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

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 Ser⁶⁵. 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. [ABSTRACT FROM AUTHOR]