Moesin is an ανβ3 integrin-interacting protein that affects endothelial cell activation and angiogenesis through balancing c-Met and VEGFR2 activation.

Moesin (Msn) is a member of the ERM (Ezrin, Radixin, and Moesin) protein family implicated in cell-cell recognition, cell adhesion, and migration. In this work, we identified Msn as an ανβ3 integrin-interacting molecule in human endothelial cells, with a role in endothelial cell signaling and angiogenesis. Msn and its active phosphorylated form are highly expressed in endothelial cells in vitro and in vivo. Pleiotrophin and vascular endothelial growth factor A165 (VEGFA165), increase Msn phosphorylation and decrease the interaction of Msn with ανβ3 integrin. Downregulation of Msn expression in endothelial cells using siRNA reduced VEGF receptor 2 (VEGFR2) expression and activation. It also decreased permeability, collective cell migration, and tube formation in vitro, concomitant with reduced angiogenesis and blood-brain barrier permeability in Msn knockout mice. Concurrently, it decreased β3 integrin expression, increased the c-Src- and phosphoinositide 3-kinase (PI3K)-dependent cell-surface localization of nucleolin, and activated ERK1/2 kinases and cMet. Pharmacological inhibitors of c-Src, PI3K, cell-surface nucleolin, ERK1/2, and cMet, but not of VEGFR2 or αvβ3 integrin, abolished siMsn-induced individual-cell motility. Taken together, these findings identify a novel binding partner of the αvβ3 integrin that regulates the activation of cMet and VEGFR2 in endothelial cells, clarifying the mechanisms underlying the activation of multiple angiogenic pathways and highlighting potential new targets for improving anti-angiogenic therapies.