Cross-Talk Between Angiotensin Ii Receptors And The Tyrosine Kinases And Phosphatases

In addition to its well known involvement in G(q/11)-mediated vasoconstriction and its key roles in the homeostasis of electrolyte balances, the angiotensin II type 1 (AT(1)) receptor activates mitogen-activated protein kinase (MAPK) and p42/44 extracellular signal-regulated kinase. The extracellular signal regulated kinase activation is mediated by activation of p21-Ras, Raf-1, and MAPK kinase in rat vascular smooth muscle cells. The mechanism for G(q)-mediated activation of the tyrosine kinase pathways has not been clear. It was found that the initial release of intracellular Ca2+ results in the activation of the epidermal growth factor receptor (EGF-R), without autocrine release of epidermal growth factor. ECF-R provides a scaffold needed for the activation of p21-Ras, which leads to the activation of MAPK. MAPK plays pivotal roles in the activation of complex growth-promoting pathways. The pathway from the EGF-R involves protein tyrosine phosphorylation initiated by AT(1) receptors. On the other hand, the angiotensin II type 2 (AT(2)) receptor counteracts the AT(1) receptor-mediated tyrosine kinase activation by activating several tyrosine phosphatases and serine/threonine phosphatases, and it suppresses the cell growth process stimulated by various growth factors. The relative importance of AT(1) and AT(2) receptor actions depends on the levels of AT(1) and AT(2) receptor expression.