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Rowshanravan, B.* ; Woodcock, S.A.* ; Botella, J.A.* ; Kiermayer, C. ; Schneuwly, S.* ; Hughes, D.A.*

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

J. Cell Sci. 127, 2849-2861 (2014)
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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The GTPase Ras can either promote or inhibit cell survival. Inactivating mutations in RasGAP (vap), a Ras GTPase-activating protein, lead to age-related brain degeneration in Drosophila. 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, 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 co-localize 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 critically dependent on the activities of two GTPases, Ras and Rab5, regulated by the interplay of RasGAP and Sprint.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Tyrosine Phosphorylation ; Sprint ; Guanine-nucleotide-exchange Factor ; Rab5 ; Drosophila ; Rasgap ; Vap; Nucleotide Exchange Factor; Gtpase-activating Protein; Programmed Cell-death; Growth-factor; Gene-expression; Nervous-system; Rab5 Effector; Migration; Pathway; Melanogaster
ISSN (print) / ISBN 0021-9533
e-ISSN 1477-9137
Quellenangaben Band: 127, Heft: 13, Seiten: 2849-2861 Artikelnummer: , Supplement: ,
Verlag Company of Biologists
Verlagsort Cambridge
Begutachtungsstatus Peer reviewed