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J. Biol. Chem., Vol. 279, Issue 10, 8837-8847, March 5, 2004
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From the Laboratory of Molecular Signalling, Signalling Programme, The Babraham Institute, Cambridge CB2 4AT, United Kingdom
Bim, a "BH3-only" protein, is expressed de novo following withdrawal of serum survival factors and promotes cell death. We have shown previously that activation of the ERK1/2 pathway promotes phosphorylation of BimEL, targeting it for degradation via the proteasome. However, the nature of the kinase responsible for BimEL phosphorylation remained unclear. We now show that BimEL is phosphorylated on at least three sites in response to activation of the ERK1/2 pathway. By using the peptidylprolyl isomerase, Pin1, as a probe for proline-directed phosphorylation, we show that ERK1/2-dependent phosphorylation of BimEL occurs at (S/T)P motifs. ERK1/2 phosphorylates BimEL, but not BimS or BimL, in vitro, and mutation of Ser65 to alanine blocks the phosphorylation of BimEL by ERK1/2 in vitro and in vivo and prevents the degradation of the protein following activation of the ERK1/2 pathway. We also find that ERK1/2, but not JNK, can physically associate with GST-BimEL, but not GST-BimL or GST-BimS, in vitro. ERK1/2 also binds to full-length BimEL in vivo, and we have localized a potential ERK1/2 "docking domain" lying within a 27-amino acid stretch of the BimEL protein. Our findings provide new insights into the post-translational regulation of BimEL and the role of the ERK1/2 pathway in cell survival signaling.
Received for publication, October 22, 2003 , and in revised form, December 4, 2003.
* This work was supported in part by Grant 202/C15785 from BBSRC and Grant SP2458/0201 from Cancer Research UK. 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.
Supported by a Biotechnology and Biological Sciences Research Council Biochemistry and Cell Biology Special Committee Ph.D. Studentship.
To whom correspondence may be addressed. Tel.: 44-1223-496381; Fax: 44-1223-496043; E-mail: becky.ley{at}bbsrc.ac.uk. ¶ 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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