View source for 4uya


==Structure of MLK4 kinase domain with ATPgammaS==
<StructureSection load='4uya' size='340' side='right'caption='[[4uya]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4uya]] is a 1 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=4UYA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UYA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AGS:PHOSPHOTHIOPHOSPHORIC+ACID-ADENYLATE+ESTER'>AGS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4uya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uya OCA], [https://pdbe.org/4uya PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4uya RCSB], [https://www.ebi.ac.uk/pdbsum/4uya PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4uya ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/M3K21_HUMAN M3K21_HUMAN] Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways.<ref>PMID:21602844</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4uya" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Brassington C]]
[[Category: Collier M]]
[[Category: Green I]]
[[Category: Overmann R]]
[[Category: Phillips C]]
[[Category: Pollard HK]]
[[Category: Read JA]]