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

Open Access
Publisher Website
Google Scholar
Abstract
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.