Caspase 8 promotes peripheral localization and activation of Rab5 |
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Authors: | Torres Vicente A Mielgo Ainhoa Barilà Daniela Anderson Deborah H Stupack Dwayne |
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Affiliation: | ‡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 |
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Abstract: | 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 p85alpha, a multifunctional adaptor for phosphatidylinositol 3-kinase, that possesses Rab-GAP activity. Interaction between caspase 8 and p85alpha 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 p85alpha in a Rab-GAP-dependent manner. Thus, we demonstrate a novel function for caspase 8 as a modulator of p85alpha Rab-GAP activity and endosomal trafficking. |
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