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J. Biol. Chem., Vol. 283, Issue 7, 3854-3865, February 15, 2008

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The Docking Interaction of Caspase-9 with ERK2 Provides a Mechanism for the Selective Inhibitory Phosphorylation of Caspase-9 at Threonine 125^*

Morag C. Martin¹, Lindsey A. Allan, Erika J. Mancini², and Paul R. Clarke³

From the Biomedical Research Centre, Ninewells Hospital and Medical School, Level 5, University of Dundee, Dundee DD1 9SY, United Kingdom and the Division of Structural Biology, Henry Wellcome Building for Genomic Medicine, Oxford OX3 7BN, United Kingdom

Caspase-9 plays a critical role in the initiation of apoptosis by the mitochondrial pathway. Activation of caspase-9 is inhibited by phosphorylation at Thr¹²⁵ by ERK1/2 MAPKs in response to growth factors. Here, we show that phosphorylation of this site is specific for these classical MAPKs and is not strongly induced when JNK and p38/β MAPKs are activated by anisomycin. By deletion and mutagenic analysis, we identify domains in caspase-9 and ERK2 that mediate their interaction. Binding of ERK2 to caspase-9 and subsequent phosphorylation of caspase-9 requires a basic docking domain (D domain) in the N-terminal prodomain of the caspase. Mutational analysis of ERK2 reveals a ¹⁵⁷TTCD¹⁶⁰ motif required for recognition of caspase-9 that acts independently of the putative common docking domain. Molecular modeling supports the conclusion that Arg¹⁰ in the D domain of caspase-9 interacts with Asp¹⁶⁰ in the TTCD motif of ERK2. Differences in the TTCD motif in other MAPK family members could account for the selective recognition of caspase-9 by ERK1/2. This selectivity may be important for the antiapoptotic role of classical MAPKs in contrast to the proapoptotic roles of stress-activated MAPKs.

Received for publication, July 10, 2007 , and in revised form, December 7, 2007.

^* This study was supported by the Medical Research Council, Cancer Research UK, and the Association for International Cancer Research. 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.

¹ Present address: Cancer Research UK, London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.

² Royal Society University Research Fellow.

³ Supported by a Royal Society-Wolfson Research Merit Award. To whom correspondence should be addressed. Tel.: 44-1382-425580; Fax: 44-1382-669993; E-mail: p.r.clarke{at}dundee.ac.uk.

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