title: Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis.
abstract: The Rab7 GTPase promotes membrane fusion reactions between late endosomes and lysosomes. In previous studies, we demonstrated that Rab7 inactivation blocks growth factor withdrawal-induced cell death. These results led us to hypothesize that growth factor withdrawal activates Rab7. Here, we show that growth factor deprivation increased both the fraction of Rab7 that was associated with cellular membranes and the percentage of Rab7 bound to guanosine triphosphate (GTP). Moreover, expressing a constitutively GTP-bound mutant of Rab7, Rab7-Q67L, was sufficient to trigger cell death even in the presence of growth factors. This activated Rab7 mutant was also able to reverse the growth factor-independent cell survival conferred by protein kinase C (PKC) delta inhibition. PKCdelta is one of the most highly induced proteins after growth factor withdrawal and contributes to the induction of apoptosis. To evaluate whether PKCdelta regulates Rab7, we first examined lysosomal morphology in cells with reduced PKCdelta activity. Consistent with a potential role as a Rab7 activator, blocking PKCdelta function caused profound lysosomal fragmentation comparable to that observed when Rab7 was directly inhibited. Interestingly, PKCdelta inhibition fragmented the lysosome without decreasing Rab7-GTP levels. Taken together, these results suggest that Rab7 activation by growth factor withdrawal contributes to the induction of apoptosis and that Rab7-dependent fusion reactions may be targeted by signaling pathways that limit growth factor-independent cell survival.
authors.affiliation: Department of Developmental and Cell Biology, University of California-Irvine, Irvine, CA 92697-2300, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Romero Rosales
authors.forename: Eigen R
authors.initials: ER
authors.lastname: Peralta
authors.forename: Garret G
authors.initials: GG
authors.lastname: Guenther
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Wong
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Edinger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency*; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding / Q000187:drug effects; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000172:deficiency; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000090802:rab7 GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; C423317:RILP protein, human; D011993:Recombinant Fusion Proteins; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; D006160:Guanosine Triphosphate; D051745:Protein Kinase C-delta; D020691:rab GTP-Binding Proteins