TRANSFORMING DOMAINS IN THE IGF-1 RECEPTOR

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We have derived cell lines from mouse embryos homozygous for a targeted disruption of the insulin like growth factor type 1 receptor (IGF-1 R) gene (Lui et al. 1993, Baker et al. 1993). The cell lines from these IGF-1 R knockout mice and from wild type littermates (R- and W respectively) differ in their growth and relative ease of transformation. The R- cells, unlike W cells, do not undergo cell division in serum free medium supplemented with PDGF, EGF, IGF-1, and cannot be transformed by the introduction of the simian virus 40 (SV4O) large T antigen. The R- cells expressing the SV4O T antigen ((tsA)R-) retain the characteristics of normal fibroblasts in serum containing medium. Reintroduction of the wild type IGF-1 R into the tsAR- cells restores the transforming capacity of the SV4O T antigen. Preliminary data indicates that there are distinct signals generated by the IGF-1 R within the cell which are specific for DNA synthesis or proliferation (i.e. entry into mitosis) and that these signals may be separate from those needed for cellular transformation. A truncated IGF-1 R allows R-cells to proliferate in response to IGF-1 but does not allow transformation in (tsA)R- cells. In order to extend these results and to examine divergence of cellular signals at the level of the IGF-1 R we propose to introduce specific mutations in the receptor and to express these mutant receptors in R- and (tsA)R- cells. The ability of these mutant receptors to induce entry into S phase, mitosis and various aspects of transformation; i.e. foci formation, anchorage independent growth, and tumorigenicity, will be determined.