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J. Biol. Chem., Vol. 283, Issue 19, 13031-13034, May 9, 2008

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Identification of a Critical Tyrosine Residue in Caspase 8 That Promotes Cell Migration^*

Simone Barbero, Daniela Barilà, Ainhoa Mielgo, Venturina Stagni, Kiran Clair, and Dwayne Stupack¹

From the Department of Pathology, University of California San Diego School of Medicine and the UCSD Moores Cancer Center, La Jolla, California 92093 and Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Santa Lucia 00179 Rome, Italy, and University of Tor Vergata 00133 Rome, Italy

Caspase 8 is a critical upstream initiator of programmed cell death but, paradoxically, has also been shown to promote cell migration. Here, we show that tyrosine 380 in the linker loop of human caspase 8 is a critical switch determining caspase 8 function. Our studies show that, in addition to its cytosolic distribution, caspase 8 is recruited to lamella of migrating cells. Although the catalytic domain of caspase 8 is sufficient for recruitment and promotion of cell migration, catalytic activity per se is not required. Instead, we find that integrin-mediated adhesion promotes caspase 8 phosphorylation on tyrosine 380. Accordingly, mutation of this site compromises localization to the periphery and the potentiation of cell migration. Mechanistically, this linker region of caspase 8 acts as a Src homology 2 binding site. In particular, tyrosine 380 is critical for interaction with Src homology 2 domains. The results identify a novel mechanism by which caspase 8 is recruited to the lamella of a migrating cell, promoting cell migration independent of its protease activity.

Received for publication, November 27, 2007 , and in revised form, December 11, 2007.

^* This work was supported, in whole or in part, by NCI, National Institutes of Health Grant CA107263 (to D. S.). This work was also supported by grants from the Italian Association for Cancer Research and the International Association for Cancer Research (AICR 07-0461) (to D. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed: Moores UCSD Cancer Center, 3855 Health Sciences Drive, MC0803, La Jolla, CA 92093-0803. Tel.: 858-822-1150; Fax: 858-822-2630; E-mail: dstupack{at}ucsd.edu.

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