Sphingosine kinase-1 associates with Integrin alpha(V)beta(3) to mediate endothelial cell survival

Abstract

Sphingosine kinase (SK)-1 promotes endothelial cell (EC) survival through the cell junction molecule CD31 (platelet endothelial cell adhesion molecule-1). The integrin vβ3 is also essential for EC survival; inhibition of vβ3 ligation promotes apoptosis. Herein we demonstrate that under basal conditions, SK-1, vβ3, and CD31 exist as a heterotrimeric complex. Under conditions that affect EC survival such as loss of contact with the extracellular matrix or growth factor activation, more of this heterotrimeric complex forms. Overexpression studies demonstrate a requirement for SK-1 phosphorylation at serine 225 for increased heterotrimeric complex formation, activation of vβ3, and EC survival signals, including Bcl-X and nuclear factor-B pathways. Moreover, β3 integrin depletion confirmed the requirement for this heterotrimeric complex in SK-1-mediated EC survival. Thus, with vβ3 integrin being identifiable primarily on angiogenic ECs and SK-1 being highly expressed in tumors, targeting SK-1 may affect multiple survival pathways, and its inhibition may be highly efficacious in controlling pathological EC survival.