Immunogen:

A synthesized peptide derived from human p38 MAPK around the phosphorylation site of Thr180/Tyr182 .

Uniprot:

>>Visit The Human Protein Atlas

Gene id:

Molecular Weight:

Observed Mol.Wt.: 43 kDa.
Predicted Mol.Wt.: 42kDa.

Subcellular Location:

Cytoplasm. Nucleus.

Tissue Specificity:

Brain, heart, placenta, pancreas and skeletal muscle. Expressed to a lesser extent in lung, liver and kidney.

Description:

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.

Sequence:

• Protein BLAST With
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        10         20         30         40         50
MSQERPTFYR QELNKTIWEV PERYQNLSPV GSGAYGSVCA AFDTKTGLRV 
        60         70         80         90        100
AVKKLSRPFQ SIIHAKRTYR ELRLLKHMKH ENVIGLLDVF TPARSLEEFN 
       110        120        130        140        150
DVYLVTHLMG ADLNNIVKCQ KLTDDHVQFL IYQILRGLKY IHSADIIHRD 
       160        170        180        190        200
LKPSNLAVNE DCELKILDFG LARHTDDEMT GYVATRWYRA PEIMLNWMHY 
       210        220        230        240        250
NQTVDIWSVG CIMAELLTGR TLFPGTDHID QLKLILRLVG TPGAELLKKI 
       260        270        280        290        300
SSESARNYIQ SLTQMPKMNF ANVFIGANPL AVDLLEKMLV LDSDKRITAA 
       310        320        330        340        350
QALAHAYFAQ YHDPDDEPVA DPYDQSFESR DLLIDEWKSL TYDEVISFVP 
       360
PPLDQEEMES                                             

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'.

Post-translational Modifications:

Dually phosphorylated on Thr-180 and Tyr-182 by the MAP2Ks MAP2K3/MKK3, MAP2K4/MKK4 and MAP2K6/MKK6 in response to inflammatory citokines, environmental stress or growth factors, which activates the enzyme. Dual phosphorylation can also be mediated by TAB1-mediated autophosphorylation. TCR engagement in T-cells also leads to Tyr-323 phosphorylation by ZAP70. Dephosphorylated and inactivated by DUPS1, DUSP10 and DUSP16. PPM1D also mediates dephosphorylation and inactivation of MAPK14 (PubMed:21283629).Acetylated at Lys-53 and Lys-152 by KAT2B and EP300. Acetylation at Lys-53 increases the affinity for ATP and enhances kinase activity. Lys-53 and Lys-152 are deacetylated by HDAC3.Ubiquitinated. Ubiquitination leads to degradation by the proteasome pathway.

Subcellular Location:

Nucleus;

Subunit Structure:

Component of a signaling complex containing at least AKAP13, PKN1, MAPK14, ZAK and MAP2K3. Within this complex, AKAP13 interacts directly with PKN1, which in turn recruits MAPK14, MAP2K3 and ZAK (PubMed:21224381). Binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR (By similarity). This interaction retains MAPK14 in the cytoplasm and prevents nuclear accumulation (By similarity). Interacts with SPAG9 and GADD45A (By similarity). Interacts with CDC25B, CDC25C, DUSP1, DUSP10, DUSP16, NP60, SUPT20H and TAB1. Interacts with casein kinase II subunits CSNK2A1 and CSNK2B. Interacts with PPM1D. Interacts with CDK5RAP3; recruits PPM1D to MAPK14 and may regulate its dephosphorylation (PubMed:21283629).

Similarity:

The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily.

Research Fields:

· Cellular Processes > Cellular community - eukaryotes > Signaling pathways regulating pluripotency of stem cells.(View pathway)
· Cellular Processes > Cell growth and death > Cellular senescence.(View pathway)
· Environmental Information Processing > Signal transduction > TNF signaling pathway.(View pathway)
· Environmental Information Processing > Signal transduction > MAPK signaling pathway.(View pathway)
· Environmental Information Processing > Signal transduction > Sphingolipid signaling pathway.(View pathway)
· Environmental Information Processing > Signal transduction > FoxO signaling pathway.(View pathway)
· Environmental Information Processing > Signal transduction > Rap1 signaling pathway.(View pathway)
· Human Diseases > Cancers: Overview > Proteoglycans in cancer.
· Human Diseases > Infectious diseases: Bacterial > Pertussis.
· Human Diseases > Infectious diseases: Bacterial > Salmonella infection.
· Human Diseases > Neurodegenerative diseases > Amyotrophic lateral sclerosis (ALS).
· Human Diseases > Infectious diseases: Bacterial > Shigellosis.
· Human Diseases > Infectious diseases: Viral > Hepatitis C.
· Human Diseases > Infectious diseases: Parasitic > Chagas disease (American trypanosomiasis).
· Human Diseases > Infectious diseases: Bacterial > Epithelial cell signaling in Helicobacter pylori infection.
· Human Diseases > Infectious diseases: Bacterial > Tuberculosis.
· Human Diseases > Infectious diseases: Viral > Influenza A.
· Human Diseases > Infectious diseases: Viral > Epstein-Barr virus infection.
· Human Diseases > Infectious diseases: Parasitic > Leishmaniasis.
· Human Diseases > Infectious diseases: Parasitic > Toxoplasmosis.
· Human Diseases > Drug resistance: Antineoplastic > Endocrine resistance.
· Organismal Systems > Immune system > Th1 and Th2 cell differentiation.(View pathway)
· Organismal Systems > Immune system > RIG-I-like receptor signaling pathway.(View pathway)
· Organismal Systems > Immune system > Toll-like receptor signaling pathway.(View pathway)
· Organismal Systems > Immune system > IL-17 signaling pathway.(View pathway)
· Organismal Systems > Immune system > Platelet activation.(View pathway)
· Organismal Systems > Immune system > T cell receptor signaling pathway.(View pathway)
· Organismal Systems > Immune system > Fc epsilon RI signaling pathway.(View pathway)
· Organismal Systems > Immune system > Leukocyte transendothelial migration.(View pathway)
· Organismal Systems > Endocrine system > Progesterone-mediated oocyte maturation.
· Organismal Systems > Endocrine system > Relaxin signaling pathway.
· Organismal Systems > Circulatory system > Adrenergic signaling in cardiomyocytes.(View pathway)
· Organismal Systems > Immune system > Th17 cell differentiation.(View pathway)
· Organismal Systems > Endocrine system > Prolactin signaling pathway.(View pathway)
· Organismal Systems > Nervous system > Neurotrophin signaling pathway.(View pathway)
· Organismal Systems > Nervous system > Dopaminergic synapse.
· Organismal Systems > Development > Osteoclast differentiation.(View pathway)
· Organismal Systems > Sensory system > Inflammatory mediator regulation of TRP channels.(View pathway)
· Organismal Systems > Immune system > NOD-like receptor signaling pathway.(View pathway)
· Organismal Systems > Nervous system > Retrograde endocannabinoid signaling.(View pathway)

 IHC Protocol.

 IF/ICC Protocol.

 Sample Preparation For Western Blotting.

 Western Blotting Handbook.