ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL

• DOI: 10.1038/sj.emboj.7601723
• Publication Date: 2007-05-25T07:43:22Z
• Authors: Katherine E Ewings; Kathryn Hadfield-...; Ceri M Wiggins; Julie A Wickenden; Kathryn Balmanno; Rebecca Gilley; Kurt Degenhardt; Eileen White; Simon J Cook
• Keywords: Mitogen-Activated Protein Kinase 1; 0301 basic medicine; Mitogen-Activated Protein Kinase 3; Bcl-2-Like Protein 11; bcl-X Protein; Membrane Proteins; Culture Media, Serum-Free; Cell Line; Neoplasm Proteins; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins; Humans; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Apoptosis Regulatory Proteins

The proapoptotic protein Bim is expressed de novo following withdrawal of serum survival factors. Here, we show that Bim-/- fibroblasts and epithelial cells exhibit reduced cell death following serum withdrawal in comparison with their wild-type counterparts. In viable cells, Bax associates with Bcl-2, Bcl-x(L) and Mcl-1. Upon serum withdrawal, newly expressed Bim(EL) associates with Bcl-x(L) and Mcl-1, coinciding with the dissociation of Bax from these proteins. Survival factors can prevent association of Bim with pro-survival proteins by preventing Bim expression. However, we now show that even preformed Bim(EL)/Mcl-1 and Bim(EL)/Bcl-x(L) complexes can be rapidly dissociated following activation of ERK1/2 by survival factors. The dissociation of Bim from Mcl-1 is specific for Bim(EL) and requires ERK1/2-dependent phosphorylation of Bim(EL) at Ser(65). Finally, ERK1/2-dependent dissociation of Bim(EL) from Mcl-1 and Bcl-x(L) may play a role in regulating Bim(EL) degradation, since mutations in the Bim(EL) BH3 domain that disrupt binding to Mcl-1 cause increased turnover of Bim(EL). These results provide new insights into the role of Bim in cell death and its regulation by the ERK1/2 survival pathway.