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J. Biol. Chem., Vol. 283, Issue 52, 36280-36289, December 26, 2008

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Caspase 8 Promotes Peripheral Localization and Activation of Rab5^*

Vicente A. Torres, Ainhoa Mielgo, Daniela Barilà, Deborah H. Anderson^¶, 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, the Department of Biology, University of Rome Tor Vergata and Laboratory of Cell Signaling, Istituto di Ricovero e, Cura a Carattere Scientifico Fondazione Santa Lucia, 00179, Rome, Italy, and the ^¶Cancer Research Unit, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada S7N 4H4

Caspase 8 is a cysteine protease that initiates apoptotic signaling via the extrinsic pathway in a manner dependent upon association with early endosomes. Previously, we identified caspase 8 as an effector of migration, promoting motility in a manner dependent upon phosphorylation on Tyr-380 by Src family kinases and its subsequent association with Src homology 2 domain-containing proteins. Here we demonstrate the regulation of the small GTPase Rab5, which mediates early endosome formation, homotypic fusion, and maturation by caspase 8. Regulation requires the Tyr-380 phosphorylation site but not caspase proteolytic activity. Tyr-380 is essential for interaction with the Src homology 2 domains of p85, a multifunctional adaptor for phosphatidylinositol 3-kinase, that possesses Rab-GAP activity. Interaction between caspase 8 and p85 promotes Rab5 GTP loading, alters endosomal trafficking, and results in the accumulation of Rab5-positive endosomes at the edge of the cell. Conversely, caspase 8-dependent GTP loading of Rab5 is overcome by increased expression of p85 in a Rab-GAP-dependent manner. Thus, we demonstrate a novel function for caspase 8 as a modulator of p85 Rab-GAP activity and endosomal trafficking.

Received for publication, July 31, 2008 , and in revised form, September 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant CA107263 (NCI, to D. S.). This work was also supported by Canadian Cancer Society, Saskatchewan Division Grant 019040 (to D. A.) and by grants from the Italian Association for Cancer Research and International Association for Cancer Research Grant 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 supplemental Figs. 1–7.

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

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