorylates the transciption factor MyoD, which results in a decrease in its transcriptional activity. p38gamma plays a cardinal role in blocking the premature differentiation of skeletal muscle stem cells, the satellite cells. Additionally, p38gamma regulates mitochondrial biogenesis and angiogenesis, and it is required for endurance exercise-induced skeletal muscle adaptation (Pogozelski et al., 2009).
Most of the work published on cellular transformation regulation by p38MAPK pathway has been focused on studying the role of the isoforms p38alpha and beta, but there are a number of recent publications providing evidences for the role of p38gamma (MAPK12) in cellular transformation. Overexpression of the active form of Rit, a Ras family member, in NIH3T3 cells, causes transformation and stimulates p38gamma, but not other isoforms of p38MAPKs, ERK1, ERK2 or ERK5 (Sakabe et al., 2002). In rat intestinal epithelial cells, Ras oncogene was found to increase p38gamma RNA and protein expression with concurrently stimulated p38alpha phosphorylation and decreased p38gamma phosphorylation (Tang et al., 2005; Loesch and Chen, 2008). These results indicate that increased p38gamma gene expression is required for Ras oncogene activity but the mechanism by which p38gamma may promote Ras transformation is not clear. Recent studies show that phospho-p38alpha can down-regulate p38gamma protein expression through c-jun dependent ubiquitin/proteasome pathways (Qi et al., 2007; Loesch and Chen, 2008). On the other hand other recent study shows that whereas p38gamma mediates Ras-induced senescence at least partly by stimulating the transcriptional activity of p53 through direct phosphorylation, p38alpha appears to regulate senescence in a p53-independent, p16INK4A dependent manner (Kwong et al., 2009).


p38gamma (MAPK12) shows 70% identity with p38delta (MAPK13), 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 MAP kinase (ERK2).



No mutation reported yet.

Implicated in

Entity name
Breast cancer
In human MCF-7 breast cancer cells, MKK6 expression inhibits DNA synthesis. This inhibitory effect is enhanced by the co-expressed p38gamma (Pramanik et al., 2003; Loesch and Chen, 2008). Ras also increases p38gamma protein expression in human breast cancer (Qi et al., 2006).
Entity name
Skin cancer
p38gamma isoform is specifically implicated in melanoma death induced by UV radiation, cisplatin treatment (Pillaire et al., 2000). Moreover, melanoma cells overexpressing PDGF-Ralpha show a marked increase of p38gamma (Faraone et al., 2009).
Entity name
p38gamma expression is increased in hepatoma cell line HLE (Liu et al., 2003).
Entity name
Ovarian cancer
p38gamma expression is regulated by the TNF-related apoptosis inducing ligand (TRIAL) and IL-8 in cellular lines from ovarian cancer (Abdollahi et al., 2003).
Entity name
Pancreatic cancer
The levels of p38gamma seems to be decreased in pancreatic cancer cells (Crnogorac-Jurcevic et al., 2001).


Pubmed IDLast YearTitleAuthors
129076262003Identification of interleukin 8 as an inhibitor of tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in the ovarian carcinoma cell line OVCAR3.Abdollahi T et al
151584512004Phosphorylation of the mitochondrial protein Sab by stress-activated protein kinase 3.Court NW et al
117048752001Gene expression profiles of pancreatic cancer and stromal desmoplasia.Crnogorac-Jurcevic T et al
99336361999Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 myogenesis.Cuenda A et al
174817472007p38 MAP-kinases pathway regulation, function and role in human diseases.Cuenda A et al
196492032009Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo.Faraone D 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
91691561997Assignment of the human stress-activated protein kinase-3 gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ hybridization.Goedert M et al
102122421999Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A mechanism for specific substrate recognition.Hasegawa M et al
192517012009p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms.Kwong J et al
86330701996ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation.Lechner C et al
126799102003Gene expression profiles of hepatoma cell line HLE.Liu LX et al
185084572008The p38 MAPK stress pathway as a tumor suppressor or more?Loesch M et al
89259121996SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases.Mertens S et al
110959752000Cisplatin and UV radiation induce activation of the stress-activated protein kinase p38gamma in human melanoma cells.Pillaire MJ et al
199362052009p38gamma mitogen-activated protein kinase is a key regulator in skeletal muscle metabolic adaptation in mice.Pogozelski AR et al
124759892003p38 isoforms have opposite effects on AP-1-dependent transcription through regulation of c-Jun. The determinant roles of the isoforms in the p38 MAPK signal specificity.Pramanik R et al
177240322007p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response.Qi X et al
168853522006p38gamma mitogen-activated protein kinase integrates signaling crosstalk between Ras and estrogen receptor to increase breast cancer invasion.Qi X et al
157293602005p38gamma regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP.Sabio G et al
147410462004Stress- and mitogen-induced phosphorylation of the synapse-associated protein SAP90/PSD-95 by activation of SAPK3/p38gamma and ERK1/ERK2.Sabio G et al
118210412002Potent transforming activity of the small GTP-binding protein Rit in NIH 3T3 cells: evidence for a role of a p38gamma-dependent signaling pathway.Sakabe K et al
158514772005Essential role of p38gamma in K-Ras transformation independent of phosphorylation.Tang J et al
127880832003ERK6 is expressed in a developmentally regulated manner in rodent skeletal muscle.Tortorella LL et al
196290692009Signal integration by JNK and p38 MAPK pathways in cancer development.Wagner EF et al

Other Information

Locus ID:

NCBI: 6300
MIM: 602399
HGNC: 6874
Ensembl: ENSG00000188130


dbSNP: 6300
ClinVar: 6300
TCGA: ENSG00000188130


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
Oocyte meiosisKEGGko04114
Oocyte meiosisKEGGhsa04114
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
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Activation of PPARGC1A (PGC-1alpha) by phosphorylationREACTOMER-HSA-2151209
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
Developmental BiologyREACTOMER-HSA-1266738
CDO in myogenesisREACTOMER-HSA-375170
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
192517012009p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms.35
129154052003Nuclear export of ERK3 by a CRM1-dependent mechanism regulates its inhibitory action on cell cycle progression.32
145929362004p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle.30
218626362011p38γ promotes breast cancer cell motility and metastasis through regulation of RhoC GTPase, cytoskeletal architecture, and a novel leading edge behavior.28
203322382010PTPH1 dephosphorylates and cooperates with p38gamma MAPK to increase ras oncogenesis through PDZ-mediated interaction.27
177240322007p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response.25
170882472007Hyperactive variants of p38alpha induce, whereas hyperactive variants of p38gamma suppress, activating protein 1-mediated transcription.24
215328882011p38γ mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer.23
225224542012TGF-β1 induces endothelial cell apoptosis by shifting VEGF activation of p38(MAPK) from the prosurvival p38β to proapoptotic p38α.22


Maria Isabel Cerezo-Guisado ; Ana Cuenda

MAPK12 (mitogen-activated protein kinase 12)

Atlas Genet Cytogenet Oncol Haematol. 2010-01-01

Online version: