CROSS-TALK BETWEEN THE INSULIN AND ANGIOTENSIN SIGNALING SYSTEMS

Angiotensin II (AII), acting via its G-protein linked receptor, is an important regulator of cardiac, vascular, and renal function. Followin g injection of AII into rats, we find that there is also a rapid tyros ine phosphorylation of the major insulin receptor substrates 1 and 2 ( IRS-1 and IRS-2) in the heart. This phenomenon appears to involve JAK2 tyrosine kinase, which associates with the AT1 receptor and IRS-1/IRS -2 after AII stimulation. AII-induced phosphorylation leads to binding of phosphatidylinositol 3-kinase (PI 3-kinase) to IRS-1 and IRS-2; ho wever, in contrast to other ligands, AII injection results in an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity. The latter occurs without any reduction in insulin receptor or IRS ph osphorylation or in the interaction of the p85 and p110 subunits of PI 3-kinase with each other or with IRS-1/IRS-2. These effects of AII ar e inhibited by AT1 receptor antagonists. Thus, there is direct cross-t alk between insulin and AII signaling pathways at the level of both ty rosine phosphorylation and PI 3-kinase activation. These interactions may play an important role in the association of insulin resistance, h ypertension, and cardiovascular disease.