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

Abstract

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 α_νβ₃ 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 α_νβ₃ 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 α_vβ₃ integrin, abolished siMsn-induced individual-cell motility. Taken together, these findings identify a novel binding partner of the α_vβ₃ 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.