MAPK14 (mitogen-activated protein kinase 14)

Gene

• Entrez ID: 1432
• Gene name: Mitogen-activated protein kinase 14
• Gene symbol: MAPK14
• Synonyms: CSBP, CSBP1, CSBP2, CSPB1, EXIP, Mxi2, PRKM14, PRKM15, RK, SAPK2A, p38, p38ALPHA
• Chromosome: 6
• Chromosome location: 6p21.31
• Summary: The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various environmental stresses and proinflammatory cytokines. The activation requires its phosphorylation by MAP kinase kinases (MKKs), or its autophosphorylation triggered by the interaction of MAP3K7IP1/TAB1 protein with this kinase. The substrates of this kinase include transcription regulator ATF2, MEF2C, and MAX, cell cycle regulator CDC25B, and tumor suppressor p53, which suggest the roles of this kinase in stress related transcription and cell cycle regulation, as well as in genotoxic stress response. Four alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT002610	hsa-miR-124-3p	Microarray	15685193
MIRT002610	hsa-miR-124-3p	Microarray	18668037
MIRT002610	hsa-miR-124-3p	Immunoblot, Luciferase reporter assay, qRT-PCR	23109423
MIRT002950	hsa-miR-24-3p	Luciferase reporter assay, Reporter assay;Other	15131085
MIRT003986	hsa-miR-199a-3p	Western blot	18456660
MIRT006423	hsa-miR-200a-3p	Luciferase reporter assay, Microarray, Western blot	22101765
MIRT006423	hsa-miR-200a-3p	HITS-CLIP	23824327
MIRT006424	hsa-miR-141-3p	Luciferase reporter assay, Microarray, Western blot	22101765
MIRT006424	hsa-miR-141-3p	HITS-CLIP	23824327
MIRT007066	hsa-miR-125b-5p	ChIP-seq, EMSA, Immunoblot, Luciferase reporter assay, qRT-PCR, Western blot	22854965
MIRT053190	hsa-miR-214-3p	Microarray, qRT-PCR	22929890
MIRT053435	hsa-miR-155-5p	Microarray	23807165
MIRT053435	hsa-miR-155-5p	Luciferase reporter assay	25535908
MIRT054882	hsa-miR-17-5p	Immunocytochemistry, Immunohistochemistry, qRT-PCR	24474786
MIRT054883	hsa-miR-106a-5p	Immunocytochemistry, Immunohistochemistry, qRT-PCR	24474786
MIRT168650	hsa-miR-19a-3p	HITS-CLIP	22473208
MIRT168651	hsa-miR-19b-3p	HITS-CLIP	22473208
MIRT168656	hsa-miR-518a-5p	HITS-CLIP	23824327
MIRT168657	hsa-miR-527	HITS-CLIP	23824327
MIRT438435	hsa-miR-128-3p	Immunoblot, Luciferase reporter assay, qRT-PCR	23109423
MIRT536131	hsa-miR-3152-5p	PAR-CLIP	22012620
MIRT536132	hsa-miR-4774-3p	PAR-CLIP	22012620
MIRT536133	hsa-miR-6836-3p	PAR-CLIP	22012620
MIRT536134	hsa-miR-585-5p	PAR-CLIP	22012620
MIRT536135	hsa-miR-668-3p	PAR-CLIP	22012620
MIRT536136	hsa-miR-6781-3p	PAR-CLIP	22012620
MIRT536137	hsa-miR-2682-3p	PAR-CLIP	22012620
MIRT536138	hsa-miR-215-3p	PAR-CLIP	22012620
MIRT536139	hsa-miR-3137	PAR-CLIP	22012620
MIRT536140	hsa-miR-6773-3p	PAR-CLIP	22012620
MIRT536141	hsa-miR-1208	PAR-CLIP	22012620
MIRT536142	hsa-miR-6760-3p	PAR-CLIP	22012620
MIRT536143	hsa-miR-1183	PAR-CLIP	22012620
MIRT536144	hsa-miR-548e-5p	PAR-CLIP	22012620
MIRT614931	hsa-miR-6820-3p	HITS-CLIP	23824327
MIRT614932	hsa-miR-3164	HITS-CLIP	23824327
MIRT614933	hsa-miR-6757-3p	HITS-CLIP	23824327
MIRT656456	hsa-miR-4454	HITS-CLIP	23824327
MIRT656457	hsa-miR-4680-5p	HITS-CLIP	23824327
MIRT656458	hsa-miR-7107-5p	HITS-CLIP	23824327
MIRT656459	hsa-miR-1234-3p	HITS-CLIP	23824327
MIRT656460	hsa-miR-186-3p	HITS-CLIP	23824327
MIRT656461	hsa-miR-764	HITS-CLIP	23824327
MIRT656462	hsa-miR-125a-3p	HITS-CLIP	23824327
MIRT656463	hsa-miR-548aw	HITS-CLIP	23824327
MIRT656464	hsa-miR-4719	HITS-CLIP	23824327
MIRT656465	hsa-miR-4762-5p	HITS-CLIP	23824327
MIRT656466	hsa-miR-34b-3p	HITS-CLIP	23824327
MIRT667443	hsa-miR-129-5p	HITS-CLIP	23824327
MIRT667444	hsa-miR-8055	HITS-CLIP	23824327
MIRT667445	hsa-miR-744-3p	HITS-CLIP	23824327
MIRT667446	hsa-miR-6864-3p	HITS-CLIP	23824327
MIRT667447	hsa-miR-3672	HITS-CLIP	23824327
MIRT667448	hsa-miR-6867-3p	HITS-CLIP	23824327
MIRT667449	hsa-miR-664b-3p	HITS-CLIP	23824327
MIRT667449	hsa-miR-664b-3p	HITS-CLIP	27418678
MIRT667450	hsa-miR-579-3p	HITS-CLIP	23824327
MIRT667450	hsa-miR-579-3p	HITS-CLIP	27418678
MIRT667451	hsa-miR-4423-5p	HITS-CLIP	23824327
MIRT667452	hsa-miR-4294	HITS-CLIP	23824327
MIRT667453	hsa-miR-6501-5p	HITS-CLIP	23824327
MIRT667454	hsa-miR-367-5p	HITS-CLIP	23824327
MIRT667455	hsa-miR-1267	HITS-CLIP	23824327
MIRT667456	hsa-miR-4685-3p	HITS-CLIP	23824327
MIRT667457	hsa-miR-4287	HITS-CLIP	23824327
MIRT667458	hsa-miR-7113-3p	HITS-CLIP	23824327
MIRT667459	hsa-miR-4469	HITS-CLIP	23824327
MIRT667460	hsa-miR-153-5p	HITS-CLIP	23824327
MIRT667460	hsa-miR-153-5p	HITS-CLIP	27418678
MIRT667461	hsa-miR-1250-3p	HITS-CLIP	23824327
MIRT667461	hsa-miR-1250-3p	HITS-CLIP	27418678
MIRT675816	hsa-miR-335-3p	HITS-CLIP	23824327
MIRT675816	hsa-miR-335-3p	HITS-CLIP	27418678
MIRT675817	hsa-miR-642a-5p	HITS-CLIP	23824327
MIRT675818	hsa-miR-5696	HITS-CLIP	23824327
MIRT675818	hsa-miR-5696	HITS-CLIP	27418678
MIRT675819	hsa-miR-2276-5p	HITS-CLIP	23824327
MIRT675820	hsa-miR-6892-3p	HITS-CLIP	23824327
MIRT715165	hsa-miR-629-3p	HITS-CLIP	19536157
MIRT715166	hsa-miR-4715-3p	HITS-CLIP	19536157
MIRT715167	hsa-miR-3064-3p	HITS-CLIP	19536157
MIRT715168	hsa-miR-4279	HITS-CLIP	19536157
MIRT715169	hsa-miR-513b-5p	HITS-CLIP	19536157
MIRT715170	hsa-miR-4252	HITS-CLIP	19536157
MIRT715171	hsa-miR-205-5p	HITS-CLIP	19536157
MIRT715172	hsa-miR-181a-2-3p	HITS-CLIP	19536157
MIRT724871	hsa-miR-4482-3p	HITS-CLIP	19536157
MIRT724872	hsa-miR-7159-3p	HITS-CLIP	19536157
MIRT724873	hsa-miR-4775	HITS-CLIP	19536157
MIRT724874	hsa-miR-6831-3p	HITS-CLIP	19536157
MIRT724875	hsa-miR-643	HITS-CLIP	19536157
MIRT724876	hsa-miR-4735-5p	HITS-CLIP	19536157
MIRT724877	hsa-miR-590-3p	HITS-CLIP	19536157
MIRT731592	hsa-miR-27a-3p	LacZ reporter assay	27165190
MIRT731991	hsa-miR-125a-5p	Luciferase reporter assay	28386337
MIRT786119	hsa-miR-4524a-3p	HITS-CLIP	27418678
MIRT786151	hsa-miR-4524b-3p	HITS-CLIP	27418678
MIRT786504	hsa-miR-4712-3p	HITS-CLIP	27418678
MIRT788587	hsa-miR-6759-3p	HITS-CLIP	27418678

Transcription factors

Transcription factor	Regulation	Reference
MEF2A	Activation	18073218

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0000077	Process	DNA damage checkpoint	IEA
GO:0000187	Process	Activation of MAPK activity	TAS
GO:0000902	Process	Cell morphogenesis	IEA
GO:0000922	Component	Spindle pole	IEA
GO:0001502	Process	Cartilage condensation	IEA
GO:0001525	Process	Angiogenesis	IEA
GO:0001890	Process	Placenta development	IEA
GO:0002062	Process	Chondrocyte differentiation	IEA
GO:0004674	Function	Protein serine/threonine kinase activity	IBA	21873635
GO:0004674	Function	Protein serine/threonine kinase activity	TAS
GO:0004707	Function	MAP kinase activity	IBA	21873635
GO:0004707	Function	MAP kinase activity	IDA	7997261, 10330143, 20932473
GO:0004708	Function	MAP kinase kinase activity	TAS	10706854
GO:0005515	Function	Protein binding	IPI	9792677, 10601328, 11238443, 16189514, 16751104, 17255097, 17255949, 17380123, 17380128, 18624398, 20347885, 20368287, 20871633, 20936779, 21283629, 21900206, 21908610, 21988832, 22521293, 23397142, 23455922, 23560844, 23602568, 25241761, 25852190, 26496610, 31515488, 31980649, 3281
GO:0005524	Function	ATP binding	IEA
GO:0005576	Component	Extracellular region	TAS
GO:0005634	Component	Nucleus	IBA	21873635
GO:0005634	Component	Nucleus	IDA	30878395
GO:0005634	Component	Nucleus	ISS
GO:0005654	Component	Nucleoplasm	TAS
GO:0005737	Component	Cytoplasm	IBA	21873635
GO:0005737	Component	Cytoplasm	ISS
GO:0005739	Component	Mitochondrion	IEA
GO:0005829	Component	Cytosol	IDA
GO:0005829	Component	Cytosol	TAS
GO:0006006	Process	Glucose metabolic process	IEA
GO:0006357	Process	Regulation of transcription by RNA polymerase II	ISS
GO:0006915	Process	Apoptotic process	IEA
GO:0006935	Process	Chemotaxis	TAS	10706854
GO:0007165	Process	Signal transduction	TAS	10706854
GO:0007166	Process	Cell surface receptor signaling pathway	TAS	10706854
GO:0007178	Process	Transmembrane receptor protein serine/threonine kinase signaling pathway	IEA
GO:0007265	Process	Ras protein signal transduction	TAS
GO:0007519	Process	Skeletal muscle tissue development	IEA
GO:0010628	Process	Positive regulation of gene expression	IGI	24299952
GO:0010628	Process	Positive regulation of gene expression	IMP	25754930, 26649771
GO:0010831	Process	Positive regulation of myotube differentiation	ISS
GO:0016607	Component	Nuclear speck	IDA
GO:0018105	Process	Peptidyl-serine phosphorylation	ISS
GO:0019395	Process	Fatty acid oxidation	IEA
GO:0019899	Function	Enzyme binding	IPI	23483889
GO:0019903	Function	Protein phosphatase binding	IPI	10391943, 21283629
GO:0030278	Process	Regulation of ossification	IEA
GO:0030316	Process	Osteoclast differentiation	ISS
GO:0031281	Process	Positive regulation of cyclase activity	IMP	22027397
GO:0031663	Process	Lipopolysaccharide-mediated signaling pathway	IEA
GO:0032495	Process	Response to muramyl dipeptide	IEA
GO:0032735	Process	Positive regulation of interleukin-12 production	IMP	25754930
GO:0034774	Component	Secretory granule lumen	TAS
GO:0035331	Process	Negative regulation of hippo signaling	IMP	27402810
GO:0035556	Process	Intracellular signal transduction	IBA	21873635
GO:0035556	Process	Intracellular signal transduction	IDA	10838079
GO:0035924	Process	Cellular response to vascular endothelial growth factor stimulus	IMP	18440775
GO:0035994	Process	Response to muscle stretch	IEA
GO:0038066	Process	P38MAPK cascade	ISS
GO:0042307	Process	Positive regulation of protein import into nucleus	IEA
GO:0042770	Process	Signal transduction in response to DNA damage	IMP	20160708
GO:0043312	Process	Neutrophil degranulation	TAS
GO:0043536	Process	Positive regulation of blood vessel endothelial cell migration	IMP	18440775
GO:0045648	Process	Positive regulation of erythrocyte differentiation	IMP	23483889
GO:0045663	Process	Positive regulation of myoblast differentiation	ISS
GO:0045944	Process	Positive regulation of transcription by RNA polymerase II	IEA
GO:0046326	Process	Positive regulation of glucose import	IEA
GO:0048010	Process	Vascular endothelial growth factor receptor signaling pathway	IMP	18440775
GO:0048010	Process	Vascular endothelial growth factor receptor signaling pathway	TAS
GO:0048273	Function	Mitogen-activated protein kinase p38 binding	IPI	11035004
GO:0051090	Process	Regulation of DNA-binding transcription factor activity	TAS
GO:0051146	Process	Striated muscle cell differentiation	IEA
GO:0051149	Process	Positive regulation of muscle cell differentiation	TAS
GO:0051525	Function	NFAT protein binding	ISS
GO:0060045	Process	Positive regulation of cardiac muscle cell proliferation	IEA
GO:0070935	Process	3'-UTR-mediated mRNA stabilization	TAS	20932473
GO:0071222	Process	Cellular response to lipopolysaccharide	IDA	23776175
GO:0071223	Process	Cellular response to lipoteichoic acid	IMP	26649771
GO:0071356	Process	Cellular response to tumor necrosis factor	IEA
GO:0071479	Process	Cellular response to ionizing radiation	IMP	20160708
GO:0090090	Process	Negative regulation of canonical Wnt signaling pathway	IEA
GO:0090336	Process	Positive regulation of brown fat cell differentiation	IEA
GO:0090400	Process	Stress-induced premature senescence	IMP	20160708
GO:0098586	Process	Cellular response to virus	IMP	25754930
GO:0098978	Component	Glutamatergic synapse	IEA
GO:0099179	Process	Regulation of synaptic membrane adhesion	IEA
GO:1900015	Process	Regulation of cytokine production involved in inflammatory response	IDA	15251176
GO:1901741	Process	Positive regulation of myoblast fusion	ISS
GO:1901796	Process	Regulation of signal transduction by p53 class mediator	TAS
GO:1904813	Component	Ficolin-1-rich granule lumen	TAS
GO:2000379	Process	Positive regulation of reactive oxygen species metabolic process	IMP	20160708

Other IDs

• MIM: 600289
• HGNC: 6876
• e!Ensembl: ENSG00000112062

Protein

• UniProt ID: Q16539
• Protein name: Mitogen-activated protein kinase 14 (MAP kinase 14) (MAPK 14) (EC 2.7.11.24) (Cytokine suppressive anti-inflammatory drug-binding protein) (CSAID-binding protein) (CSBP) (MAP kinase MXI2) (MAX-interacting protein 2) (Mitogen-activated protein kinase p38 alpha) (MAP kinase p38 alpha) (Stress-activated protein kinase 2a) (SAPK2a)
• Protein function: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'. ; (Microbial infection) Activated by phosphorylation by M.tuberculosis EsxA in T-cells leading to inhibition of IFN-gamma production; phosphorylation is apparent within 15 minute and is inhibited by kinase-specific inhibitors SB203580 and siRNA (PubMed:21586573).
• PDB: 1A9U, 1BL6, 1BL7, 1BMK, 1DI9, 1IAN, 1KV1, 1KV2, 1M7Q, 1OUK, 1OUY, 1OVE, 1OZ1, 1R39, 1R3C, 1W7H, 1W82, 1W83, 1W84, 1WBN, 1WBO, 1WBS, 1WBT, 1WBV, 1WBW, 1WFC, 1YQJ, 1ZYJ, 1ZZ2, 1ZZL, 2BAJ, 2BAK, 2BAL, 2BAQ, 2FSL, 2FSM, 2FSO, 2FST, 2GFS, 2I0H, 2LGC, 2NPQ, 2OKR, 2ONL, 2QD9, 2RG5, 2RG6, 2Y8O, 2YIS, 2YIW, 2YIX
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00069	Pkinase	24 → 308	Protein kinase domain	Domain

• Sequence:

  MSQERPTFYRQELNKTIWEVPERYQNLSPVGSGAYGSVCAAFDTKTGLRVAVKKLSRPFQ
  SIIHAKRTYRELRLLKHMKHENVIGLLDVFTPARSLEEFNDVYLVTHLMGADLNNIVKCQ
  KLTDDHVQFLIYQILRGLKYIHSADIIHRDLKPSNLAVNEDCELKILDFGLARHTDDEMT
  GYVATRWYRAPEIMLNWMHYNQTVDIWSVGCIMAELLTGRTLFPGTDHIDQLKLILRLVG
  TPGAELLKKISSESARNYIQSLTQMPKMNFANVFIGANPLAVDLLEKMLVLDSDKRITAA
  QALAHAYFAQYHDPDDEPVADPYDQSFESRDLLIDEWKSLTYDEVISFVPPPLDQEEMES
  

• Sequence length: 360