| Structural highlights
5etf is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | MAPK14, CSBP, CSBP1, CSBP2, CSPB1, MXI2, SAPK2A (HUMAN) |
| Activity: | Mitogen-activated protein kinase, with EC number 2.7.11.24 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[MK14_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 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. 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 which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [MP2K6_HUMAN] Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. With MAP3K3/MKK3, catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinases p38 MAPK11, MAPK12, MAPK13 and MAPK14 and plays an important role in the regulation of cellular responses to cytokines and all kinds of stresses. Especially, MAP2K3/MKK3 and MAP2K6/MKK6 are both essential for the activation of MAPK11 and MAPK13 induced by environmental stress, whereas MAP2K6/MKK6 is the major MAPK11 activator in response to TNF. MAP2K6/MKK6 also phosphorylates and activates PAK6. The p38 MAP kinase signal transduction pathway leads to direct activation of transcription factors. Nuclear targets of p38 MAP kinase include the transcription factors ATF2 and ELK1. Within the p38 MAPK signal transduction pathway, MAP3K6/MKK6 mediates phosphorylation of STAT4 through MAPK14 activation, and is therefore required for STAT4 activation and STAT4-regulated gene expression in response to IL-12 stimulation. The pathway is also crucial for IL-6-induced SOCS3 expression and down-regulation of IL-6-mediated gene induction; and for IFNG-dependent gene transcription. Has a role in osteoclast differentiation through NF-kappa-B transactivation by TNFSF11, and in endochondral ossification and since SOX9 is another likely downstream target of the p38 MAPK pathway. MAP2K6/MKK6 mediates apoptotic cell death in thymocytes. Acts also as a regulator for melanocytes dendricity, through the modulation of Rho family GTPases.[18] [19] [20] [21] [22] [23] [24] [25]
Publication Abstract from PubMed
The causative agent of toxoplasmosis, the intracellular parasite Toxoplasma gondii, delivers a protein, GRA24, into the cells it infects that interacts with the mitogen-activated protein (MAP) kinase p38alpha (MAPK14), leading to activation and nuclear translocation of the host kinase and a subsequent inflammatory response that controls the progress of the parasite. The purification of a recombinant complex of GRA24 and human p38alpha has allowed the molecular basis of this activation to be determined. GRA24 is shown to be intrinsically disordered, binding two kinases that act independently, and is the only factor required to bypass the canonical mitogen-activated protein kinase activation pathway. An adapted kinase interaction motif (KIM) forms a highly stable complex that competes with cytoplasmic regulatory partners. In addition, the recombinant complex forms a powerful in vitro tool to evaluate the specificity and effectiveness of p38alpha inhibitors that have advanced to clinical trials, as it provides a hitherto unavailable stable and highly active form of p38alpha.
Structural Basis for the Subversion of MAP Kinase Signaling by an Intrinsically Disordered Parasite Secreted Agonist.,Pellegrini E, Palencia A, Braun L, Kapp U, Bougdour A, Belrhali H, Bowler MW, Hakimi MA Structure. 2016 Nov 14. pii: S0969-2126(16)30338-0. doi:, 10.1016/j.str.2016.10.011. PMID:27889209[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Deak M, Clifton AD, Lucocq LM, Alessi DR. Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J. 1998 Aug 3;17(15):4426-41. PMID:9687510 doi:10.1093/emboj/17.15.4426
- ↑ 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
- ↑ Pierrat B, Correia JS, Mary JL, Tomas-Zuber M, Lesslauer W. RSK-B, a novel ribosomal S6 kinase family member, is a CREB kinase under dominant control of p38alpha mitogen-activated protein kinase (p38alphaMAPK). J Biol Chem. 1998 Nov 6;273(45):29661-71. PMID:9792677
- ↑ Zhao M, New L, Kravchenko VV, Kato Y, Gram H, di Padova F, Olson EN, Ulevitch RJ, Han J. Regulation of the MEF2 family of transcription factors by p38. Mol Cell Biol. 1999 Jan;19(1):21-30. PMID:9858528
- ↑ Yang SH, Galanis A, Sharrocks AD. Targeting of p38 mitogen-activated protein kinases to MEF2 transcription factors. Mol Cell Biol. 1999 Jun;19(6):4028-38. PMID:10330143
- ↑ Tamura K, Sudo T, Senftleben U, Dadak AM, Johnson R, Karin M. Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell. 2000 Jul 21;102(2):221-31. PMID:10943842
- ↑ Sanz V, Arozarena I, Crespo P. Distinct carboxy-termini confer divergent characteristics to the mitogen-activated protein kinase p38alpha and its splice isoform Mxi2. FEBS Lett. 2000 Jun 2;474(2-3):169-74. PMID:10838079
- ↑ Sayed M, Kim SO, Salh BS, Issinger OG, Pelech SL. Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase. J Biol Chem. 2000 Jun 2;275(22):16569-73. PMID:10747897 doi:10.1074/jbc.M000312200
- ↑ Scheper GC, Morrice NA, Kleijn M, Proud CG. The mitogen-activated protein kinase signal-integrating kinase Mnk2 is a eukaryotic initiation factor 4E kinase with high levels of basal activity in mammalian cells. Mol Cell Biol. 2001 Feb;21(3):743-54. PMID:11154262 doi:10.1128/MCB.21.3.743-754.2001
- ↑ Bulavin DV, Higashimoto Y, Popoff IJ, Gaarde WA, Basrur V, Potapova O, Appella E, Fornace AJ Jr. Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature. 2001 May 3;411(6833):102-7. PMID:11333986 doi:10.1038/35075107
- ↑ Lominadze G, Rane MJ, Merchant M, Cai J, Ward RA, McLeish KR. Myeloid-related protein-14 is a p38 MAPK substrate in human neutrophils. J Immunol. 2005 Jun 1;174(11):7257-67. PMID:15905572
- ↑ Zwang Y, Yarden Y. p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy. EMBO J. 2006 Sep 20;25(18):4195-206. Epub 2006 Aug 24. PMID:16932740 doi:10.1038/sj.emboj.7601297
- ↑ Khurana A, Nakayama K, Williams S, Davis RJ, Mustelin T, Ronai Z. Regulation of the ring finger E3 ligase Siah2 by p38 MAPK. J Biol Chem. 2006 Nov 17;281(46):35316-26. Epub 2006 Sep 25. PMID:17003045 doi:10.1074/jbc.M606568200
- ↑ 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
- ↑ Webber JL, Tooze SA. Coordinated regulation of autophagy by p38alpha MAPK through mAtg9 and p38IP. EMBO J. 2010 Jan 6;29(1):27-40. Epub 2009 Nov 5. PMID:19893488 doi:emboj2009321
- ↑ 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
- ↑ Xu P, Derynck R. Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell. 2010 Feb 26;37(4):551-66. doi: 10.1016/j.molcel.2010.01.034. PMID:20188673 doi:10.1016/j.molcel.2010.01.034
- ↑ Raingeaud J, Whitmarsh AJ, Barrett T, Derijard B, Davis RJ. MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol. 1996 Mar;16(3):1247-55. PMID:8622669
- ↑ Stein B, Brady H, Yang MX, Young DB, Barbosa MS. Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. J Biol Chem. 1996 May 10;271(19):11427-33. PMID:8626699
- ↑ Moriguchi T, Kuroyanagi N, Yamaguchi K, Gotoh Y, Irie K, Kano T, Shirakabe K, Muro Y, Shibuya H, Matsumoto K, Nishida E, Hagiwara M. A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem. 1996 Jun 7;271(23):13675-9. PMID:8663074
- ↑ Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563-71. PMID:9218798 doi:http://dx.doi.org/10.1093/emboj/16.12.3563
- ↑ Visconti R, Gadina M, Chiariello M, Chen EH, Stancato LF, Gutkind JS, O'Shea JJ. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood. 2000 Sep 1;96(5):1844-52. PMID:10961885
- ↑ Bode JG, Ludwig S, Freitas CA, Schaper F, Ruhl M, Melmed S, Heinrich PC, Haussinger D. The MKK6/p38 mitogen-activated protein kinase pathway is capable of inducing SOCS3 gene expression and inhibits IL-6-induced transcription. Biol Chem. 2001 Oct;382(10):1447-53. PMID:11727828 doi:http://dx.doi.org/10.1515/BC.2001.178
- ↑ Kaur R, Liu X, Gjoerup O, Zhang A, Yuan X, Balk SP, Schneider MC, Lu ML. Activation of p21-activated kinase 6 by MAP kinase kinase 6 and p38 MAP kinase. J Biol Chem. 2005 Feb 4;280(5):3323-30. Epub 2004 Nov 18. PMID:15550393 doi:http://dx.doi.org/10.1074/jbc.M406701200
- ↑ Kim MY, Choi TY, Kim JH, Lee JH, Kim JG, Sohn KC, Yoon KS, Kim CD, Lee JH, Yoon TJ. MKK6 increases the melanocyte dendricity through the regulation of Rho family GTPases. J Dermatol Sci. 2010 Nov;60(2):114-9. doi: 10.1016/j.jdermsci.2010.08.006. Epub, 2010 Sep 24. PMID:20869211 doi:http://dx.doi.org/10.1016/j.jdermsci.2010.08.006
- ↑ Pellegrini E, Palencia A, Braun L, Kapp U, Bougdour A, Belrhali H, Bowler MW, Hakimi MA. Structural Basis for the Subversion of MAP Kinase Signaling by an Intrinsically Disordered Parasite Secreted Agonist. Structure. 2016 Nov 14. pii: S0969-2126(16)30338-0. doi:, 10.1016/j.str.2016.10.011. PMID:27889209 doi:http://dx.doi.org/10.1016/j.str.2016.10.011
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