A tale of three GTPases and a RIN in endothelial cell adhesion

Abstract

Endothelial cell adhesion to the extracellular matrix regulates migration and outgrowth of blood vessels during angiogenesis. Cell adhesion is mediated by integrins, which transduce signals from the extracellular environment into the cell and, in turn, are regulated by intracellular signaling molecules. In a paper recently published in Cell Research, Sandri et al. show that RIN2 connects three GTPases, R-Ras, Rab5 and Rac1, to promote endothelial cell adhesion through the regulation of integrin internalization and Rac1 activation.

The salivary peptide histatin‐1 promotes endothelial cell adhesion, migration, and angiogenesis

“…7). We showed that the so-called Rab5-Rac1 signaling axis (20,21) is activated by histatin-1, although upstream components in this signaling axis, such as the small GTPase R-Ras and b 1 integrins (21), were not addressed in this study. Alternatively, earlier studies suggested that histatin-1-driven migration of oral keratinocytes require G-coupled protein receptors (15); however, further studies are needed to confirm this possibility and the potential relationship with the activation of Rab5 and Rac1 by histatin-1.…”

“…Endothelial cell adhesion and migration are central events leading to the outgrowth of blood vessels during angiogenesis (17). These events require cell adhesion to the extracellular matrix and subsequent activation of Rac1, which is activated by a signaling cascade initiated at the early endosomes (20,21). Specifically, endothelial cell adhesion leads to the activation of Rab5, which is a key regulator of signaling endosomes, leading to the activation of Rac1, actin polymerization, and endothelial cell migration (21).…”

“…3E). Because activation of the so-called Rab5-Rac1 circuitry involves the recruitment of the Rab5-GEF, RIN2, within early endosomes (20,21), we evaluated the effects of histatin-GTP-bound Rac1 (lower panels). C, D) EA.hy926 cells were transfected by 24 h with either pEGFP-C1 (empty vector, EV) or pEGFP-Rab5/S34N (Rab5 inactive mutant, S34N), and then used for GST-PBD pull-down assays, Western blot analysis of wholecell lysates, and migration assays.…”

“…Several signals have been shown to initiate and sustain these responses, which include the extracellular factors VEGF and basic fibroblast growth factor (16,17), as well as intracellular signals that converge in the activation of the small GTPase Rac1, which is essential to the reorganization of the actin cytoskeleton and migration in endothelial cells (18,19). Rac1 activation in endothelial cells was recently shown to be dependent on signaling endosomes in a process controlled by the endosomal small GTPase Rab5 (20,21). Specifically, endothelial cell adhesion to the extracellular matrix via integrins leads to the activation of Rab5 via its guanine nucleotide exchange factor (GEF), Ras and Rab interactor 2 (RIN2), an event that is followed by the recruitment of Tiam1 (a Rac1-GEF) within early endosomes and the consequent activation of Rac1, leading to endothelial cell migration and vascular morphogenesis (21,22).…”

RIN2 syndrome: Expanding the clinical phenotype

“…Ultrastructural studies revealed a dilated endoplasmic reticulum (ER) and abnormal Golgi apparatus morphology [Basel‐Vanagaite et al, ; Albrecht et al, ; Syx et al, ], suggesting compromised sorting, modification, and/or secretion of diverse molecules, such as collagen and elastin, which could contribute to the ultrastructural abnormalities in extracellular matrix (ECM) organization [Basel‐Vanagaite et al, ; Albrecht et al, ; Syx et al, ]. Given the suggested association between RIN2 and Ras signalling [Fernandez‐Borja, ], altered signaling could also contribute to the pathogenic mechanism. More recently, the R‐Ras/RIN2/Rab5 complex was shown to be involved in the regulation of β1‐integrin internalization in endothelial cells.…”