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

Katherine E. Ewings, Kathryn Hadfield-Moorhouse, Ceri M. Wiggins, Julie A. Wickenden, Kathryn Balmanno, Rebecca Gilley, Kurt Degenhardt, Eileen White, Simon J. Cook

Research output: Contribution to journalArticle

128 Scopus citations

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 Bim EL 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 Bim EL/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.

Original languageEnglish (US)
Pages (from-to)2856-2867
Number of pages12
JournalEMBO Journal
Volume26
Issue number12
DOIs
StatePublished - Jun 20 2007

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Keywords

  • Apoptosis
  • Bcl-x
  • Bim
  • ERK1/2
  • Mcl-1

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    Ewings, K. E., Hadfield-Moorhouse, K., Wiggins, C. M., Wickenden, J. A., Balmanno, K., Gilley, R., Degenhardt, K., White, E., & Cook, S. J. (2007). ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL. EMBO Journal, 26(12), 2856-2867. https://doi.org/10.1038/sj.emboj.7601723