title: Caspase 8 promotes peripheral localization and activation of Rab5.
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.
authors.affiliation: Department of Pathology, University of California San Diego School of Medicine and the UCSD Moores Cancer Center, La Jolla, California 92093-0803, USA.
authors.forename: Vicente A
authors.initials: VA
authors.lastname: Torres
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Anderson
authors.forename: Dwayne
authors.initials: D
authors.lastname: Stupack
mesh_terms: D053181:Caspase 8 / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D015151:Immunoblotting; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D014168:Transferrin; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D053181:Caspase 8; D020558:GTP Phosphohydrolases; D020696:rab5 GTP-Binding Proteins