AN EPIDERMAL GROWTH-FACTOR RECEPTOR RET CHIMERA GENERATES MITOGENIC AND TRANSFORMING SIGNALS - EVIDENCE FOR A RET-SPECIFIC SIGNALING PATHWAY

A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) recepto r (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chim era) was generated. Upon ectopic expression in mammalian cells, the EG FR/ret chimera was correctly synthesized and transported to the cell s urface, where it was shown capable of binding EGF and transducing an E GF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative anal ysis of the growth-promoting activity of the EGFR/ret chimera expresse d in fibroblastic or hematopoietic cells revealed a biological phenoty pe clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transducti on of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitog enic signaling.