MAPK14 (mitogen-activated protein kinase 14)

2010-12-01   Almudena Porras , Carmen Guerrero 

Departamento de Bioquimica y Biologia Molecular II, Facultad de Farmacia, UCM, Ciudad Universitaria, 28040 Madrid, Spain (AP); Centro de Investigacion del Cancer, IBMCC, Universidad de Salamanca-CSIC, 37007 Salamanca, Spain (CG)


Atlas Image
Schematic representation of human chromosome 6 indicating the position of MAPK14 locus (p21.31) (red bar).


Atlas Image
MAPK14 gene locus. Representation of the MAPK14 gene organization indicating the position of the exons (coding region) and untranslated regions.


The gene spans a region of 83.53 kb and the coding part is divided into 41 different exons. Larger transcripts contain 12 or 13 exons. (GATExplorer).


9 types of transcripts have been described, although only 5 are protein coding transcripts. The larger 4319-nucleotide transcript encodes a protein of 360 amino acid residues. The first and last exons are partially untranslated.


None described so far.


Atlas Image
MAPK14 protein domains. Schematic representation of MAPK14 protein indicating the position of its functional domains. 30-54: protein kinase ATP signature, ATP-binding region; 59-162: MAPK signature; 24-308: protein kinase domain.


MAPK14 is a Ser/Thr kinase composed of 90 to 360 residues depending on the transcript variant.
Atlas Image
Crystal structure of MAPK14 at 2.3 A resolution. From PDB (access number: 1WFC).


p38alpha MAPK is ubiquitously expressed, being the p38 most abundant isoform.


p38alpha is mainly present in the cytosol, but it can translocate to the nucleus. In addition, it can be localized in the mitochondria or in other subcellular compartments.


p38alpha is mainly activated by various environmental stresses and proinflammatory cytokines, but many other extracellular signals, including growth factors, also lead to p38alpha activation. The canonical activation requires its phosphorylation in threonine and tyrosine residues by dual-specificity MAP kinase kinases (MKKs), MKK3, MKK6 and MKK4. Substrates of this kinase include transcription factors, such as ATF1, ATF2, ATF6, p53, MEF2 or C/EBPbeta and protein kinases, such as MAPKAP-K2 and MAPKAP-K3 (also known as MK-2 and MK-3), MSK-1, MNK-1/MNK-2 and other proteins. p38alpha MAPK is essential for embryonic development and it regulates different cellular functions such as proliferation, differentiation, cell death, adhesion, migration, as well as the response to stress and many metabolic pathways, among others. It does so through regulation of transcription, mRNA stability, chromatin remodelling, protein synthesis, etc. Concerning cell death, although p38alpha plays an important role as a pro-apoptotic signal, it can play a dual role, acting as either a mediator of cell survival or of cell death, depending on the cell type and the stimuli. Related with its function as a negative regulator of proliferation and a mediator of apoptosis, p38alpha acts as a tumor suppressor in the initial stages of a tumorigenic process, while at later stages it can promote metastasis.
Atlas Image
Signaling through p38alphaMAPK. Signaling through MAPK14 cascade and its role in the regulation of cellular functions. MAPK14 is involved in signaling pathways triggered by a variety of stimuli such as growth factors, oxidative stress, UV, cytokines and DNA damage. Depending on the stimulus, different receptors and intermediates (adaptors, GTPases or kinases) are activated leading to the activation of the p38alpha MAPK cascade. This cascade is initiated by activation of MAPKKKs, which phosphorylate and activate MAPKKs (MKK3/6/4), which in turn lead to activation of MAPK14 through dual phosphorylation in Tyr and Thr. Once phosphorylated, MAPK14 phosphorylates a number of cytosolic and nuclear substrates, including transcription factors, which lead to the control of many cellular responses.



4 somatic mutations according to Ensembl: COSM21366; COSM20563; COSM35409; COSM12875.

Implicated in

Entity name
Hematopoietic malignancies
p38 MAPK, mainly the p38alpha isoform, is a key player in the maintenance of hematopoiesis homeostasis, as it balances both proliferative and growth inhibitory signals triggered by the growth factors and cytokines that regulate normal hematopoiesis. Alterations in this p38 MAPK-controlled balance may result in either overproduction or depletion of myelosuppressive cytokines leading to the development of certain bone marrow failure syndromes. For example, p38alpha is responsible for the enhanced stem cell apoptosis characteristic of low grade myeolodysplastic syndromes (MDSs). On the other hand, imbalance toward the proliferative side may conduct to the development of myeloproliferative syndromes (MPSs), such as leukemia, lymphomas and myelomas. In particular, p38alpha MAPK plays a pro-apoptotic role in chronic myeloid leukemia (CML). In fact, p38alpha MAP kinase pathway mediates the growth inhibitory effects of IFNalpha and STI-571, two drugs used in the CML treatment, which underscores the importance of this pathway in the generation of antileukemic responses.
Entity name
Alzheimers disease
Alzheimer is an incurable, neurodegenerative disease characterized by a progressive deterioration of the cognitive, memory and learning ability due to the accumulation of plaques containing amyloidogenic Abeta proteins and tangles containing hyperphosphorylated tau protein. The ASK1-MKK6-p38 signaling pathway participates in amyeloid precursor protein (APP) and tau phosphorylation in response to oxidative stress and contributes to the expression of the beta-secretase gene and the induction of neuronal apoptosis triggered by ROS.
Entity name
Parkinson disease
Parkinson is a degenerative disorder of the central nervous system characterized by muscle rigidity, tremor and loss of physical movement caused by a progressive loss of dopaminergic neurons. Mutations in alpha-synuclein are one of the main causes of Parkinson. alpha-synuclein activates p38alpha MAPK in human microglia promoting a potent inflammatory stimulation of microglial cells. Additionally, the p38alpha MAPK plays a role in dopaminergic neural apoptosis through the phosphorylation of p53 and expression of the pro-apoptotic protein Bax.
Entity name
Amyotrophic lateral sclerosis
ALS is a progressive, lethal, degenerative disorder of motor neurons leading to paralysis of voluntary muscles. Numerous evidences point to a role of p38 MAPK in the development and progression of ALS induced by mutations in SOD1 (superoxide dismutase 1) gene. Mutant SOD1 provokes aberrant oxyradical reactions that increase the activation of p38 MAPK in motor neurons and glial cells. This increase in active p38 MAPK may phosphorylate cytoskeletal proteins and activate cytokines and nitric oxide, thus contributing to neurodegeneration through different mechanisms including apoptosis.


Pubmed IDLast YearTitleAuthors
109490322000Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development.Adams RH et al
169090172005Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase.Bendotti C et al
105812581999Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation.Bulavin DV et al
206263502010Mechanisms and functions of p38 MAPK signalling.Cuadrado A et al
174817472007p38 MAP-kinases pathway regulation, function and role in human diseases.Cuenda A et al
109157802000The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive element-binding protein-dependent pathways.D'Amico M et al
93652411997Pro-apoptotic effect of the c-Abl tyrosine kinase in the cellular response to 1-beta-D-arabinofuranosylcytosine.Huang Y et al
190200422008Selective activation of p38 mitogen-activated protein kinase in dopaminergic neurons of substantia nigra leads to nuclear translocation of p53 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice.Karunakaran S et al
150195672004Inhibition of mixed lineage kinase 3 attenuates MPP+-induced neurotoxicity in SH-SY5Y cells.Mathiasen JR et al
115712312001Involvement of p38 kinase in hydroxyurea-induced differentiation of K562 cells.Park JI et al
127258662003The p38 mitogen-activated protein kinase pathway and its role in interferon signaling.Platanias LC et al
146178002004P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli.Porras A et al
154880252004Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding betaA plaques in APP Tg2576 mice.Puig B et al
79233531994A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins.Rouse J et al
108111252000A role for the p38 mitogen-acitvated protein kinase pathway in the transcriptional activation of p53 on genotoxic stress by chemotherapeutic agents.Sanchez-Prieto R et al
157194222005Mixed lineage kinase-c-jun N-terminal kinase signaling pathway: a new therapeutic target in Parkinson's disease.Silva RM et al
126840282003H2O2 and 4-hydroxynonenal mediate amyloid beta-induced neuronal apoptosis by activating JNKs and p38MAPK.Tamagno E et al
128127522003Persistent activation of p38 mitogen-activated protein kinase in a mouse model of familial amyotrophic lateral sclerosis correlates with disease progression.Tortarolo M et al
196290692009Signal integration by JNK and p38 MAPK pathways in cancer development.Wagner EF et al
89103611996Crystal structure of p38 mitogen-activated protein kinase.Wilson KP et al
173513442007p38 MAP kinase regulates stem cell apoptosis in human hematopoietic failure.Zhou L et al
168443432007Negative regulation of Akt activity by p38alpha MAP kinase in cardiomyocytes involves membrane localization of PP2A through interaction with caveolin-1.Zuluaga S et al

Other Information

Locus ID:

NCBI: 1432
MIM: 600289
HGNC: 6876
Ensembl: ENSG00000112062


dbSNP: 1432
ClinVar: 1432
TCGA: ENSG00000112062


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
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
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
activated TAK1 mediates p38 MAPK activationREACTOMER-HSA-450302
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
Activation of the AP-1 family of transcription factorsREACTOMER-HSA-450341
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathwaysREACTOMER-HSA-168643
NOD1/2 Signaling PathwayREACTOMER-HSA-168638
Platelet homeostasisREACTOMER-HSA-418346
Platelet sensitization by LDLREACTOMER-HSA-432142
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Signal amplificationREACTOMER-HSA-392518
ADP signalling through P2Y purinoceptor 1REACTOMER-HSA-418592
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
Nuclear Events (kinase and transcription factor activation)REACTOMER-HSA-198725
Signaling by VEGFREACTOMER-HSA-194138
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Regulation of mRNA stability by proteins that bind AU-rich elementsREACTOMER-HSA-450531
KSRP (KHSRP) binds and destabilizes mRNAREACTOMER-HSA-450604
Cell-Cell communicationREACTOMER-HSA-1500931
DSCAM interactionsREACTOMER-HSA-376172
Developmental BiologyREACTOMER-HSA-1266738
CDO in myogenesisREACTOMER-HSA-375170
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Regulation of TP53 ActivityREACTOMER-HSA-5633007
Regulation of TP53 Activity through PhosphorylationREACTOMER-HSA-6804756
Endocrine resistanceKEGGko01522
Endocrine resistanceKEGGhsa01522
Neutrophil degranulationREACTOMER-HSA-6798695
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
PA30588MAP2K3GenePathwayassociated20124951, 23922006
PA30591MAP2K6GenePathwayassociated20124951, 23922006


Pubmed IDYearTitleCitations
223073242012Cardiac natriuretic peptides act via p38 MAPK to induce the brown fat thermogenic program in mouse and human adipocytes.259
189224732008TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta.217
184513032008Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.169
118964012002Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site.163
174687552007p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation.142
153044862004Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1.114
125811562003Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway.110
195282292009p38 Mitogen-activated protein kinase- and HuR-dependent stabilization of p21(Cip1) mRNA mediates the G(1)/S checkpoint.102
197065212009The intrinsic dynamics of enzymes plays a dominant role in determining the structural changes induced upon inhibitor binding.101
198934882010Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP.100


Almudena Porras ; Carmen Guerrero

MAPK14 (mitogen-activated protein kinase 14)

Atlas Genet Cytogenet Oncol Haematol. 2010-12-01

Online version: