Structure-function relationship of the insulin-like growth factor-I receptor tyrosine kinase.
Insulin-like growth factor I (IGF-I) and insulin receptors are structurally similar with ligand-stimulated tyrosine kinase activity in their cytoplasmic domains. The function of the insulin receptor tyrosine kinase in signal transduction has been studied extensively in contrast to the IGF-I receptor tyrosine kinase. In the present study we have analyzed the regulatory function of the IGF-I receptor tyrosine kinase and carboxyl-terminal domains in mitogenic signaling by overexpression of mutant IGF-I receptors in mouse NIH-3T3 fibroblasts. A mutant IGF-I receptor, in which 3 tyrosines (Tyr1131, Tyr1135, and Tyr1136) analogous to the three major autophosphorylation sites in the insulin receptor kinase were replaced by phenylalanines, was devoid of kinase activity in vivo and in vitro and inactive with respect to IGF-I internalization and stimulation of thymidine incorporation. Another mutant IGF-I receptor, which lacks the 49 carboxyl-terminal amino acids (residues 1289-1337) of the beta-subunit, was fully active. Our data suggest that the structure-function relationship of the IGF-I receptor tyrosine kinase activation and signal transduction is similar to that of the insulin receptor.
Grønborg
M
M
Department of Clinical Chemistry, Bispebjerg Hospital, Copenhagen, Denmark.
Wulff
B S
BS
Rasmussen
J S
JS
Kjeldsen
T
T
Gammeltoft
S
S
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002453:Cell Cycle; D006801:Humans; D066298:In Vitro Techniques; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009838:Oligodeoxyribonucleotides / Q000737:chemistry; D010766:Phosphorylation; D019000:Phosphotyrosine; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000737:chemistry
D009838:Oligodeoxyribonucleotides; D011994:Recombinant Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D020794:Receptor Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1