ANGIOTENSIN-II STIMULATES PROTEIN-TYROSINE-PHOSPHATASE ACTIVITY THROUGH A G-PROTEIN INDEPENDENT MECHANISM

Most of angiotensin II's (Ang II) documented effects have been attribu ted to the interaction of this peptide with a G-protein coupled recept or termed AT1. The role and the signalling mechanisms of the more rece ntly characterized AT2 receptor, which does not appear to interact wit h G-proteins, are however still unclear. We report here that this rece ptor mediates the rapid dephosphorylation of tyrosine residues of spec ific proteins in the 60 to 150 KDa range in PC12W cells which express only AT2 receptors. We further characterized this phosphatase activity using the synthetic substrate para-nitrophenyl phosphate. Dephosphory lation of this substrate in response to Ang II is not affected by Ser/ Thr phosphatase inhibitors, but is completely prevented by the protein tyrosine phosphatase (PTPase) inhibitor sodium orthovanadate. This ef fect is mimicked by the AT2 selective agonist CGP 42112 and is not aff ected by the AT1 antagonist losartan, In contrast to the recently repo rted PTPase stimulation by somatostatin and dopamine, PTPase stimulati on by Ang II is not affected by the guanyl nucleotides GTP(gamma)S and GDP(beta)S. Moreover, depletion of solubilized membrane preparations from G-proteins by lectin affinity chromatography does not alter Ang I I stimulation of the measured PTPase activity. These findings indicate that Ang II stimulates a PTPase activity through AT2 receptors via G- protein independent pathways. This signalling mechanism may be involve d in AT2 receptor mediated actions of Ang II such as particulate guany late cyclase inhibition, modulation of T-type Ca++ channels and regula tion of cell proliferation and differentiation.