The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling  

作　　者：Chiara Sandri Francesca Caccavari Donatella Valdembri Chiara Camillo Stefan Veltel Martina Santambrog Letizia Lanzetti Federico Bussolino Johanna Ivaska Guido Serini 

机构地区：[1]Laboratory of Cell Adhesion Dynamics, Institute for Cancer Research and Treatment (IRCC), Strada Provinciale 142, Km 3.95, 10060 Candiolo (TO), Italy,' [2]Department of Oncological Sciences, University of Torino School of Medicine, 10060 Candiolo (TO), Italy [3]University of Turku Centre for Biotechnology and VTT Medical Biotechnology, FIN-20520, Turku, Finland,' [4]Laboratory of Membrane Trafficking, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (TO), Italy [5]Laboratory of Vascular Oncology, Institute for Cancer Research and Treatment (IRCC), 10060 Candiolo (TO), ltaly [6]Center for Complex Systems in Molecular Biology and Medicine - SysBioM-University of Torino, c/o Department of Animal and Human Biology (DBA U), 10123 Torino, Italy

出　　处：《Cell Research》2012年第10期1479-1501,共23页细胞研究（英文版）

摘　　要：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 Racl-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 pl integrins and the ensuing funneling of R-Ras- GTP toward early endosomes to elicit the pro-adhesive and TIAMl-mediated activation of Racl.

关 键 词：INTEGRINS R-RAS Rab5 endosomal signaling angiogenesis 

分 类 号：Q463[生物学—生理学] Q513