tailieunhanh - Báo cáo khoa học: Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing with avb3 integrin for vitronectin binding

Functional cooperationbetween integrins andgrowth factor receptors has been reported for several systems, oneofwhich is the modulation of insulin signaling by avb3 integrin. Plasminogen activator inhibitor type-1 (PAI-1), competes withavb3 integrin for vitronectin (VN) binding. Here we report that PAI-1, in a VN-dependent manner, prevents the cooperation of avb3 integrin with insulin signaling in NIH3T3 fibroblasts, resulting in a decrease in insulin-induced protein kinase B (PKB) phosphorylation, vascular endothelial growth factor (VEGF) expression and cell migration. . | Eur. J. Biochem. 270 814-821 2003 FEBS 2003 doi PRIORITY PAPER Plasminogen activator inhibitor type-1 inhibits insulin signaling by competing with avp3 integrin for vitronectin binding Roser Lopez-Alemany1 Juan M. Redondo2 Yoshikuni Nagamine3 and Pura Munoz-Canoves1 4 1Institut de Recerca Oncològica IRO Centre d Oncologia Molecular L Hospitalet de Llobregat Barcelona Spain . Severo Ochoa . . Facultat de Ciencias Madrid Spain 3 Friedrich Miescher Institute for Biomedical Research Novartis Research Foundation Basel Switzerland 4Centre de Regulació Genòmica CRG Programa de Diferenciacio i Cancer Barcelona Spain Functional cooperation between integrins and growth factor receptors has been reported for several systems one of which is the modulation of insulin signaling by avb3 integrin. Plasminogen activator inhibitor type-1 PAI-1 competes with avb3 integrin for vitronectin VN binding. Here we report that PAI-1 in a VN-dependent manner prevents the cooperation of avb3 integrin with insulin signaling in NIH3T3 fibroblasts resulting in a decrease in insulin-induced protein kinase B PKB phosphorylation vascular endothelial growth factor VEGF expression and cell migration. Insulin-induced HUVEC migration and angio-tube formation was also enhanced in the presence of VN and this enhancement is inhibited by PAI-1. By using specific PAI-1 mutants with either VN binding or plasminogen activator PA inhibiting activities ablated we have shown that the PAI-1-mediated interference with insulin signaling occurs through its direct interaction with VN and not through its PA neutralizing activity. Moreover using cells deficient for uPA receptor uPAR we have demonstrated that the inhibition of PAI-1 on insulin signaling is independent of uPAR-VN binding. These results constitute the first demonstration of the interaction of PAI-1 with the insulin response. Keywords plasminogen activator inhibitor type-1 vitronectin insulin angiogenesis .