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Functional Trans-inactivation of Insulin Receptor Kinase by Growth-Inhibitory Angiotensin II AT₂ Receptor

Institut Cochin de Génétique Moléculaire Centre Nationale de la Recherche Scientifique UPR 0415 75014 Paris, France

The present study demonstrates negative intracellular cross-talk between angiotensin II type 2 (AT₂) and insulin receptors. AT₂ receptor stimulation leads to inhibition of insulin-induced extracellular signal-regulated protein kinase (ERK2) activity and cell proliferation in transfected Chinese hamster ovary (CHO-hAT2) cells. We show that AT₂ receptor interferes at the initial step of insulin signaling cascade, by impairing tyrosine phosphorylation of the insulin receptor (IR) ß-chain. AT₂-mediated inhibition of IR phosphorylation is insensitive to pertussis toxin and is also detected in neuroblastoma N1E-115 and pancreatic acinar AR42J cells that express endogenous receptors. We present evidence that AT₂ receptor inhibits the autophosphorylating tyrosine kinase activity of IR, with no significant effect on insulin binding properties. AT₂-mediated inactivation of IR does not mainly involve tyrosine dephosphorylation by vanadate-sensitive tyrosine phosphatases nor serine/threonine phosphorylation by protein kinase C. As a consequence of IR inactivation, AT₂ receptor inhibits tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and signal-regulatory protein (SIRP1) and prevents subsequent association of both IRS-1 and SIRP1 with Src homology 2 (SH2)-containing tyrosine phosphatase SHP-2. Our results thus demonstrate functional trans-inactivation of IR kinase by G protein-coupled AT₂ receptor, illustrating a novel mode of negative communication between two families of membrane receptors.

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