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J Cell Sci. 2014 Jul 1;127(Pt 13):2849-61. doi: 10.1242/jcs.139329. Epub 2014 May 9.

RasGAP mediates neuronal survival in Drosophila through direct regulation of Rab5-dependent endocytosis.

Author information

1
The Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
2
Lehrstuhl für Entwicklungsbiologie, Universität Regensburg, 93040 Regensburg, Germany.
3
Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.
4
The Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK david.a.hughes@manchester.ac.uk.

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.

KEYWORDS:

Drosophila; Guanine-nucleotide-exchange factor; Rab5; RasGAP; Sprint; Tyrosine phosphorylation; Vap

PMID:
24816559
DOI:
10.1242/jcs.139329
[Indexed for MEDLINE]
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