PMID:22825554

Citation	Sandri, C, Caccavari, F, Valdembri, D, Camillo, C, Veltel, S, Santambrogio, M, Lanzetti, L, Bussolino, F, Ivaska, J and Serini, G (2012) The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell Res. 22:1479-501
Abstract	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 β1 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 β1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1.
Links	PubMed PMC3463263 Online version:10.1038/cr.2012.110
Keywords	Antigens, CD29/metabolism; Carrier Proteins/antagonists & inhibitors; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Adhesion; Cells, Cultured; Endocytosis; Endosomes/metabolism; Endothelial Cells/cytology; Endothelial Cells/metabolism; Extracellular Matrix/metabolism; Guanine Nucleotide Exchange Factors/antagonists & inhibitors; Guanine Nucleotide Exchange Factors/genetics; Guanine Nucleotide Exchange Factors/metabolism; HeLa Cells; Humans; Phosphatidylinositol Phosphates/metabolism; Protein Binding; RNA Interference; RNA, Small Interfering/metabolism; Signal Transduction; rab5 GTP-Binding Proteins/metabolism; rac GTP-Binding Proteins/metabolism; ras Proteins/antagonists & inhibitors; ras Proteins/genetics; ras Proteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:RRAS		GO:0045785: positive regulation of cell adhesion	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11689
HUMAN:RRAS		GO:0010595: positive regulation of endothelial cell migration	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11691
HUMAN:RRAS		GO:2001214: positive regulation of vasculogenesis	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11692
HUMAN:RRAS		GO:1904906: positive regulation of endothelial cell-matrix adhesion via fibronectin	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11693
HUMAN:RIN2		GO:1904906: positive regulation of endothelial cell-matrix adhesion via fibronectin	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11690
HUMAN:RIN2		GO:0010595: positive regulation of endothelial cell migration	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11694
HUMAN:RIN2		GO:2001214: positive regulation of vasculogenesis	ECO:0000315:		P		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11695
HUMAN:RIN2		GO:0050840: extracellular matrix binding	ECO:0000315:		F		Figure 1. R-Ras and RIN2 promote EC-to-ECM binding, adhesion, migration, and vascular morphogenesis; RIN2 mediates the pro-adhesive effects of R-Ras.	complete CACAO 11696

References

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