ANGIOTENSIN-II TYPE-2 RECEPTORS MEDIATE INHIBITION OF MITOGEN-ACTIVATED PROTEIN-KINASE CASCADE AND FUNCTIONAL ACTIVATION OF SHP-1 TYROSINE PHOSPHATASE

Angiotensin II type 2 (AT(2)) receptors are involved in the inhibition of cell proliferation as well as in apoptosis and neuronal differenti ation, through intracellular signalling pathways that remain poorly de fined. The present study examines the effect of AT(2)-receptor stimula tion on growth-factor-induced pathways leading to the activation of mi togen-activated protein (MAP) kinases. In N1E-115 neuroblastoma cells, AT(2) receptors inhibit the activity of MAP kinases induced by serum as well as by epidermal growth factor, The inhibitory effect of angiot ensin II (Ang II) is rapid and transient, and affects both ERK1 and ER K2 (extracellular signal-related protein kinase) isoforms of the enzym e. AT(2)-mediated MAP kinase inactivation is not sensitive to pertussi s toxin or okadaic acid, but involves a vanadate-sensitive protein tyr osine phosphatase (PTP). Expression of MAP kinase phosphatase-l (MKP-1 ) is not significantly modified upon AT(2)-receptor activation, and in sensitivity to actinomycin D also rules out transcriptional induction of other MKPs as a possible mechanism for AT(2)-mediated inactivation of MAP kinases. In addition, eve report here that both in N1E-115 cell s and in Chinese hamster ovary cells expressing recombinant human AT(2 ) receptors, Ang II rapidly stimulates the catalytic activity of SHP-1 , a soluble PTP that has been implicated in termination of signalling by cytokine and growth-factor receptors. These findings thus demonstra te functional negative cross-talk between heptahelical AT(2) receptors and receptor tyrosine kinases, and suggest that SHP-1 tyrosine phosph atase is an early transducer of the AT(2) receptor signalling pathway.