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| Subject Categories: Signal Transduction |
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| The EMBO Journal
(2007) 26, 2856–2867, doi:10.1038/sj.emboj.7601723 Published online 24 May 2007 |
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| ERK1/2-dependent phosphorylation of BimEL promotes its rapid dissociation from Mcl-1 and Bcl-xL |
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| Katherine E Ewings1, Kathryn Hadfield-Moorhouse1, Ceri M Wiggins1, Julie A Wickenden1, Kathryn Balmanno1, Rebecca Gilley1, Kurt Degenhardt2, Eileen White2 and Simon J Cook1, 3 |
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1 Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge, UK 2 Howard Hughes Medical Institute, Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA 3 SC dedicates this study to Peter Lockyer who passed away December 28, 2006 and is sorely missed by friends and colleagues alike To whom correspondence should be addressed Simon J Cook, Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK. Tel.: +44 1223 496453; Fax: +44 1223 496043; E-mail: simon.cook@bbsrc.ac.uk Received 21 November 2006; Accepted 20 April 2007; Published online 24 May 2007. |
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| Abstract |
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| 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. |
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| Keywords: apoptosis, Bcl-xL, Bim, ERK1/2, Mcl-1 |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHERK1/2-dependent phosphorylation of Bim EL promotes its rapid dissociation from Mcl-1 and Bcl-x L The EMBO Journal Article Leukemia Original Article Leukemia Original Article |
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