| Structural highlights
Disease
[MK12_HUMAN] Note=MAPK is overexpressed in highly metastatic breast cancer cell lines and its expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples.
Function
[MK12_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 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 such as ELK1 and ATF2. 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 such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.[1] [2] [3] [4] [5] [6] [7]
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
BACKGROUND: Mitogen-activated protein (MAP) kinases mediate the cellular response to stimuli such as pro-inflammatory cytokines and environmental stress. P38gamma is a new member of the MAP kinase family, and is expressed at its highest levels in skeletal muscle. P38gamma is 63% identical in sequence to P38alpha. The structure of P38alpha MAP kinase has been determined in the apo, unphosphorylated, inactive form. The structures of apo unphosphorylated ERK2, a related MAP kinase, and apo phosphorylated ERK2 have also been determined. RESULTS: We have determined the structure of doubly phosphorylated P38gamma in complex with an ATP analog by X-ray crystallography. This is the first report of a structure of an activated kinase in the P38 subfamily, and the first bound to a nucleotide. P38gamma residue phosphoryl-Thr183 forms hydrogen bonds with five basic amino acids, and these interactions induce an interdomain rotation. The conformation of the activation loop of P38gamma is almost identical to that observed in the structure of activated ERK2. However, unlike ERK2, the crystal structure and solution studies indicate that activated P38gamma exists as a monomer. CONCLUSIONS: Interactions mediated by phosphoryl-Thr183 induce structural changes that direct the domains and active-site residues of P38gamma into a conformation consistent with catalytic activity. The conformation of the phosphorylation loop is likely to be similar in all activated MAP kinases, but not all activated MAP kinases form dimers.
The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation.,Bellon S, Fitzgibbon MJ, Fox T, Hsiao HM, Wilson KP Structure. 1999 Sep 15;7(9):1057-65. PMID:10508788[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lechner C, Zahalka MA, Giot JF, Moller NP, Ullrich A. ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4355-9. PMID:8633070
- ↑ Enslen H, Raingeaud J, Davis RJ. Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. J Biol Chem. 1998 Jan 16;273(3):1741-8. PMID:9430721
- ↑ Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J. Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Mol Cell Biol. 2000 Jul;20(13):4543-52. PMID:10848581
- ↑ Ho RC, Alcazar O, Fujii N, Hirshman MF, Goodyear LJ. p38gamma MAPK regulation of glucose transporter expression and glucose uptake in L6 myotubes and mouse skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2004 Feb;286(2):R342-9. Epub 2003 Oct 30. PMID:14592936 doi:10.1152/ajpregu.00563.2003
- ↑ Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Chen G. p38alpha antagonizes p38gamma activity through c-Jun-dependent ubiquitin-proteasome pathways in regulating Ras transformation and stress response. J Biol Chem. 2007 Oct 26;282(43):31398-408. Epub 2007 Aug 27. PMID:17724032 doi:10.1074/jbc.M703857200
- ↑ Sabio G, Cerezo-Guisado MI, Del Reino P, Inesta-Vaquera FA, Rousseau S, Arthur JS, Campbell DG, Centeno F, Cuenda A. p38gamma regulates interaction of nuclear PSF and RNA with the tumour-suppressor hDlg in response to osmotic shock. J Cell Sci. 2010 Aug 1;123(Pt 15):2596-604. doi: 10.1242/jcs.066514. Epub 2010, Jul 6. PMID:20605917 doi:10.1242/jcs.066514
- ↑ Kukkonen-Macchi A, Sicora O, Kaczynska K, Oetken-Lindholm C, Pouwels J, Laine L, Kallio MJ. Loss of p38gamma MAPK induces pleiotropic mitotic defects and massive cell death. J Cell Sci. 2011 Jan 15;124(Pt 2):216-27. doi: 10.1242/jcs.068254. Epub 2010 Dec , 15. PMID:21172807 doi:10.1242/jcs.068254
- ↑ Bellon S, Fitzgibbon MJ, Fox T, Hsiao HM, Wilson KP. The structure of phosphorylated p38gamma is monomeric and reveals a conserved activation-loop conformation. Structure. 1999 Sep 15;7(9):1057-65. PMID:10508788
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