THE ROLE OF TYROSINE PHOSPHORYLATION IN ANGIOTENSIN-II MEDIATED INTRACELLULAR SIGNALING AND CELL-GROWTH

Most cell types, including vascular smooth muscle cells and rat kidney mesangial cells, are controlled mainly by two types of cell surface r eceptors: (a) single membrane-spanning tyrosine kinase receptors for g rowth factors and (b) seven-transmembrane G-protein linked receptors f or vasoactive peptides such as angiotensin II, vasopressin, and endoth elin. These vasoactive peptide hormones also act as growth factors in normal and abnormal cell development. However, in contrast to the grow th factor receptors (e.g., epidermal growth factor receptor and platel et-derived growth factor receptor), the G-protein linked receptors, su ch as the angiotensin II AT(1) receptor, lack cytoplasmic tyrosine kin ase domains. Nevertheless, angiotensin II has recently been demonstrat ed to cause increased tyrosine phosphorylation of numerous proteins in several cellular systems. For example, angiotensin II has been report ed to induce the tyrosine phosphorylation of the gamma-isoform of phos pholipase C, pp120, pp125(FAK), and members of the janus kinase/signal transducer and activator of transcription pathway. Furthermore, angio tensin II seems to modulate the activity of the soluble cytoplasmic ty rosine kinase pp60(c-src), and this tyrosine kinase has been implicate d in the phosphorylation of some of the above proteins. Understanding the biochemistry of tyrosine phosphorylation involved in G-protein cou pled receptors, such as the AT(1) receptor, may therefore lead to the development of new pharmacological interventions important in cardiova scular diseases.