THE IMPORTANCE OF TYROSINE PHOSPHORYLATION IN ANGIOTENSIN-II SIGNALING

Angiotensin II plays a critical rob in the regulation of vascular resi stance and intravascular volume. Virtually all of the physiologic effe cts of angiotensin II are mediated by the AT, receptor a seven-transme mbrane spanning receptor Although G proteins play an important rob in the signaling of this class of receptors, it has become increasingly c lear that tyrosine phosphorylation is also intimately involved in AT(1 ) receptor signaling. In response to angiotensin II, both smooth muscI e and glomerular mesangial cells tyrosine phosphorylate the gamma isof orm of phospholipase C. This is critical to downstream signaling event s, including the intracellular generation of 1,4,5-inositol triphospha te. The soluble cytoplasmic kinase Svc appears to be activated by angi otensin II and to play an important rob in the phosphorylation of phos pholipase C. Angiotensin II, acting through the AT(1) receptor causes Jak kinase phosphorylation and activation. This, in turn, bads to STAT phosphorylation and translocation to the nucleus. Finally, we present data that indicate that angiotensin II activates Ras and bads to Ras- Raf-1 complex formation. Activation of this pathway also appears to re quire active Src. These studies provide compelling evidence that tyros ine phosphorylation plays an important rob in the signaling of angiote nsin II. The exact biochemical mechanism by which a severe-transmembra ne receptor stimulates intracellular kinases to be elucidated.