STRUCTURE-FUNCTION RELATIONSHIP OF THE INSULIN-LIKE GROWTH FACTOR-I RECEPTOR TYROSINE KINASE

Insulin-like growth factor I (IGF-1) and insulin receptors are structu rally similar with ligand-stimulated tyrosine kinase activity in their cytoplasmic domains. The function of the insulin receptor tyrosine ki nase in signal transduction has been studied extensively in contrast t o the IGF-I receptor tyrosine kinase. In the present study we have ana lyzed the regulatory function of the IGF-I receptor tyrosine kinase an d carboxyl-terminal domains in mitogenic signaling by overexpression o f mutant IGF-I receptors in mouse NIH-3T3 fibroblasts. A mutant IGF-I receptor, in which 3 tyrosines (Tyr1131, Tyr1135, and Tyr1136) analogo us to the three major autophosphorylation sites in the insulin recepto r kinase were replaced by phenylalanines, was devoid of kinase activit y in vivo and in vitro and inactive with respect to IGF-I internalizat ion and stimulation of thymidine incorporation. Another mutant IGF-I r eceptor, which lacks the 49 carboxyl-terminal amino acids (residues 12 89-1337) of the beta-subunit, was fully active. Our data suggest that the structure-function relationship of the IGF-I receptor tyrosine kin ase activation and signal transduction is similar to that of the insul in receptor.