Cell transformation by fibroblast growth factors can be suppressed by truncated 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, truncated fibroblast growth factor (FGF) receptors (FGFR-1 and FGFR-2) to block the FGF response in cells that express both types of endogenous FGF receptors. When these dominant negative receptors are expressed in NIH 3T3 cells transformed by the secreted FGF-4, the transformed properties of the cells can be reverted to various degrees, with better reversion phenotype correlating with higher levels of truncated receptor expression. Furthermore, truncated FGFR-2 is significantly more efficient at producing reversion than FGFR-1, indicating that FGF-4 preferentially utilizes the FGFR-2 signalling pathway. NIH 3T3 clones expressing these truncated receptors are more resistant to FGF-induced mitogenesis and also exhibit reduced tyrosine phosphorylation upon treatment with FGF. The block in FGF-signalling, however, can be overcome by the addition of excess growth factor. The truncated receptors have binding affinities that are four- to eightfold lower than those of wild-type receptors, as measured by Scatchard analysis. We also observed a partial specificity in the responses of truncated-receptor-expressing clones to FGF-2 or FGF-4. Our results suggest that the block to signal transduction produced by kinase-negative FGF receptors is achieved through a combination of dominant negative effects and competition for growth factor binding with functional receptors.
Li
Y
Y
Department of Microbiology and Kaplan Cancer Center, New York University School of Medicine, New York 10016.
Basilico
C
C
Mansukhani
A
A
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D016296:Mutagenesis; D010641:Phenotype; D010766:Phosphorylation; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection
D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors