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

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1479-1501
Number of pages23
JournalCell Research
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 2012

Fingerprint

Endocytosis
Guanosine Triphosphate
Morphogenesis
Cell Adhesion
Integrins
Endothelial Cells
Guanine Nucleotide Exchange Factors
Endosomes
Extracellular Matrix
Adhesives
rab5 GTP-Binding Proteins
Blood Vessels
Semaphorins
ras Proteins
Pseudopodia
Monomeric GTP-Binding Proteins
Ligands
Lipids
Neoplasms

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. / Sandri, Chiara; Caccavari, Francesca; Valdembri, Donatella; Camillo, Chiara; Veltel, Stefan; Santambrogio, Martina; Lanzetti, Letizia; Bussolino, Federico; Ivaska, Johanna; Serini, Guido.

In: Cell Research, Vol. 22, No. 10, 10.2012, p. 1479-1501.

Research output: Contribution to journalArticle

Sandri, Chiara ; Caccavari, Francesca ; Valdembri, Donatella ; Camillo, Chiara ; Veltel, Stefan ; Santambrogio, Martina ; Lanzetti, Letizia ; Bussolino, Federico ; Ivaska, Johanna ; Serini, Guido. / The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling. In: Cell Research. 2012 ; Vol. 22, No. 10. pp. 1479-1501.
@article{682a548464ac4e498cdeb257663fe48e,
title = "The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling",
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.",
author = "Chiara Sandri and Francesca Caccavari and Donatella Valdembri and Chiara Camillo and Stefan Veltel and Martina Santambrogio and Letizia Lanzetti and Federico Bussolino and Johanna Ivaska and Guido Serini",
year = "2012",
month = "10",
doi = "10.1038/cr.2012.110",
language = "English",
volume = "22",
pages = "1479--1501",
journal = "Cell Research",
issn = "1001-0602",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - The R-Ras/RIN2/Rab5 complex controls endothelial cell adhesion and morphogenesis via active integrin endocytosis and Rac signaling

AU - Sandri, Chiara

AU - Caccavari, Francesca

AU - Valdembri, Donatella

AU - Camillo, Chiara

AU - Veltel, Stefan

AU - Santambrogio, Martina

AU - Lanzetti, Letizia

AU - Bussolino, Federico

AU - Ivaska, Johanna

AU - Serini, Guido

PY - 2012/10

Y1 - 2012/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84867084482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867084482&partnerID=8YFLogxK

U2 - 10.1038/cr.2012.110

DO - 10.1038/cr.2012.110

M3 - Article

C2 - 22825554

AN - SCOPUS:84867084482

VL - 22

SP - 1479

EP - 1501

JO - Cell Research

JF - Cell Research

SN - 1001-0602

IS - 10

ER -