Rowshanravan, Behzad and Woodcock, Simon A. and Botella, Jose A. and Kiermayer, Claudia and Schneuwly, Stephan and Hughes, David A. (2014) RasGAP mediates neuronal survival in Drosophila through direct regulation of Rab5-dependent endocytosis. JOURNAL OF CELL SCIENCE, 127 (13). pp. 2849-2861. ISSN 0021-9533, 1477-9137
Full text not available from this repository. (Request a copy)Abstract
The GTPase Ras can either promote or inhibit cell survival. Inactivating mutations in Drosophila RasGAP (encoded by vap), a Ras GTPase-activating protein, lead to age-related brain degeneration. Genetic interactions implicate the epidermal growth factor receptor (EGFR)-Ras pathway in promoting neurodegeneration but the mechanism is not known. Here, we show that the Src homology 2 (SH2) domains of RasGAP are essential for its neuroprotective function. By using affinity purification and mass spectrometry, we identify a complex containing RasGAP together with Sprint, which is a Ras effector and putative activator of the endocytic GTPase Rab5. Formation of the RasGAP-Sprint complex requires the SH2 domains of RasGAP and tyrosine phosphorylation of Sprint. RasGAP and Sprint colocalize with Rab5-positive early endosomes but not with Rab7-positive late endosomes. We demonstrate a key role for this interaction in neurodegeneration: mutation of Sprint (or Rab5) suppresses neuronal cell death caused by the loss of RasGAP. These results indicate that the long-term survival of adult neurons in Drosophila is crucially dependent on the activities of two GTPases, Ras and Rab5, regulated by the interplay of RasGAP and Sprint.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NUCLEOTIDE EXCHANGE FACTOR; GTPASE-ACTIVATING PROTEIN; PROGRAMMED CELL-DEATH; GROWTH-FACTOR; GENE-EXPRESSION; NERVOUS-SYSTEM; RAB5 EFFECTOR; MIGRATION; PATHWAY; MELANOGASTER; Tyrosine phosphorylation; Sprint; Guanine-nucleotide-exchange factor; Rab5; Drosophila; RasGAP; Vap |
| Subjects: | 500 Science > 590 Zoological sciences |
| Divisions: | Biology, Preclinical Medicine > Institut für Zoologie > Entwicklungsbiologie (Prof. Dr. Stephan Schneuwly) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 17 Oct 2019 11:26 |
| Last Modified: | 17 Oct 2019 11:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/9964 |
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