SINGLE TYROSINE SUBSTITUTION IN THE INSULIN-LIKE GROWTH-FACTOR-I RECEPTOR INHIBITS LIGAND-INDUCED RECEPTOR AUTOPHOSPHORYLATION AND INTERNALIZATION, BUT NOT MITOGENESIS

The tyrosine kinase domains of the insulin and insulin-like growth fac tor I (IGF-I) receptors play an essential role in signal transduction. After ligand binding, these receptors undergo autophosphorylation, wi th a cluster of three tyrosines (residues 1131, 1135, and 1136 in the IGF-I receptor) being the first to be phosphorylated. Mutation of the ATP-binding site or substitution of this triple tyrosine cluster in th e catalytic domain blocks essentially all of the functions of these re ceptors. Using stably transfected NIH-3T3 cell lines, we studied the e ffect of a mutation of tyrosine 1131 of the triple tyrosine cluster of the IGF-I receptor to phenylalanine. This mutation significantly redu ced IGF-I-induced beta-subunit autophosphorylation, whereas phosphoryl ation of the endogenous substrate IRS-1 was unaffected. Despite the re duction in autophosphorylation and receptor internalization, IGF-I-ind uced thymidine incorporation and cellular proliferation were unaffecte d. Thus, the extent of receptor autophosphorylation and internalizatio n does not appear to be a limiting factor for IGF-I-stimulated mitogen esis.