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 alpha, a multifunctional adaptor for phosphatidylinositol 3-kinase, that possesses Rab-GAP activity. Interaction between caspase 8 and p85 alpha 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 alpha in a Rab-GAP-dependent manner. Thus, we demonstrate a novel function for caspase 8 as a modulator of p85 alpha Rab-GAP activity and endosomal trafficking.

Torres, V., Mielgo, A., Barila', D., Anderson, D., Stupack, D. (2008). Caspase 8 promotes peripheral localization and activation of Rab5. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 283(52), 36280-36289 [10.1074/jbc.M805878200].

Caspase 8 promotes peripheral localization and activation of Rab5

BARILA', DANIELA;
2008-01-01

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 p85 alpha, a multifunctional adaptor for phosphatidylinositol 3-kinase, that possesses Rab-GAP activity. Interaction between caspase 8 and p85 alpha 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 alpha in a Rab-GAP-dependent manner. Thus, we demonstrate a novel function for caspase 8 as a modulator of p85 alpha Rab-GAP activity and endosomal trafficking.
2008
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/18 - GENETICA
English
Con Impact Factor ISI
chemical reactions; apoptotic signaling; caspase; cysteine protease; endosome; endosomes; novel functions; phosphatidylinositol 3 kinase; phosphorylation sites; proteolytic activities; Src homology 2 domains; Src-family kinase; phosphorylation; guanosine triphosphate; phosphatidylinositol 3 kinase; protein p85; protein rab5; rab protein; unclassified drug; article; controlled study; endosome; enzyme activity; human; human cell; outcome assessment; priority journal; protein localization; protein phosphorylation; protein protein interaction; 1-Phosphatidylinositol 3-kinase; caspase 8; cell Line, tumor; endosomes; gene expression regulation; GTP phosphohydrolases; humans; immunoblotting; models, biological; plasmids; rab5 GTP-Binding proteins; src homology domains; transferrin; tyrosine
http://www.jbc.org/content/283/52/36280.full.pdf+html?sid=80a94cf9-be36-442e-a2bc-c90c5c43f52e
Torres, V., Mielgo, A., Barila', D., Anderson, D., Stupack, D. (2008). Caspase 8 promotes peripheral localization and activation of Rab5. THE JOURNAL OF BIOLOGICAL CHEMISTRY, 283(52), 36280-36289 [10.1074/jbc.M805878200].
Torres, V; Mielgo, A; Barila', D; Anderson, D; Stupack, D
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/7949
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