Journal
CELL RESEARCH
Volume 22, Issue 10, Pages 1479-1501Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cr.2012.110
Keywords
integrins; R-Ras; Rab5; endosomal signaling; angiogenesis
Categories
Funding
- Telethon Italy [GGP04127, GGP09175]
- Compagnia di San Paolo - Neuroscience Program Multicentre Projects
- Associazione Augusto per la Vita
- Fondazione Guido Berlucchi
- Associazione Italiana per la Ricerca sul Cancro [9211, 10133]
- Fondazione Piemontese per la Ricerca sul Cancro - ONLUS - Intramural Grant
- Ministero della Salute - Programma Ricerca Oncologica
- Ricerca Finalizzata
- Regione Piemonte - Ricerca Sanitaria Finalizzata
- Ricerca Scientifica Applicata
- Ricerca industriale e sviluppo precompetitivo
- Piattaforme Tecnologiche per le Biotecnologie [DRUIDI]
- Ricerca Tecnologie Convergenti [PHOENICS]
- Ricerca Industriale [BANP]
- Ministero dell'Universita e della Ricerca - Fondo per gli Investimenti della Ricerca di Base [NEWTON-RBAP11BYNP]
- University of Torino-Progetti di Ateneo [Rethe - ORTO11RKTW]
- Academy of Finland
- ERC
- EMBO LTF
- Alexander Von Humbolt Foundation
- [D10]
- [A150]
- [PRESTO]
- [SPLASERBA]
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During developmental and tumor angiogenesis, semaphorins regulate blood vessel navigation by signaling through plexin receptors that inhibit the R-Ras subfamily of small GTPases. R-Ras is mainly expressed in vascular cells, where it induces adhesion to the extracellular matrix (ECM) through unknown mechanisms. We identify the Ras and Rab5 interacting protein RIN2 as a key effector that in endothelial cells interacts with and mediates the pro-adhesive and -angiogenic activity of R-Ras. Both R-Ras-GTP and RIN2 localize at nascent ECM adhesion sites associated with lamellipodia. Upon binding, GTP-loaded R-Ras converts RIN2 from a Rab5 guanine nucleotide exchange factor (GEF) to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocytosis of ligand-bound/active beta 1 integrins and then causes the translocation of R-Ras to early endosomes. Here, the R-Ras/RIN2/Rab5 signaling module activates Rac1-dependent cell adhesion via TIAM1, a Rac GEF that localizes on early endosomes and is stimulated by the interaction with both Ras proteins and the vesicular lipid phosphatidylinositol 3-monophosphate. In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound/active beta 1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1.
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