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

Chiara Sandri, Francesca Caccavari, Donatella Valdembri, Chiara Camillo, Stefan Veltel, Martina Santambrogio, Letizia Lanzetti, Federico Bussolino, Johanna Ivaska, Guido Serini (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

62 Citations (Scopus)


Carbon nanobuds (CNBs) are a novel nanoscale carbon hybrid material consisting of fullerene-like structures covalently bonded to the outer surface of 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.
Original languageEnglish
Pages (from-to)1479-1501
JournalCell Research
Issue number10
Publication statusPublished - 2012
MoE publication typeA1 Journal article-refereed


Cite this

Sandri, C., Caccavari, F., Valdembri, D., Camillo, C., Veltel, S., Santambrogio, M., Lanzetti, L., Bussolino, F., Ivaska, J., & Serini, G. (2012). The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. Cell Research, 22(10), 1479-1501.