PLATELET-DERIVED GROWTH-FACTOR TYROSINE KINASE RECEPTOR-MEDIATED PROLIFERATION

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse f ibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-recepto rs results in receptor dimerization and subsequent activation of tyros ine kinase activity in the cytoplasmic protein domain, autophosphoryla tion of the receptor being the first event in the transduction cascade . Before the ligand-receptor complex is internalized and degraded, rec eptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphory lation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentrat ion of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited b y the PDGF-receptor association are phosphatidylinositol-3'-kinase, ra s-GTPase-activating protein, phospholipase C-gamma, serine-threonine k inase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear f actors such as c-fos and c-myc genes and dephosphorylation of c-jun oc curs. V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studi ed as a model system for the autocrine stimulation of the PDGF recepto r.