Recent evidence has shown that the insulin-like growth factor I (IGF-I) receptor plays a major role in the establishment and maintenance of transformation. To identify domains in the IGF-I receptor that are necessary for transformation, the tyrosine at residue 950 of the human IGF-I receptor cDNA was mutated to phenylalanine, and the plasmid expressing the mutant receptor was stably transfected into R- cells, which are mouse embryo fibroblasts with a targeted disruption of the type 1 receptor for the insulin-like growth factors. At variance with the wild-type receptor, the Y950 mutant receptor has lost its ability to transmit an IGF-I-mediated mitogenic signal or to transform R- cells. These experiments show, for the first time, that tyrosine 950 of the IGF-I receptor is necessary for its mitogenic and transforming activities.