POINT MUTATION OF AN FGF RECEPTOR ABOLISHES PHOSPHATIDYLINOSITOL TURNOVER AND CA2+ FLUX BUT NOT MITOGENESIS

STIMULATION of certain receptor tyrosine kinases results in the tyrosine phosphorylation and activation of phospholipase C(gamma)(PLC-gamma), an enzyme that catalyses the hydrolysis of phosphatidylinositol ( PtdIns)1-8. This hydrolysis generates diacylglycerol and free inositol phosphate, which in turn activate protein kinase C and increase intracellular Ca2+, respectively. PLC-gamma physically associates with activated receptor tyrosine kinases, suggesting that it is a substrate for direct phosphorylation by these kinases7-10. Here we report that a fibroblast growth factor (FGF) receptor with a single point mutation at residue 766 replacing tyrosine with phenylalanine fails to associate with PLC-gamma in response to FGF. This mutant receptor also failed to mediate PtdIns hydrolysis and Ca2+ mobilization after FGF stimulation. However, the mutant receptor phosphorylated itself and several other cellular proteins, and it mediated mitogenesis in response to FGF. These findings show that a point mutation in the FGF receptor selectively eliminates activation of PLC-gamma and that neither Ca2+ mobilization nor PtdIns hydrolysis are required for FGF-induced mitogenesis.