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J. Biol. Chem., Vol. 280, Issue 18, 17657-17663, May 6, 2005

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Identification of a DEF-type Docking Domain for Extracellular Signal-regulated Kinases 1/2 That Directs Phosphorylation and Turnover of the BH3-only Protein Bim_EL^*

Rebecca Ley, Kathryn Hadfield, Elizabeth Howes, and Simon J. Cook

From the Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, United Kingdom

The BH3-only protein, Bim, exists as three splice variants (Bim_S, Bim_L, and Bim_EL) of differing pro-apoptotic potency. Bim_EL, the least effective killer, is degraded by the proteasome in response to phosphorylation by extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2-dependent phosphorylation correlates with the presence of a domain unique to the Bim_EL splice variant that includes the major ERK1/2 phosphorylation site Ser⁶⁵. However, efficient phosphorylation by ERK1/2, c-Jun N-terminal kinase, or p38 requires the presence in the substrate of a discrete kinase-docking domain as well as the phosphoacceptor site. Here we show that the region unique to Bim_EL (amino acids 41–97) harbors two potential DEF-type ERK1/2 kinase-docking domains, DEF1 and DEF2. Peptide competition assays revealed that the DEF2 peptide could act autonomously to bind active ERK1/2, whereas the DEF1 peptide did not. Truncation analysis identified a minimal region, residues 80–97, containing the DEF2 motif as sufficient for ERK1/2 binding. Mutation of key residues in the DEF2 motif abolished the interaction of ERK1/2 and Bim_EL and also abolished ERK1/2-dependent phosphorylation of Bim_EL in vivo, thereby stabilizing the protein and enhancing cytotoxicity. Our results identify a new physiologically relevant functional motif in Bim_EL that may account for the distinct biological properties of this splice variant.

Received for publication, November 1, 2004 , and in revised form, February 23, 2005.

^* This work was supported by Grants 202/C15785 from the Biotechnology and Biological Sciences Research Council (BBSRC) and SP2458/0201 from Cancer Research UK and a competitive strategic grant from the BBSRC to the Babraham Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. Tel: 44-1223-496381; Fax: 44-1223-496043; E-mail: becky.ley{at}bbsrc.ac.uk. A Senior Cancer Research Fellow of Cancer Research UK. To whom correspondence may be addressed. Tel.: 44-1223-496453; Fax: 44-1223-496043; E-mail: simon.cook{at}bbsrc.ac.uk.

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