Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming

• Type of Material: Article
• Authors: Jason E. Conage-Pough, Emory University; Lawrence Boise, Emory University
• Language: English
• Date: 2018-07-01
• Publisher: Wiley: FEBS Journal
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Federation of European Biochemical Societies
• Final Published Version (URL): http://dx.doi.org/10.1111/febs.14505
• Title of Journal or Parent Work: FEBS Journal
• ISSN: 1742-464X
• Volume: 285
• Issue: 14
• Start Page: 2626
• End Page: 2640
• Grant/Funding Information: This work was supported by R01 CA192844 and by the UNCF/Merck Science Initiative.
• Keywords: Mcl-1 stability; Biochemistry & Molecular Biology; BH3-ONLY LIGANDS; priming; Life Sciences & Biomedicine; BREAST-CANCER CELLS; BIM(EL) PHOSPHORYLATION; MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; BCL-2 FAMILY; PROAPOPTOTIC ACTIVITY; BH3 DOMAINS; INDUCED APOPTOSIS; Bim phosphorylation; Science & Technology; WALDENSTROM MACROGLOBULINEMIA; OLIGOMERIZES BAK
• Research Categories: Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Mcl-1 is a highly labile protein, subject to extensive post-translational regulation. This distinguishes Mcl-1 from other antiapoptotic proteins and necessitates further study to better understand how interactions with proapoptotic Bcl-2 proteins affect its regulation. One such protein, Bim, is known to stabilize Mcl-1, and Bim phosphorylation has been associated with increased Mcl-1 binding. Consequently, we investigated the potential impact of Bim phosphorylation on Mcl-1 stability. We found that Bim stabilizes and primes Mcl-1 in RPCI-WM1 cells and is constitutively phosphorylated. Additionally, introduction of several phospho-mimetic and unphosphosphorylateable Bim mutations resulted in altered Mcl-1 stability and distinct Bim binding to antiapoptotic proteins. These findings suggest Bim phosphorylation not only regulates Mcl-1 stability but also is a potential mechanism for enforcing Mcl-1 dependence.