CELL-TRANSFORMATION BY FIBROBLAST GROWTH-FACTORS CAN BE SUPPRESSED BYTRUNCATED FIBROBLAST GROWTH-FACTOR RECEPTORS

Ligand-induced dimerization and transphosphorylation are thought to be important events by which receptor tyrosine kinases generate cellular signals. We have investigated the ability of signalling-defective, tr uncated fibroblast growth factor (FGF) receptors (FGFR-1 and FGFR-2) t o block the FGF response in cells that express both types of endogenou s FGF receptors. When these dominant negative receptors are expressed in NIH 3T3 cells transformed by the secreted FGF-4 the transformed pro perties of the cells can be reverted to various degrees, with better r eversion phenotype correlating with higher levels of truncated recepto r expression. Furthermore, truncated FGFR-2 is significantly more effi cient at producing reversion than FGFR-1, indicating that FGF-4 prefer entially utilizes the FGFR-2 signalling pathway. NIH 3T3 clones expres sing these truncated receptors are more resistant to FGF-induced mitog enesis and also exhibit reduced tyrosine phosphorylation upon treatmen t with FGF. The block in FGF-signalling, however, can be overcome by t he addition of excess growth factor. The truncated receptors have bind ing affinities that are four- to eightfold lower than those of wild-ty pe receptors, as measured by Scatchard analysis. We also observed a pa rtial specificity in the responses of truncated-receptor-expressing cl ones to FGF-2 or FGF-4. Our results suggest that the block to signal t ransduction produced by kinase-negative FGF receptors is achieved thro ugh a combination of dominant negative effects and competition for gro wth factor binding with functional receptors.