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ERK1/2‐dependent phosphorylation of Bim EL promotes its rapid dissociation from Mcl‐1 and Bcl‐x L
Author(s) -
Ewings Katherine E,
HadfieldMoorhouse Kathryn,
Wiggins Ceri M,
Wickenden Julie A,
Balmanno Kathryn,
Gilley Rebecca,
Degenhardt Kurt,
White Eileen,
Cook Simon J
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601723
Subject(s) - biology , phosphorylation , microbiology and biotechnology , kinase , biophysics
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.