The cellular effects of angiotensin II are mediated by a seven transmembrane receptor called AT1. We have found that AT1 receptor signaling stimulates three important signalling pathways via tyrosine (Y) phosphorylation. In rat vascular smooth muscle and renal mesangial cells, ang II stimulated the rapid Y phosphorylation of PLC-yl. The time course of phosphorylation was coincident with the time course of 1,4,5-IP3 generation. Inhibitors of Y kinases blocked both ang II mediated production of 1,4,5-IP3 and the release of intracellular Ca2+, This was not a toxic effect as shown by thapsigargin release of Ca2+. When smooth muscle cells were electroporated with anti-Src antibody, the ang H-mediated Y phosphorylation of PLC-γ1 was blocked and 1,4,5-IP3 production was markedly diminished. Ang II directly stimulated Src as measured by autophosphorylation. In smooth muscle cells ang II stimulates Ras-GTP production, the formation of a coprecipitable Ras-Rafl complex, and Y phosphorylation of GAPs. The electroporation of anti-Src antibody blocked these manifestations of Ras pathway activation. Ang II also stimulates Jak2 Y phosphorylation and activation. This leads to Stall phosphorylation and translocation to the nucleus. Our studies underline the importance of Y phosphorylation in the signaling of a seven transmembrane receptor. Src appears to play an important role in these signaling pathways.
|Original language||English (US)|
|State||Published - Dec 1 1996|
ASJC Scopus subject areas
- Molecular Biology