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mitogen-activated protein kinase 14; mitogen-activated protein kinase p38 alpha; MAP kinase p38 alpha; cytokine suppressive anti-inflammatory drug-binding protein; CSAID-binding protein; CSBP; MAX-interacting protein 2; MAP kinase MXI2; SAPK2A (MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2)

Function: - responds to activation by environmental stress, pro-inflammatory cytokines & lipopolysaccharide (LPS) by phosphorylating a number of transcription factors, such as ELK1 & ATF2 & several downstream kinases, such as MAPKAPK2 & MAPKAPK5 - phosphorylates myelin basic protein, MAX, ATF2 & GADD153 - role in production of some cytokines, including IL-6 - may play a role in stabilization of EPO mRNA during hypoxic stress - isoform Mxi2 activation is stimulated by mitogens & oxidative stress & only poorly phosphorylates ELK1 & ATF2 - isoform Exip may play a role in the early onset of apoptosis - binds to a kinase interaction motif within the protein tyrosine phosphatase, PTPRR; this interaction retains MAPK14 in the cytoplasm & prevents nuclear accumulation - interacts with SPAG9 (putative) - interacts with NP60 & FAM48A - activated by Thr & Tyr phosphorylation by either of two dual specificity kinases, MAP2K3 or MAP2K6, & potentially also MAP2K4 - can also be activated by autophosphorylation after interaction with TAB1 bypassing usual kinase cascade [2]. forms complex of TRAF6/TAB1/p38MAPK-alpha - inhibited by dual specificity phosphatases, such as DUSP1 - inhibited by binding of pyridinyl-imidazole compounds, which are cytokine-suppressive anti-inflammatory drugs; isoform Mxi2 is 100-fold less sensitive to these agents than the other isoforms & is not inhibited by DUSP1 - isoform Exip is not activated by MAP2K6 - dually phosphorylated on Thr-180 & Tyr-182, which activates the enzyme - phosphorylated upon DNA damage, probably by ATM or ATR Cofactor: Mg+2 Structure: - TXY motif contains Thr & Tyrbwhose phosphorylation activates the MAP kinases - belongs to the protein kinase superfamily, CMGC Ser/Thr protein kinase family, MAP kinase subfamily - contains 1 protein kinase domain Compartment: - cytoplasm (putative) - nucleus Alternative splicing: named isoforms=4; CSBP2, CSBP1, Mxi2, Exip Expression: - brain, heart, placenta, pancreas & skeletal muscle - expressed to a lesser extent in lung, liver & kidney Pharmacology: - inhibitor of MAPK14 neflamapimod is an investigational agent for treatment of Alzheimer's disease Notes: - some references seem to use p38 MAPK to refer to p38 MAPK-alpha as opposed to the p38MAPK subfamily of MAP kinases

Interactions

molecular events

Related

mitogen-activated protein kinase 14 Ag in tissue

General

p38MAPK subfamily

Properties

SIZE: entity length = 360 aa MW = 41 kD COMPARTMENT: cytoplasm cell nucleus STATE: active state MOTIF: Ser phosphorylation site {S2} Thr phosphorylation site {T16} kinase domain SITE: 24-308 MOTIF: ATP-binding site NAME: ATP-binding site SITE: 30-38 ATP-binding site NAME: ATP-binding site SITE: 53-53 aspartate residue {D168} TXY {180-182} Thr phosphorylation site {T180} Tyr phosphorylation site {Y182} Thr phosphorylation site {T263}

References

  1. UniProt :accession Q16539
  2. Ge B, Gram H, Di Padova F, Huang B, New L, Ulevitch RJ, Luo Y, Han J. MAPKK-independent activation of p38alpha mediated by TAB1- dependent autophosphorylation of p38alpha. Science. 2002 Feb 15;295(5558):1291-4. PMID: 11847341
  3. Wikipedia; Note: P38 mitogen-activated protein kinases entry http://en.wikipedia.org/wiki/P38_mitogen-activated_protein_kinases

Databases & Figures

OMIM 600289 UniProt Q16539 Pfam PF00069 Entrez Gene 1432 Kegg hsa:1432 ENZYME 2.7.11.24 MAP kinase pathways