Functional trans-inactivation of insulin receptor kinase by growth-inhibitory angiotensin II AT(2) receptor

The present study demonstrates negative intracellular cross-talk between an giotensin II type 2 (AT(2)) and insulin receptors. AT(2) receptor stimulati on leads to inhibition of insulin-induced extracellular signal-regulated pr otein kinase (ERK2) activity and cell proliferation in transfected Chinese hamster ovary (CHO-hAT(2)) cells. We show that AT(2) receptor interferes at the initial step of insulin signaling cascade, by impairing tyrosine phosp horylation of the insulin receptor (IR) beta-chain. AT(2)-mediated inhibiti on of IR phosphorylation is insensitive to pertussis toxin and is also dete cted in neuroblastoma N1E-115 and pancreatic acinar AR42J cells that expres s endogenous receptors. We present evidence that AT(2) receptor inhibits th e autophosphorylating tyrosine kinase activity of IR, with no significant e ffect on insulin binding properties. AT(2)-mediated inactivation of IR does not mainly involve tyrosine dephosphorylation by vanadate-sensitive tyrosi ne phosphatases nor serine/threonine phosphorylation by protein kinase C. A s a consequence of IR inactivation, AT(2) receptor inhibits tyrosine phosph orylation of insulin receptor substrate-1 (IRS-1) and signal-regulatory pro tein (SIRP alpha 1) and prevents subsequent association of both IRS-1 and S IRP alpha 1 with Src homology 2 (SH2)-containing tyrosine phosphatase SHP-2 . Our results thus demonstrate functional trans-inactivation of IR kinase b y G protein-coupled AT(2) receptor, illustrating a novel mode of negative c ommunication between two families of membrane receptors.