INSULIN AND INSULIN-LIKE GROWTH-FACTOR-I RECEPTORS SIMILARLY STIMULATE DEOXYRIBONUCLEIC-ACID SYNTHESIS DESPITE DIFFERENCES IN CELLULAR PROTEIN-TYROSINE PHOSPHORYLATION

Signal transduction pathways stimulated by insulin or insulin-like gro wth factor-I (IGF-I) were compared in transfected NIH3T3 fibroblast ce ll lines expressing the human insulin receptor, IGF-I receptor, or a c himeric IGF-I receptor with its carboxy-terminal tail replaced with th at of the insulin receptor (-1 X 10(6) receptors/cell). Although recep tor autophosphorylation was very similar in the three cell lines overe xpressing receptors (EC(50) = 1-3 nM), there were differences detected in the protein tyrosine phosphorylation stimulated by insulin and IGF -I in these cells. Although no substrates specific for the insulin rec eptor were detected, phosphorylation of a 170-kilodalton (kDa; IRS1) a nd a 70-kDa protein was 10 times more sensitive to insulin than to IGF -I (EC(50) = 1.5-2.5 us. 14-23 nM). The chimeric receptor stimulated s ignificantly lower levels of phosphorylation of several proteins relat ive to the wild-type IGF-I receptor. Activation of phosphatidylinosito l 3 '-kinase paralleled phosphorylation of the 170- and 70-kDa protein s. Despite these differences in protein tyrosine phosphorylation, stim ulation of mitogen-activated protein (MAP) kinase and DNA synthesis we re very similar in the three cell lines overexpressing receptors. Litt le difference was detected in She phosphorylation or MAP kinase activa tion through the three receptors, although activation of MAP kinase wa s more efficiently coupled to the platelet-derived growth factor recep tor than to any of the overexpressed receptors. All three receptors st imulated DNA synthesis to levels comparable to 10% serum, with similar sensitivities (EC(50) = 1.5-3.5 nM).