MAP kinase-activated protein kinase 2

UniProt P49137 Organism Homo sapiens Gene MAPKAPK2 EC 2.7.11.1

Also known as: MAPKAPK2

Function

Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity, leading to inhibition of dependent degradation of ARE-containing transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.

Classification

Family (Pfam): PF00069 Pkinase
InterPro: Kinase-like_dom_sf, MAPKAPK_C, Prot_kinase_dom, Protein_kinase_ATP_BS, Ser/Thr_kinase_AS
Functional cluster: S-Adenosylmethionine Synthases & related

Experimental structures · PDB · 31

1KWP X-ray 2.80A
1NXK X-ray 2.70A
1NY3 X-ray 3.00A
2JBO X-ray 3.10A
2JBP X-ray 3.31A
2OKR X-ray 2.00A
2ONL X-ray 4.00A
2OZA X-ray 2.70A
2P3G X-ray 3.80A
2PZY X-ray 2.90A
3A2C X-ray 2.90A
3FPM X-ray 3.30A
… and 19 more

A predicted model is available from AlphaFold.

Gene Ontology · 30

Drugs targeting this protein · 1

AT-13148 inhibitor

Related proteins · sequence + function similarity

Co-cited proteins · studied together in the literature

MAP kinase-activated protein kinase 3 4 shared papers
MAP kinase-activated protein kinase 2 1 shared papers
Lymphocyte-specific protein 1 1 shared papers
Lymphocyte-specific protein 1 1 shared papers
Heterogeneous nuclear ribonucleoprotein A0 2 shared papers
Heat shock protein beta-1 3 shared papers
Polyhomeotic-like protein 2 1 shared papers
Heterogeneous nuclear ribonucleoprotein A0 1 shared papers
Polyunsaturated fatty acid 5-lipoxygenase 1 shared papers
Centrosomal protein of 131 kDa 1 shared papers
Mitogen-activated protein kinase 14 1 shared papers
LIM domain kinase 1 1 shared papers

Literature · 36 cited papers

p38- and MK2-dependent signalling promotes stress-induced centriolar satellite remodelling via 14-3-3-dependent sequestration of CEP131/AZI1. Nat. Commun. · 2015
An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation. Blood · 2011
DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol. Cell · 2010
A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. · 2008
MK2 and MK3--a pair of isoenzymes? Front. Biosci. · 2008
Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem. J. · 2008
The discovery of carboline analogs as potent MAPKAP-K2 inhibitors. Bioorg. Med. Chem. Lett. · 2007
MAPKAPK2-mediated LSP1 phosphorylation and FMLP-induced neutrophil polarization. Biochem. Biophys. Res. Commun. · 2007
Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J. Med. Chem. · 2007
… and 24 more in the literature graph

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