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4uy9

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Revision as of 07:30, 24 April 2019

Structure of MLK1 kinase domain with leucine zipper 1

Structural highlights

4uy9 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.
Related:	4uya
Activity:	Mitogen-activated protein kinase kinase kinase, with EC number 2.7.11.25
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[M3K9_HUMAN] May play a role in esophageal cancer susceptibility and/or development.

Function

[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.^[1] ^[2] ^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Durkin JT, Holskin BP, Kopec KK, Reed MS, Spais CM, Steffy BM, Gessner G, Angeles TS, Pohl J, Ator MA, Meyer SL. Phosphoregulation of mixed-lineage kinase 1 activity by multiple phosphorylation in the activation loop. Biochemistry. 2004 Dec 28;43(51):16348-55. PMID:15610029 doi:http://dx.doi.org/10.1021/bi049866y
↑ Xu Z, Maroney AC, Dobrzanski P, Kukekov NV, Greene LA. The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol. 2001 Jul;21(14):4713-24. PMID:11416147 doi:http://dx.doi.org/10.1128/MCB.21.14.4713-4724.2001
↑ Chen J, Guo L, Peiffer DA, Zhou L, Chan OT, Bibikova M, Wickham-Garcia E, Lu SH, Zhan Q, Wang-Rodriguez J, Jiang W, Fan JB. Genomic profiling of 766 cancer-related genes in archived esophageal normal and carcinoma tissues. Int J Cancer. 2008 May 15;122(10):2249-54. doi: 10.1002/ijc.23397. PMID:18241037 doi:http://dx.doi.org/10.1002/ijc.23397
↑ 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. Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis. Cancer Res. 2015 Dec 4. pii: canres.0701.2015. PMID:26637668 doi:http://dx.doi.org/10.1158/0008-5472.CAN-15-0701-T

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4uy9"

@@ Line 1: / Line 1: @@
 ==Structure of MLK1 kinase domain with leucine zipper 1==
-<StructureSection load='4uy9' size='340' side='right' caption='[[4uy9]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
+<StructureSection load='4uy9' size='340' side='right'caption='[[4uy9]], [[Resolution|resolution]] 2.81&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4uy9]] is a 2 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UY9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4uy9]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UY9 FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4uya|4uya]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinase_kinase Mitogen-activated protein kinase kinase kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.25 2.7.11.25] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4uy9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uy9 OCA], [http://pdbe.org/4uy9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4uy9 RCSB], [http://www.ebi.ac.uk/pdbsum/4uy9 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4uy9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4uy9 OCA], [http://pdbe.org/4uy9 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4uy9 RCSB], [http://www.ebi.ac.uk/pdbsum/4uy9 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4uy9 ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 25: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Mitogen-activated protein kinase kinase kinase]]
 [[Category: Brassington, C]]

4uy9

From Proteopedia

Revision as of 07:30, 24 April 2019

Structure of MLK1 kinase domain with leucine zipper 1

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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