| Structural highlights
4fa2 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Related: | 4ewq, 4f9w, 4f9y |
| 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]
Publication Abstract from PubMed
Serine-threonine protein kinases are critical to CNS function, yet there is a dearth of highly selective, CNS-active kinase inhibitors for in vivo investigations. Further, prevailing assumptions raise concerns about whether single kinase inhibitors can show in vivo efficacy for CNS pathologies, and debates over viable approaches to the development of safe and efficacious kinase inhibitors are unsettled. It is critical, therefore, that these scientific challenges be addressed in order to test hypotheses about protein kinases in neuropathology progression and the potential for in vivo modulation of their catalytic activity. Identification of molecular targets whose in vivo modulation can attenuate synaptic dysfunction would provide a foundation for future disease-modifying therapeutic development as well as insight into cellular mechanisms. Clinical and preclinical studies suggest a critical link between synaptic dysfunction in neurodegenerative disorders and the activation of p38alphaMAPK mediated signaling cascades. Activation in both neurons and glia also offers the unusual potential to generate enhanced responses through targeting a single kinase in two distinct cell types involved in pathology progression. However, target validation has been limited by lack of highly selective inhibitors amenable to in vivo use in the CNS. Therefore, we employed high-resolution co-crystallography and pharmacoinformatics to design and develop a novel synthetic, active site targeted, CNS-active, p38alphaMAPK inhibitor (MW108). Selectivity was demonstrated by large-scale kinome screens, functional GPCR agonist and antagonist analyses of off-target potential, and evaluation of cellular target engagement. In vitro and in vivo assays demonstrated that MW108 ameliorates beta-amyloid induced synaptic and cognitive dysfunction. A serendipitous discovery during co-crystallographic analyses revised prevailing models about active site targeting of inhibitors, providing insights that will facilitate future kinase inhibitor design. Overall, our studies deliver highly selective in vivo probes appropriate for CNS investigations and demonstrate that modulation of p38alphaMAPK activity can attenuate synaptic dysfunction.
Development of Novel Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction.,Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, Staniszewski A, Pelletier JC, Minasov G, Anderson WF, Arancio O, Van Eldik LJ PLoS One. 2013 Jun 26;8(6):e66226. Print 2013. PMID:23840427[18]
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
- ↑ Watterson DM, Grum-Tokars VL, Roy SM, Schavocky JP, Bradaric BD, Bachstetter AD, Xing B, Dimayuga E, Saeed F, Zhang H, Staniszewski A, Pelletier JC, Minasov G, Anderson WF, Arancio O, Van Eldik LJ. Development of Novel Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction. PLoS One. 2013 Jun 26;8(6):e66226. Print 2013. PMID:23840427 doi:10.1371/journal.pone.0066226
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