3she

Structural highlights

Function

[MAPK3_HUMAN] Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling 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. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair 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, such as TTP/ZFP36, leading to regulate 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 transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ McLaughlin MM, Kumar S, McDonnell PC, Van Horn S, Lee JC, Livi GP, Young PR. Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem. 1996 Apr 5;271(14):8488-92. PMID:8626550
2. ↑ Clifton AD, Young PR, Cohen P. A comparison of the substrate specificity of MAPKAP kinase-2 and MAPKAP kinase-3 and their activation by cytokines and cellular stress. FEBS Lett. 1996 Sep 2;392(3):209-14. PMID:8774846
3. ↑ Rogalla T, Ehrnsperger M, Preville X, Kotlyarov A, Lutsch G, Ducasse C, Paul C, Wieske M, Arrigo AP, Buchner J, Gaestel M. Regulation of Hsp27 oligomerization, chaperone function, and protective activity against oxidative stress/tumor necrosis factor alpha by phosphorylation. J Biol Chem. 1999 Jul 2;274(27):18947-56. PMID:10383393
4. ↑ Voncken JW, Niessen H, Neufeld B, Rennefahrt U, Dahlmans V, Kubben N, Holzer B, Ludwig S, Rapp UR. MAPKAP kinase 3pK phosphorylates and regulates chromatin association of the polycomb group protein Bmi1. J Biol Chem. 2005 Feb 18;280(7):5178-87. Epub 2004 Nov 24. PMID:15563468 doi:http://dx.doi.org/M407155200
5. ↑ Mendoza H, Campbell DG, Burness K, Hastie J, Ronkina N, Shim JH, Arthur JS, Davis RJ, Gaestel M, Johnson GL, Ghosh S, Cohen P. Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem J. 2008 Feb 1;409(3):711-22. PMID:18021073 doi:10.1042/BJ20071149
6. ↑ Ronkina N, Menon MB, Schwermann J, Tiedje C, Hitti E, Kotlyarov A, Gaestel M. MAPKAP kinases MK2 and MK3 in inflammation: complex regulation of TNF biosynthesis via expression and phosphorylation of tristetraprolin. Biochem Pharmacol. 2010 Dec 15;80(12):1915-20. doi: 10.1016/j.bcp.2010.06.021., Epub 2010 Jun 23. PMID:20599781 doi:http://dx.doi.org/10.1016/j.bcp.2010.06.021
7. ↑ Oubrie A, Kaptein A, de Zwart E, Hoogenboom N, Goorden R, van de Kar B, van Hoek M, de Kimpe V, van der Heijden R, Borsboom J, Kazemier B, de Roos J, Scheffers M, Lommerse J, Schultz-Fademrecht C, Barf T. Novel ATP competitive MK2 inhibitors with potent biochemical and cell-based activity throughout the series. Bioorg Med Chem Lett. 2011 Nov 3. PMID:22119462 doi:10.1016/j.bmcl.2011.10.071