Phosphorylation alters Bim-mediated Mcl-1 stabilization and priming

• Authors: Jason E. Conage-Pough, Emory University; Lawrence Boise, Emory University
• Journal Title: FEBS Journal
• Volume: Volume 285, Number 14
• Publisher: Wiley: FEBS Journal | 2018-07-01, Pages 2626-2640
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/febs.14505
• Subjects: Health Sciences, Oncology; Chemistry, Biochemistry
• Keywords: Science & Technology; Life Sciences & Biomedicine; Biochemistry & Molecular Biology; Bim phosphorylation; Mcl-1 stability; priming; MITOCHONDRIAL-MEMBRANE PERMEABILIZATION; BREAST-CANCER CELLS; BCL-2 FAMILY; INDUCED APOPTOSIS; BH3 DOMAINS; WALDENSTROM MACROGLOBULINEMIA; BIM(EL) PHOSPHORYLATION; PROAPOPTOTIC ACTIVITY; BH3-ONLY LIGANDS; OLIGOMERIZES BAK

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.