TRANSFORMING POTENTIAL OF THE INSULIN-RECEPTOR SUBSTRATE-1

The role of the insulin receptor substrate 1 (IRS-1) in cellular trans formation was studied in R- cells, which are 3T3-like fibroblasts deri ved from mouse embryos with a targeted disruption of the insulin-like growth factor I receptor gene. These cells cannot be transformed by on cogenes that readily transform cells originating from wild-type litter mate embryos (or other 3T3-like cells). In the present study, we demon strate that in R- cells, the overexpression of the functional IRS-1 pr otein was sufficient to induce a mitogenic response to insulin but did not promote transformation, as measured by colony formation in soft a gar. The coexpression of IRS-1 and the SV40 T antigen, however, induce d transformation. Conversely, expression of an antisense IRS-1 RNA rev ersed the transformed phenotype in wildtype cells carrying the T antig en. Since the type 1 insulin-like growth factor receptor, by itself, i s fully transforming, we propose the hypothesis that the transforming competence of this receptor is based on at least two signaling pathway s, one of which is IRS-1-dependent, whereas the other(s) can be substi tuted with the SV40 T antigen.