CD93 Signaling via Rho Proteins Drives Cytoskeletal Remodeling in Spreading Endothelial Cells.

Stefano Barbera,Anna Dimberg,Luisa Raucci,Gian Marco Tosi,Annalisa Santucci,Roberta Lugano,Federico Galvagni,Maurizio Orlandini

doi:10.3390/ijms222212417

Abstract

During angiogenesis, cell adhesion molecules expressed on the endothelial cell surface promote the growth and survival of newly forming vessels. Hence, elucidation of the signaling pathways activated by cell-to-matrix adhesion may assist in the discovery of new targets to be used in antiangiogenic therapy. In proliferating endothelial cells, the single-pass transmembrane glycoprotein CD93 has recently emerged as an important endothelial cell adhesion molecule regulating vascular maturation. In this study, we unveil a signaling pathway triggered by CD93 that regulates actin cytoskeletal dynamics responsible of endothelial cell adhesion. We show that the Src-dependent phosphorylation of CD93 and the adaptor protein Cbl leads to the recruitment of Crk, which works as a downstream integrator in the CD93-mediated signaling. Moreover, confocal microscopy analysis of FRET-based biosensors shows that CD93 drives the coordinated activation of Rac1 and RhoA at the cell edge of spreading cells, thus promoting the establishment of cell polarity and adhesion required for cell motility.

Highlights

Migration of endothelial cells (ECs) is essential for the outgrowth of new blood vessels both in physiological and pathological conditions
These observations were further substantiated by immunofluorescence analyses showing that active Src was strongly decreased at the cell border of CD93-silenced ECs compared to ECs transduced with a lentivirus expressing an unrelated shRNA (Figure 1c)
We show that, to what has been observed in migrating ECs [16], the transmembrane protein CD93 activates a signaling cascade involving Rac1 and RhoA

Summary

Introduction

Migration of endothelial cells (ECs) is essential for the outgrowth of new blood vessels both in physiological and pathological conditions. The integration of several cues, largely provided by adhesion to the substrate, is critical to activate intracellular signals that bias cytoskeletal remodeling, cell shape, and polarity [2]. Uncovering the molecular mechanisms that underpin the regulation of EC adhesion could allow a better understanding of both physiological and pathological angiogenesis. In addition to integrins, stimulated endothelia express alternative adhesive proteins that can bind extracellular matrix (ECM) components and activate signaling pathways during cell motility [3]. Among these proteins, the C-type lectin transmembrane protein

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Results

Conclusion