UniProt Accession

 MK14_HUMAN; Q16539; A6ZJ92; A8K6P4; B0LPH0; O60776; Q13083; Q14084; Q8TDX0 

Genbank Protein ID

 L35263; L35264; L35253; U19775; AF100544; AB074150; AK291709; BT006933; CR536505; EU332860; Z95152; CH471081; BC000092; BC031574 

Genbank Nucleotide ID

 AAA57455.1; AAA57456.1; AAA74301.1; AAC50329.1; AAF36770.1; BAB85654.1; BAF84398.1; AAP35579.1; CAG38743.1; ABY87549.1; EAX03869.1; AAH00092.1; AAH31574.1 

Protein Name

 Mitogen-activated protein kinase 14 

Protein Synonyms/Alias

 MAP kinase 14; MAPK 14; 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 

Gene Name

 MAPK14 

Gene Synonyms/Alias

 CSBP; CSBP1; CSBP2; CSPB1; MXI2; SAPK2A 

Created Date

 July 27, 2013 

Organism

 Homo sapiens (Human) 

NCBI Taxa ID

 9606 

Lysine Modification

Position	Peptide	Type	References
15	FYRQELNKTIWEVPE	ubiquitination	[1, 2]
45	VCAAFDTKTGLRVAV	ubiquitination	[2]
53	TGLRVAVKKLSRPFQ	acetylation	[3]
54	GLRVAVKKLSRPFQS	ubiquitination	[2]
66	FQSIIHAKRTYRELR	ubiquitination	[2]
79	LRLLKHMKHENVIGL	ubiquitination	[2]
121	NNIVKCQKLTDDHVQ	ubiquitination	[2]
139	YQILRGLKYIHSADI	ubiquitination	[1, 2]
152	DIIHRDLKPSNLAVN	acetylation	[3]
152	DIIHRDLKPSNLAVN	ubiquitination	[2]
165	VNEDCELKILDFGLA	ubiquitination	[2]
233	TDHIDQLKLILRLVG	ubiquitination	[2]
248	TPGAELLKKISSESA	ubiquitination	[1, 2]
249	PGAELLKKISSESAR	ubiquitination	[2]
295	MLVLDSDKRITAAQA	ubiquitination	[2]

Reference

 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] Refined preparation and use of anti-diglycine remnant (K-ε-GG) antibody enables routine quantification of 10,000s of ubiquitination sites in single proteomics experiments.
 Udeshi ND, Svinkina T, Mertins P, Kuhn E, Mani DR, Qiao JW, Carr SA.
 Mol Cell Proteomics. 2013 Mar;12(3):825-31. [PMID: 23266961]
 [3] Acetylation of a conserved lysine residue in the ATP binding pocket of p38 augments its kinase activity during hypertrophy of cardiomyocytes.
 Pillai VB, Sundaresan NR, Samant SA, Wolfgeher D, Trivedi CM, Gupta MP.
 Mol Cell Biol. 2011 Jun;31(11):2349-63. [PMID: 21444723] 

Functional Description

 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'. 

Sequence Annotation

 DOMAIN 24 308 Protein kinase.
 NP_BIND 30 38 ATP.
 REGION 70 71 Inhibitor-binding.
 REGION 106 110 Inhibitor-binding.
 REGION 168 169 Inhibitor-binding.
 MOTIF 180 182 TXY.
 ACT_SITE 168 168 Proton acceptor.
 BINDING 35 35 Inhibitor.
 BINDING 53 53 ATP.
 BINDING 53 53 Inhibitor.
 BINDING 71 71 Inhibitor.
 BINDING 109 109 Inhibitor; via amide nitrogen and
 BINDING 154 154 Inhibitor; via carbonyl oxygen.
 BINDING 168 168 Inhibitor; via amide nitrogen and
 BINDING 197 197 Inhibitor.
 BINDING 252 252 Inhibitor; via amide nitrogen.
 MOD_RES 2 2 N-acetylserine.
 MOD_RES 2 2 Phosphoserine.
 MOD_RES 16 16 Phosphothreonine.
 MOD_RES 53 53 N6-acetyllysine.
 MOD_RES 152 152 N6-acetyllysine.
 MOD_RES 180 180 Phosphothreonine; by MAP2K3, MAP2K4,
 MOD_RES 182 182 Phosphotyrosine; by MAP2K3, MAP2K4,
 MOD_RES 263 263 Phosphothreonine.
 MOD_RES 323 323 Phosphotyrosine; by ZAP70.  

Keyword

 3D-structure; Acetylation; Alternative splicing; Apoptosis; ATP-binding; Complete proteome; Cytoplasm; Direct protein sequencing; Kinase; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; Serine/threonine-protein kinase; Stress response; Transcription; Transcription regulation; Transferase; Ubl conjugation. 

Sequence Source

 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 

Protein Length

 360 AA 

Protein Sequence

Gene Ontology

 GO:0005829; C:cytosol; TAS:Reactome.
 GO:0005739; C:mitochondrion; IEA:Compara.
 GO:0005654; C:nucleoplasm; TAS:Reactome.
 GO:0000922; C:spindle pole; IEA:Compara.
 GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
 GO:0004707; F:MAP kinase activity; IDA:UniProtKB.
 GO:0004708; F:MAP kinase kinase activity; TAS:ProtInc.
 GO:0051525; F:NFAT protein binding; ISS:BHF-UCL.
 GO:0070935; P:3'-UTR-mediated mRNA stabilization; TAS:UniProtKB.
 GO:0001525; P:angiogenesis; IEA:Compara.
 GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
 GO:0000902; P:cell morphogenesis; IEA:Compara.
 GO:0006928; P:cellular component movement; TAS:ProtInc.
 GO:0071479; P:cellular response to ionizing radiation; IMP:BHF-UCL.
 GO:0035924; P:cellular response to vascular endothelial growth factor stimulus; IMP:BHF-UCL.
 GO:0006935; P:chemotaxis; TAS:ProtInc.
 GO:0002062; P:chondrocyte differentiation; IEA:Compara.
 GO:0000077; P:DNA damage checkpoint; IEA:Compara.
 GO:0019395; P:fatty acid oxidation; IEA:Compara.
 GO:0010467; P:gene expression; TAS:Reactome.
 GO:0006006; P:glucose metabolic process; IEA:Compara.
 GO:0045087; P:innate immune response; TAS:Reactome.
 GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Compara.
 GO:0016071; P:mRNA metabolic process; TAS:Reactome.
 GO:0042692; P:muscle cell differentiation; TAS:Reactome.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
 GO:0030316; P:osteoclast differentiation; ISS:BHF-UCL.
 GO:0018105; P:peptidyl-serine phosphorylation; ISS:BHF-UCL.
 GO:0030168; P:platelet activation; TAS:Reactome.
 GO:0045648; P:positive regulation of erythrocyte differentiation; IEA:Compara.
 GO:0051149; P:positive regulation of muscle cell differentiation; TAS:Reactome.
 GO:0042307; P:positive regulation of protein import into nucleus; IEA:Compara.
 GO:2000379; P:positive regulation of reactive oxygen species metabolic process; IMP:BHF-UCL.
 GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Compara.
 GO:0007265; P:Ras protein signal transduction; TAS:Reactome.
 GO:0051090; P:regulation of sequence-specific DNA binding transcription factor activity; TAS:Reactome.
 GO:0032495; P:response to muramyl dipeptide; IEA:Compara.
 GO:0042770; P:signal transduction in response to DNA damage; IMP:BHF-UCL.
 GO:0007519; P:skeletal muscle tissue development; IEA:Compara.
 GO:0051403; P:stress-activated MAPK cascade; TAS:Reactome.
 GO:0090400; P:stress-induced premature senescence; IMP:BHF-UCL.
 GO:0051146; P:striated muscle cell differentiation; IEA:Compara.
 GO:0034166; P:toll-like receptor 10 signaling pathway; TAS:Reactome.
 GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
 GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0034146; P:toll-like receptor 5 signaling pathway; TAS:Reactome.
 GO:0034162; P:toll-like receptor 9 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
 GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0048010; P:vascular endothelial growth factor receptor signaling pathway; IMP:BHF-UCL. 

Interpro

 IPR011009; Kinase-like_dom.
 IPR003527; MAP_kinase_CS.
 IPR008352; MAPK_p38.
 IPR000719; Prot_kinase_cat_dom.
 IPR017441; Protein_kinase_ATP_BS.
 IPR002290; Ser/Thr_dual-sp_kinase_dom. 

Pfam

 PF00069; Pkinase 

SMART

 SM00220; S_TKc 

PROSITE

 PS01351; MAPK
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00108; PROTEIN_KINASE_ST 

PRINTS

 PR01773; P38MAPKINASE.