Essential role of tyrosine residues 1131, 1135, and 1136 of the insulin-like growth factor-I (IGF-I) receptor in IGF-I action.
The insulin and insulin-like growth factor-I (IGF-I) receptors are related heterotetramers consisting of two extracellular ligand-binding alpha-subunits and two transmembrane beta-subunits whose cytoplasmic domains exhibit tyrosine kinase activity. Previous studies have shown that ATP binding by the cytoplasmic tyrosine kinase domains of these receptors is necessary to initiate the signal transduction pathway triggered by ligands or by ligand-mimetic antibodies, suggesting that receptor autophosphorylation is a necessary proximal step in this pathway. In the case of the insulin receptor, it has additionally been demonstrated that a cluster of three tyrosines in the kinase domain itself are the first to be phosphorylated, and that autophosphorylation of these particular residues is necessary for receptor activity. Using stably transfected NIH-3T3 cell lines, we now show that mutation of the analogous residues in the IGF-I receptor abolishes all short, intermediate, and long-term responses to IGF-I. These data suggest that the initial mechanisms of activation of the insulin and IGF-I receptors are very similar. Additionally, we have identified two parameters, induction of c-fos gene expression and ornithine decarboxylase enzyme activity, which are extremely sensitive to IGF-I stimulation and which will be particularly useful in evaluating the biological activity of other mutated versions of the IGF-I receptor.
Kato
H
H
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Faria
T N
TN
Stannard
B
B
Roberts
C T
CT
LeRoith
D
D
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D020690:GTPase-Activating Proteins; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009955:Ornithine Decarboxylase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D019000:Phosphotyrosine; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D020690:GTPase-Activating Proteins; D011506:Proteins; D012333:RNA, Messenger; D019000:Phosphotyrosine; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017526:Receptor, IGF Type 1; D009955:Ornithine Decarboxylase; D005947:Glucose