PLC beta 1-SHP-2 complex, PLC beta 1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling?

Abstract: Background: Angiotensin II (Ang II) signaling occurs via two major receptors which activate non-receptor tyrosin kinases that then interact with protein tyrosin-phosphatases (PTPs) to regulate cell function. SHP-2 is one such important PTP that also functions as an adaptor to promote downstream signaling pathway. Its role in Ang II signaling remains to be clarified. Results: Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLC beta 1 are present as a preformed complex. Complex PLC beta 1 is tyr-phosphorylated basally and Ang II increased SHP-2-PLC beta 1 complexes and caused complex associated PLC beta 1 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 PLC beta 1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2. Conclusions: Ang II signals are shown for the first time to involve a preformed SHP-2-PLC beta 1 complex. Changes in the complex's PLC beta 1 tyr-phosphorylation and SHP-2's tyr-phosphorylation as well as SHP-2-PLC beta 1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLC beta 1 tyrphosphorylation 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.