The insulin-like growth factor I receptor (IGF-IR) controls the extent of cell proliferation in a variety of cell types by at least 3 different ways: it is mitogenic, it causes transformation, and it protects cells from apoptosis. Previous reports indicated that certain domains in the C terminus of the IGF-IR transmitted a transforming signal that is additional to and separate from the mitogenic signal. We have now mutated the four serine residues at 1280-1283 of the IGF-IR, and transfected the mutant receptor into R cells. Cells expressing the mutant receptor are fully responsive to IGF-I-mediated mitogenesis, but are not transformed (no colony formation in soft agar). Several downstream signal transducers are not affected by the mutation, again suggesting a separate pathway for transformation. The mutant receptor can act as a dominant negative for growth, but cannot induce apoptosis in cells with endogenous wild-type receptors.

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