| Structural highlights
Function
[MAPK2_HUMAN] Stress-activated serine/threonine-protein kinase involved in cytokines 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, ELAVL1, HNRNPA0, HSF1, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, 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 ELAVL1, HNRNPA0, PABPC1 and 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. 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 stabilize GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.
2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode.,Argiriadi MA, Ericsson AM, Harris CM, Banach DL, Borhani DW, Calderwood DJ, Demers MD, Dimauro J, Dixon RW, Hardman J, Kwak S, Li B, Mankovich JA, Marcotte D, Mullen KD, Ni B, Pietras M, Sadhukhan R, Sousa S, Tomlinson MJ, Wang L, Xiang T, Talanian RV Bioorg Med Chem Lett. 2010 Jan 1;20(1):330-3. Epub 2009 Oct 29. PMID:19919896[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Stokoe D, Caudwell B, Cohen PT, Cohen P. The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. Biochem J. 1993 Dec 15;296 ( Pt 3):843-9. PMID:8280084
- ↑ Jakob U, Gaestel M, Engel K, Buchner J. Small heat shock proteins are molecular chaperones. J Biol Chem. 1993 Jan 25;268(3):1517-20. PMID:8093612
- ↑ 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
- ↑ 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
- ↑ Rousseau S, Morrice N, Peggie M, Campbell DG, Gaestel M, Cohen P. Inhibition of SAPK2a/p38 prevents hnRNP A0 phosphorylation by MAPKAP-K2 and its interaction with cytokine mRNAs. EMBO J. 2002 Dec 2;21(23):6505-14. PMID:12456657
- ↑ Werz O, Szellas D, Steinhilber D, Radmark O. Arachidonic acid promotes phosphorylation of 5-lipoxygenase at Ser-271 by MAPK-activated protein kinase 2 (MK2). J Biol Chem. 2002 Apr 26;277(17):14793-800. Epub 2002 Feb 13. PMID:11844797 doi:10.1074/jbc.M111945200
- ↑ Bollig F, Winzen R, Gaestel M, Kostka S, Resch K, Holtmann H. Affinity purification of ARE-binding proteins identifies polyA-binding protein 1 as a potential substrate in MK2-induced mRNA stabilization. Biochem Biophys Res Commun. 2003 Feb 14;301(3):665-70. PMID:12565831
- ↑ Coxon PY, Rane MJ, Uriarte S, Powell DW, Singh S, Butt W, Chen Q, McLeish KR. MAPK-activated protein kinase-2 participates in p38 MAPK-dependent and ERK-dependent functions in human neutrophils. Cell Signal. 2003 Nov;15(11):993-1001. PMID:14499342
- ↑ Tran H, Maurer F, Nagamine Y. Stabilization of urokinase and urokinase receptor mRNAs by HuR is linked to its cytoplasmic accumulation induced by activated mitogen-activated protein kinase-activated protein kinase 2. Mol Cell Biol. 2003 Oct;23(20):7177-88. PMID:14517288
- ↑ Stoecklin G, Stubbs T, Kedersha N, Wax S, Rigby WF, Blackwell TK, Anderson P. MK2-induced tristetraprolin:14-3-3 complexes prevent stress granule association and ARE-mRNA decay. EMBO J. 2004 Mar 24;23(6):1313-24. Epub 2004 Mar 11. PMID:15014438 doi:10.1038/sj.emboj.7600163
- ↑ Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005 Jan 7;17(1):37-48. PMID:15629715 doi:10.1016/j.molcel.2004.11.021
- ↑ Kobayashi M, Nishita M, Mishima T, Ohashi K, Mizuno K. MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration. EMBO J. 2006 Feb 22;25(4):713-26. Epub 2006 Feb 2. PMID:16456544 doi:10.1038/sj.emboj.7600973
- ↑ Wang X, Khaleque MA, Zhao MJ, Zhong R, Gaestel M, Calderwood SK. Phosphorylation of HSF1 by MAPK-activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding. J Biol Chem. 2006 Jan 13;281(2):782-91. Epub 2005 Nov 8. PMID:16278218 doi:M505822200
- ↑ Wu Y, Zhan L, Ai Y, Hannigan M, Gaestel M, Huang CK, Madri JA. MAPKAPK2-mediated LSP1 phosphorylation and FMLP-induced neutrophil polarization. Biochem Biophys Res Commun. 2007 Jun 22;358(1):170-5. Epub 2007 Apr 24. PMID:17481585 doi:S0006-291X(07)00821-2
- ↑ 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
- ↑ Reinhardt HC, Hasskamp P, Schmedding I, Morandell S, van Vugt MA, Wang X, Linding R, Ong SE, Weaver D, Carr SA, Yaffe MB. DNA damage activates a spatially distinct late cytoplasmic cell-cycle checkpoint network controlled by MK2-mediated RNA stabilization. Mol Cell. 2010 Oct 8;40(1):34-49. doi: 10.1016/j.molcel.2010.09.018. PMID:20932473 doi:10.1016/j.molcel.2010.09.018
- ↑ Argiriadi MA, Ericsson AM, Harris CM, Banach DL, Borhani DW, Calderwood DJ, Demers MD, Dimauro J, Dixon RW, Hardman J, Kwak S, Li B, Mankovich JA, Marcotte D, Mullen KD, Ni B, Pietras M, Sadhukhan R, Sousa S, Tomlinson MJ, Wang L, Xiang T, Talanian RV. 2,4-Diaminopyrimidine MK2 inhibitors. Part I: Observation of an unexpected inhibitor binding mode. Bioorg Med Chem Lett. 2010 Jan 1;20(1):330-3. Epub 2009 Oct 29. PMID:19919896 doi:10.1016/j.bmcl.2009.10.102
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