4UYA
Structure of MLK4 kinase domain with ATPgammaS
Summary for 4UYA
| Entry DOI | 10.2210/pdb4uya/pdb |
| Related | 4UY9 |
| Descriptor | MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE MLK4, PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | mixed-lineage kinase, atp-binding, nucleotide-binding, phosphoprotein, serine/threonine-protein kinase, sh3 domain, transferase, leucine zipper 1 |
| Biological source | HOMO SAPIENS (HUMAN) |
| Total number of polymer chains | 1 |
| Total formula weight | 39045.09 |
| Authors | Read, J.A.,Brassington, C.,Pollard, H.K.,Phillips, C.,Green, I.,Overmann, R.,Collier, M. (deposition date: 2014-08-29, release date: 2015-09-30, Last modification date: 2024-01-10) |
| Primary citation | Marusiak, A.A.,Stephenson, N.L.,Baik, H.,Trotter, E.W.,Li, Y.,Blyth, K.,Mason, S.,Chapman, P.,Puto, L.A.,Read, J.A.,Brassington, C.,Pollard, H.K.,Phillips, C.,Green, I.,Overman, R.,Collier, M.,Testoni, E.,Miller, C.,Hunter, T.,Sansom, O.J.,Brognard, J. Recurrent Mlk4 Loss-of-Function Mutations Suppress Jnk Signaling to Promote Colon Tumorigenesis. Cancer Res., 76:724-, 2016 Cited by PubMed Abstract: 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 have 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 tumorigenic phenotypes, 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. PubMed: 26637668DOI: 10.1158/0008-5472.CAN-15-0701-T PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.8 Å) |
Structure validation
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