Vitronectin Negatively Regulates IGF-II-Induced Mitogenic Signaling and Migration Mediated by The Insulin Receptor Isoform-A

Author(s): Pierluigi Scalia, Emma Heart, Alison Doughty, Antonio Giordano, Stephen J Williams

Abstract

Vitronectin (VTN) is an extracellular matrix glycoprotein regulating both cell adhesion and spreading via Integrin alpha V-beta 3 and a variety of secreted/membrane anchored factors, however the cell signaling underlying VTN-induced effects is unclear. Here we show VTN to specifically modulate cellular effects of Insulin like growth factor II. Specifically, we find that vitronectin, either by addition or induced cell membrane expression, markedly reduced or neutralized IGF-II-induced proliferation and migration on mouse embryo fibroblasts genetically deprived of the IGF1R and expressing the human insulin receptor isoform (R-IRA) with high affinity for IGF-II. VTN transient expression at increasing amounts in these cells inhibited, accordingly, the IGF-II-mediated Ser473 acute phosphorylation of AKT. Under the same conditions, the IGF-II acute stimuli (5 min) on ERK1/2 (Thr202/Tyr204) activation via the IRA was also inhibited. Higher VTN expression levels in R-IRA cells associated a reproducible delayed increase in AKT S473 phosphorylation following 30 minutes stimulation for both AKT and ERK1/2. Altogether these data demonstrate that VTN, when overexpressed in the extracellular matrix, negatively modulates the IGF-II proliferative signal and biological effects mediated by the insulin receptor short isoform (IRA) and suggest potential new strategies for the modulation of the IGF-II effects in vivo.