We have been isolating and analyzing NRK cell mutants, which fail to transform by epidermal growth factor (EGF) and transforming growth factor (TGF)-β. One such mutant, R14, can respond to the growth inhibitory signal of TGF-β to the same extent as parental NRK but fail to respond to the growth stimulatory signal of EGF. This mutant has a defect in EGF receptor (EGFR) expression. When R14 mutant expressed a high level of EGFR, however, EGF not only induced proliferation in this mutant but also induced transformation without the aid of TGF-β. These findings suggest that the major role of TGF-β in this transformation system should be to counteract the ligand-dependent down-regulation of EGFR, thereby sustaining high-level EGF-signaling.
