Data from Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis

• DOI: 10.1158/0008-5472.c.6507875.v1
• Publication Date: 2023-03-31T22:42:01Z
• Authors: Anna A. Marusiak; Natalie L. Stephe...; Hayeon Baik; Eleanor W. Trotter; Yaoyong Li; Karen Blyth; Susan Mason; Phil Chapman; Lorena A. Puto; Jon A. Read; Claire Brassington; Hannah K. Pollard; Chris Phillips; Isabelle Green; Ross Overman; Matthew Collier; Ewelina Testoni; Crispin J. Miller; Tony Hunter; Owen J. Sansom; John Brognard
• Keywords: V600E

<div>Abstract<p>MLK4 is a member of the mixed-lineage family kinases that regulate JNK, p38, and ERK kinase signaling pathways. MLK4 mutations have been identified in various human cancers, including frequently colorectal cancer, where their function pathobiological importance uncertain. In this study, we assessed functional consequences colon tumorigenesis. Biochemical data indicated majority are loss-of-function (LOF) can exert dominant-negative effects. seeking to understand abrogated activity these mutants, elucidated new catalytic domain structure. To determine whether required maintain tumorigenic phenotypes, reconstituted its axis cancer cells harboring MLK4-inactivating mutations. We found restoring reduced cell viability, proliferation, colony formation <i>in vitro</i> delayed tumor growth vivo</i>. Mechanistic investigations established selectively induced JNK pathway downstream targets, cJUN, ATF3, cyclin-dependent inhibitors CDKN1A CDKN2B. Our work indicates novel tumor-suppressing frequent LOF lead diminished enhanced proliferation cancer. <i>Cancer Res; 76(3); 724–35. ©2015 AACR</i>.</p></div>