4uy9

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'''Unreleased structure'''
 
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The entry 4uy9 is ON HOLD
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==Structure of MLK1 kinase domain with leucine zipper 1==
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<StructureSection load='4uy9' size='340' side='right'caption='[[4uy9]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4uy9]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UY9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UY9 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.81&#8491;</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4uy9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uy9 OCA], [https://pdbe.org/4uy9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uy9 RCSB], [https://www.ebi.ac.uk/pdbsum/4uy9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uy9 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[https://www.uniprot.org/uniprot/M3K9_HUMAN M3K9_HUMAN] May play a role in esophageal cancer susceptibility and/or development.
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== Function ==
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[https://www.uniprot.org/uniprot/M3K9_HUMAN M3K9_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade through the phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7 which in turn activate the JNKs. The MKK/JNK signaling pathway regulates stress response via activator protein-1 (JUN) and GATA4 transcription factors. Plays also a role in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis.<ref>PMID:15610029</ref> <ref>PMID:11416147</ref> <ref>PMID:18241037</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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MLK4 is a member of the mixed-lineage family of kinases that regulate the JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers including frequently in colorectal cancer, where their function and pathobiological importance has been uncertain. In this study, we assessed the functional consequences of MLK4 mutations in colon tumorigenesis. Biochemical data indicated that a majority of MLK4 mutations are loss-of-function (LOF) mutations that can exert dominant negative effects. In seeking to understand the abrogated activity of these mutants, we elucidated a new MLK4 catalytic domain structure. To determine whether MLK4 is required to maintain the tumorigenic phenotype, we reconstituted its signaling axis in colon cancer cells harboring MLK4 inactivating mutations. We found that restoring MLK4 activity reduced cell viability, proliferation, and colony formation in vitro and delayed tumor growth in vivo. Mechanistic investigations established that restoring the function of MLK4 selectively induced the JNK pathway and its downstream targets, cJUN, ATF3 and the cyclin-dependent kinase inhibitors CDKN1A and CDKN2B. Our work indicates that MLK4 is a novel tumor suppressing kinase harboring frequent LOF mutations that lead to diminished signaling in the JNK pathway and enhanced proliferation in colon cancer.
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Authors: READ, J.A., BRASSINGTON, C., POLLARD, H.K., PHILLIPS, C., GREEN, I., OVERMANN, R., COLLIER, M.
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Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis.,Marusiak AA, Stephenson NL, Baik H, Trotter EW, Li Y, Blyth K, Mason S, Chapman P, Puto LA, Read JA, Brassington C, Pollard HK, Phillips C, Green I, Overman R, Collier M, Testoni E, Miller C, Hunter T, Sansom OJ, Brognard J Cancer Res. 2015 Dec 4. pii: canres.0701.2015. PMID:26637668<ref>PMID:26637668</ref>
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Description: Structure of MLK1 kinase domain with leucine zipper 1
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Overmann, R]]
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<div class="pdbe-citations 4uy9" style="background-color:#fffaf0;"></div>
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[[Category: Green, I]]
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== References ==
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[[Category: Read, J.A]]
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<references/>
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[[Category: Phillips, C]]
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__TOC__
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[[Category: Pollard, H.K]]
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</StructureSection>
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[[Category: Collier, M]]
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[[Category: Homo sapiens]]
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[[Category: Brassington, C]]
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[[Category: Large Structures]]
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[[Category: Brassington C]]
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[[Category: Collier M]]
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[[Category: Green I]]
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[[Category: Overmann R]]
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[[Category: Phillips C]]
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[[Category: Pollard HK]]
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[[Category: Read JA]]

Current revision

Structure of MLK1 kinase domain with leucine zipper 1

PDB ID 4uy9

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