QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 20, Issue 12, 2831-2840, June 15, 2009

This Article Full Text Full Text (PDF) All Versions of this Article: E08-09-0911v1 20/12/2831    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Romero Rosales, K. Articles by Edinger, A. L. Search for Related Content PubMed PubMed Citation Articles by Romero Rosales, K. Articles by Edinger, A. L.

Rab7 Activation by Growth Factor Withdrawal Contributes to the Induction of Apoptosis

Department of Developmental and Cell Biology, University of California–Irvine, Irvine, CA 92697-2300

Submitted September 8, 2008; Revised April 8, 2009; Accepted April 13, 2009
Monitoring Editor: Benjamin Margolis

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) inhibition. PKC is one of the most highly induced proteins after growth factor withdrawal and contributes to the induction of apoptosis. To evaluate whether PKC regulates Rab7, we first examined lysosomal morphology in cells with reduced PKC activity. Consistent with a potential role as a Rab7 activator, blocking PKC function caused profound lysosomal fragmentation comparable to that observed when Rab7 was directly inhibited. Interestingly, PKC 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.

Address correspondence to: Aimee L. Edinger (aedinger{at}uci.edu)

This article has been cited by other articles:

				E. R. Peralta, B. C. Martin, and A. L. Edinger Differential Effects of TBC1D15 and Mammalian Vps39 on Rab7 Activation State, Lysosomal Morphology, and Growth Factor Dependence J. Biol. Chem., May 28, 2010; 285(22): 16814 - 16821. [Abstract] [Full Text] [PDF]

				W. Liu, K. Tundwal, Q. Liang, N. Goplen, S. Rozario, N. Quayum, M. Gorska, S. Wenzel, S. Balzar, and R. Alam Establishment of Extracellular Signal-Regulated Kinase 1/2 Bistability and Sustained Activation through Sprouty 2 and Its Relevance for Epithelial Function Mol. Cell. Biol., April 1, 2010; 30(7): 1783 - 1799. [Abstract] [Full Text] [PDF]

				B. A. McCray, E. Skordalakes, and J. P. Taylor Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation Hum. Mol. Genet., March 15, 2010; 19(6): 1033 - 1047. [Abstract] [Full Text] [PDF]