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-xL and Mcl-1. Upon serum withdrawal, newly expressed BimEL associates with Bcl-xL 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 BimEL/Mcl-1 and BimEL/Bcl-xL complexes can be rapidly dissociated following activation of ERK1/2 by survival factors. The dissociation of Bim from Mcl-1 is specific for BimEL and requires ERK1/2-dependent phosphorylation of BimEL at Ser65. Finally, ERK1/2-dependent dissociation of BimEL from Mcl-1 and Bcl-xL may play a role in regulating BimEL degradation, since mutations in the BimEL BH3 domain that disrupt binding to Mcl-1 cause increased turnover of BimEL. These results provide new insights into the role of Bim in cell death and its regulation by the ERK1/2 survival pathway.