MAPK14

Mitogen-activated protein kinase 14
250px PDB rendering based on 1a9u.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 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, 2ZAZ, 2ZB0, 2ZB1, 3BV2, 3BV3, 3BX5, 3C5U, 3CTQ, 3D7Z, 3D83, 3DS6, 3DT1, 3E92, 3E93, 3FC1, 3FI4, 3FKL, 3FKN, 3FKO, 3FL4, 3FLN, 3FLQ, 3FLS, 3FLW, 3FLY, 3FLZ, 3FMH, 3FMJ, 3FMK, 3FML, 3FMM, 3FMN, 3FSF, 3FSK, 3GC7, 3GCP, 3GCQ, 3GCS, 3GCU, 3GCV, 3GFE, 3GI3, 3HA8, 3HEC, 3HEG, 3HL7, 3HLL, 3HP2, 3HP5, 3HRB, 3HUB, 3HUC, 3HV3, 3HV4, 3HV5, 3HV6, 3HV7, 3HVC, 3IPH, 3ITZ, 3IW5, 3IW6, 3IW7, 3IW8, 3K3I, 3K3J, 3KF7, 3KQ7, 3L8S, 3L8X, 3LFA, 3LFB, 3LFC, 3LFD, 3LFE, 3LFF, 3LHJ, 3MGY, 3MH0, 3MH1, 3MH2, 3MH3, 3MPA, 3MPT, 3MVL, 3MVM, 3MW1, 3NEW, 3NNU, 3NNV, 3NNW, 3NNX, 3NWW, 3O8P, 3O8T, 3O8U, 3OBG, 3OBJ, 3OC1, 3OCG, 3OD6, 3ODY, 3ODZ, 3OEF, 3PG3, 3QUD, 3QUE, 3RIN, 3ROC, 3S3I, 3S4Q, 3U8W, 3UVP, 3UVQ, 3UVR, 3ZS5, 3ZSG, 3ZSH, 3ZSI, 3ZYA, 4A9Y, 4AA0, 4AA4, 4AA5, 4AAC, 4DLI, 4DLJ, 4E5A, 4E5B, 4E6A, 4E6C, 4E8A, 4EH2, 4EH3, 4EH4, 4EH5, 4EH6, 4EH7, 4EH8, 4EH9, 4EHV, 4EWQ, 4F9W, 4F9Y, 4FA2, 4GEO, 4KIN, 4KIP, 4KIQ, 4L8M, 4R3C
Identifiers
Symbols	MAPK14 ; CSBP; CSBP1; CSBP2; CSPB1; EXIP; Mxi2; PRKM14; PRKM15; RK; SAPK2A; p38; p38ALPHA
External IDs	OMIM: 600289 MGI: 1346865 HomoloGene: 31777 ChEMBL: 260 GeneCards: MAPK14 Gene
EC number	2.7.11.24
Gene ontology Molecular function • protein serine/threonine kinase activity • MAP kinase activity • MAP kinase kinase activity • protein binding • ATP binding • protein C-terminus binding • enzyme binding • NFAT protein binding Cellular component • spindle pole • nucleus • nucleoplasm • cytoplasm • mitochondrion • cytosol • extracellular exosome Biological process • DNA damage checkpoint • activation of MAPK activity • cell morphogenesis • cartilage condensation • angiogenesis • placenta development • chondrocyte differentiation • toll-like receptor signaling pathway • MyD88-dependent toll-like receptor signaling pathway • MyD88-independent toll-like receptor signaling pathway • glucose metabolic process • transcription, DNA-templated • regulation of transcription from RNA polymerase II promoter • apoptotic process • movement of cell or subcellular component • chemotaxis • organelle organization • mitochondrion organization • signal transduction • cell surface receptor signaling pathway • transmembrane receptor protein serine/threonine kinase signaling pathway • Ras protein signal transduction • skeletal muscle tissue development • blood coagulation • response to glucose • gene expression • positive regulation of gene expression • positive regulation of myotube differentiation • myoblast differentiation involved in skeletal muscle regeneration • peptidyl-serine phosphorylation • fatty acid oxidation • platelet activation • osteoclast differentiation • positive regulation of cyclase activity • lipopolysaccharide-mediated signaling pathway • response to muramyl dipeptide • toll-like receptor 2 signaling pathway • toll-like receptor 3 signaling pathway • toll-like receptor 4 signaling pathway • toll-like receptor 5 signaling pathway • toll-like receptor 9 signaling pathway • toll-like receptor 10 signaling pathway • intracellular signal transduction • TRIF-dependent toll-like receptor signaling pathway • cellular response to vascular endothelial growth factor stimulus • response to muscle stretch • p38MAPK cascade • toll-like receptor TLR1:TLR2 signaling pathway • toll-like receptor TLR6:TLR2 signaling pathway • positive regulation of protein import into nucleus • muscle cell differentiation • signal transduction in response to DNA damage • positive regulation of blood vessel endothelial cell migration • innate immune response • positive regulation of erythrocyte differentiation • positive regulation of myoblast differentiation • positive regulation of transcription from RNA polymerase II promoter • positive regulation of glucose import • protein autophosphorylation • vascular endothelial growth factor receptor signaling pathway • neurotrophin TRK receptor signaling pathway • regulation of sequence-specific DNA binding transcription factor activity • striated muscle cell differentiation • positive regulation of muscle cell differentiation • stress-activated MAPK cascade • positive regulation of cardiac muscle cell proliferation • 3'-UTR-mediated mRNA stabilization • cellular response to lipopolysaccharide • cellular response to ionizing radiation • negative regulation of canonical Wnt signaling pathway • positive regulation of brown fat cell differentiation • stress-induced premature senescence • cellular response to virus • regulation of cytokine production involved in inflammatory response • positive regulation of myoblast fusion • positive regulation of reactive oxygen species metabolic process • positive regulation of interleukin-12 secretion Sources: Amigo / QuickGO
RNA expression pattern
File:PBB GE MAPK14 202530 at tn.png
File:PBB GE MAPK14 210449 x at tn.png
File:PBB GE MAPK14 211087 x at tn.png
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	1432	26416
Ensembl	ENSG00000112062	ENSMUSG00000053436
UniProt	Q16539	P47811
RefSeq (mRNA)	NM_001315	NM_001168508
RefSeq (protein)	NP_001306	NP_001161980
Location (UCSC)	Chr 6: 36.03 – 36.11 Mb	Chr 17: 28.69 – 28.75 Mb
PubMed search	[1]	[2]

Main article: P38 mitogen-activated protein kinases

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

MAPK14 encodes p38α mitogen-activated protein kinase (MAPK) which is the prototypic member of the p38 MAPK family. p38 MAPKs are also known as stress-activated serine/threonine-specific kinases (SAPKs). In addition to MAPK14 for p38α MAPK, the p38 MAPK family has three additional members, including MAPK11, MAPK12 and MAPK13 which encodes p38β MAPK, p38γ MAPK and p38δ MAPK isoforms, respectively. p38α MAPK was originally identified as a tyrosine phosphorylated protein detected in activated immune cell macrophages with an essential role in inflammatory cytokine induction, such as Tumor Necrotic Factor α (TNFα). However, p38α MAPK mediated kinase activity has been implicated in many tissues beyond immune systems. p38α MAPK is mainly activated through MAPK kinase kinase cascades and exerts its biological function via downstream substrate phosphorylation. p38α MAPK is implicated in diverse cellular function, from gene expression to programmed cell death through a network of signaling molecules and transcription factors. Pharmacological and genetic inhibition of p38α MAPK not only revealed its biological significance in physiological function but also the potential of targeting p38α MAPK in human diseases such as immune disorder and heart failure.

Structure

MAPK14 is a 41 kDa protein composed of 360 amino acids.

Function

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.

p38α MAPK is ubiquitously expressed in many cell types, in contrast, p38β MAPK is highly expressed in brain and lung, p38γ MAPK mostly in skeletal muscle and nerve system, and p38δ MAPK in uterus and pancreas. Like all MAP kinases, p38α MAPK has 11 conserved domains (Domains I to XI) and a Thr-Gly-Tyr (TGY) dual phosphorylation motif. Activation of p38 MAPK pathway has been implicated in a variety of stress response in addition to inflammation, including osmotic shock, heat, and oxidative stress. The canonical pathway for p38 MAPK activation involve a cascade of protein kinases, including MAP3K such as MEKK1, 2, 3 and 4, TGFβ-activated kinase (TAK1), TAO1-3, mixed-lineage kinase 2/3 (MLK2/3), and apoptosis signal-regulating kinase 1/2 (ASK1/2), as well as MAP2Ks, such as MKK3, 6 and 4. MAP2K mediated phosphorylation of the TGY motif results in conformational change of p38 MAPK which allows kinase activation and accessibility to substrates. In addition, TAK1-binding protein 1 (TAB1) and ZAP70 can induce p38 MAPK via non-canonical autophosphorylation. Furthermore, acetylation of p38 MAPK at lys-53 of the ATP-binding pocket also enhances p38 MAPK activity during cellular stress Under basal conditions, p38α MAPK is detected in both the nucleus and the cytoplasm. One of the consequences of p38 MAPK activation is translocates into the nucleus. involving both p38 MAPK phosphorylation and microtuble- and dynein-dependent process. In addition, one substrate of p38 MAPK, MAP kinase-activated protein kinase 2 (MAPAK2 or MK2) can modulate and direct p38α MAPK localization to cytosole via direct interaction. p38α MAPK activation can be reversed by dephosphorylation of the TGY motif carried out by protein phosphatases, including ser-thr protein phosphatases (PPs), protein tyrosine phosphatases (PTP), and dual-specificity phosphatases (DUSP). For example, ser/thr phosphatases PP2Cα/β suppress activity of p38s MAPK through direct interaction as well as suppression of MKKs/TAK1 in mammalian cells. Hematopoietic PTP (HePTP) and striatal-enriched phosphatase (STEP) bind to MAPKs through a kinase-interaction motif (KIM) and inactivates them by dephosphorylating the phosphotyrosine residue in their activation loop. DUSPs, which have a docking domain to MAPKs and dual-specific phosphatase activity, can also bind to p38 MAPKs and dephosphorylate of both phosphotyrosine and phosphothreonine residues. In addition to these phosphatases, other molecular components such as Hsp90-Cdc37 chaperone complex can also modulate p38 MAPK autophosphorylation activity and prevents non-canonical activation.

p38α MAPK is implicated in cell survival/apoptosis, proliferation, differentiation, migration, mRNA stability, and inflammatory response in different cell types through variety of different target molecules MK2 is one of the well-studied downstream targets of p38α MAPK. Their downstream substrates include small heat shock protein 27 (HSP27), lymphocyte-specific protein1 (LSP1), cAMP response element-binding protein (CREB), cyclooxygenase 2 (COX2), activating transcription factor 1 (ATF1), serum response factor (SRF), and mRNA-binding protein tristetraprolin (TTP) In addition to protein kinases, many transcription factors are downstream targets of p38α MAPK, including ATF1/2/6, c-Myc, c-FOS, GATA4, MEF2A/C, SRF, STAT1, and CHOP

Role in cardiovascular system

p38α MAPK constitutes the main p38 MAPK activity in heart. During cardiomyocyte maturation in new born mouse heart, p38α MAPK activity can regulate myocyte cytokinesis and promote cell cycle exit. while inhibition of p38 MAPK activity leads to induction of mitosis in both adult and fetal cardiomyocyte. Therefore, p38 MAPK is associated with cell-cycle arrest in mammalian cardiomyocytes and its inhibition may represent a strategy to promote cardiac regeneration in response to injury. In addition, p38α MAPK induction promotes myocyte apoptosis. via downstream targets STAT1, CHOP, FAK, SMAD, cytochrome c, NF-kB, PTEN, and p53. p38 MAPK can also target IRS-1 mediated AKT signaling and promotes myocyte death under chronic insulin stimulation. Inhibition of p38 MAPK activity confers cardioprotection against ischemia reperfusion injury in heart However, some reports demonstrated that p38 MAPK also involves in anti-apoptotic effect via phosphorylation of αβ-Crystallin or induction of Pim-3 during early response to oxidative stress or anoxic preconditioning respectively More interestingly, p38α MAPK and p38β MAPK appear to have an opposite role in apoptosis. Whereas p38α MAPK has a pro-apoptotic role via p53 activation, p38β MAPK has a pro-survival role via inhibition of ROS formation. In general, chronic activation of p38 MAPK activity is viewed as pathological and pro-apoptotic, and inhibition of p38 MAPK activity is in clinical evaluation as a potential therapy to mitigate acute injury in ischemic heart failure. p38 MAPK activity is also implicated in cardiac hypertrophy which is a significant feature of pathological remodeling in the diseased hearts and a major risk factor for heart failure and advert outcome. Most in vitro evidence supports that p38 MAPK activation promotes cardiomyocyte hypertrophy. However, in vivo evidence suggest that chronic activation of p38 MAPK activity triggers restrictive cardiomyopathy with limited hypertrophy, while genetic inactivation p38α MAPK in mouse heart results in an elevated cardiac hypertrophy in response to pressure overload or swimming exercise. Therefore, the functional role of p38 MAPK in cardiac hypertrophy remains controversial and yet to be further elucidated.

Interactions

MAPK14 has been shown to interact with:

• AKT1,
• ATF2,
• CDC25B,
• CDC25C,
• CSNK2A1,
• DUSP10,
• DUSP16,
• DUSP1,
• FUBP1,
• HTRA2,
• KRT8
• MAP2K6,
• MAP3K7IP1,
• MAPK1,
• MEF2A,
• MAPKAPK3,
• MEF2A,
• RPS6KA4, and
• ZFP36L1.

External links

• MAP Kinase Resource .