CAAX PEPTIDOMIMETIC FTI-244 DECREASES PLATELET-DERIVED GROWTH-FACTOR RECEPTOR TYROSINE PHOSPHORYLATION LEVELS AND INHIBITS STIMULATION OF PHOSPHATIDYLINOSITOL 3-KINASE BUT NOT MITOGEN-ACTIVATED PROTEIN-KINASE

Cysteine farnesylation of the Pas carboxyl terminal tetrapeptide CAAX motif (where C=cysteine, A=leucine, isoleucine, or valine, and X=methi onine or serine) is required for Ras biological activity. In this repo rt, we describe the effects of inhibitors of farnesyltransferase (FTas e), the enzyme responsible for this lipid modification, on platelet-de rived growth factor (PDGF) signaling in NIH-3T3 cells. In vitro, the C AAX peptidomimetic FTI-232 exhibits potent inhibition of FTase activit y (IC50 = 150 nM) and its carboxyl-methylated counterpart, FTI-244, in hibits Pas processing in vivo. Treatment of NIH-3T3 cells with FTI-244 inhibits PDGF-induced DNA synthesis but not stimulation of mitogen-ac tivated protein kinase (MAPK). However, FTI-244 significantly reduces PDGF-induced tyrosine phosphorylation levels of PDGF receptor (PDGFR) as well as its association with, and activation of, phosphatidylinosit ol-3-kinase (PI-3-K), a key enzyme in PDGF-induced mitogenesis. (C) 19 95 Academic Press, Inc.