PLCβ1-SHP-2 complex, PLCβ1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling?

Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLCβ1 are present as a preformed complex. Complex PLCβ1 is tyr-phosphorylated basally and Ang II increased SHP-2-PLCβ1 complexes and caused complex associated PLCβ1 tyr-phosphorylation to decline while complex associated SHP-2's tyr-phosphorylation increased and did so via the Ang II type 1 receptors as shown by Ang II type 1 receptor blocker losartan's effects. Moreover, Ang II induced both increased complex phosphatase activity and decreased complex associated PLCβ1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2.Ang II signals are shown for the first time to involve a preformed SHP-2-PLCβ1 complex. Changes in the complex's PLCβ1 tyr-phosphorylation and SHP-2's tyr-phosphorylation as well as SHP-2-PLCβ1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLCβ1 tyr-phosphorylation requiring RGS-2. These findings might significantly expand the number and complexity of Ang II signaling pathways. Further studies are needed to delineate the role/s of this complex in the Ang II signaling system.Angiotensin II (Ang II) is a major regulator of a broad spectrum of important biological processes ranging from vasoconstriction to inflammatory processes including atherosclerosis and vascular ageing, which proceeds, in part, via phosphoinositide-specific phospholipase C (PLC) generated second messengers [1-4]. Ang II type 1 receptors couple first to PLCβ1 via Gαq/11βγ and Gαq/12 βγ and then to PLCγ via tyrosine kinase activity [5]. Ang II also induces phosphorylation of growth signaling kinases by redox-sensitive regulation of protein tyrosine phosphatases (PTPs) [6] via oxidation/inactivation and blunted phosphorylation of the PTP, SHP-2. Ali et al [7] demonstrated that Ang II induces SHP-2 tyrosine phosphorylation and activation of its phosphatase activity. In a