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 factor I (IGF-I) receptors play an essential role in signal transduction. After ligand binding, these receptors undergo autophosphorylation, with 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 the catalytic domain blocks essentially all of the functions of these receptors. Using stably transfected NIH-3T3 cell lines, we studied the effect of a mutation of tyrosine 1131 of the triple tyrosine cluster of the IGF-I receptor to phenylalanine. This mutation significantly reduced IGF-I-induced beta-subunit autophosphorylation, whereas phosphorylation of the endogenous substrate IRS-1 was unaffected. Despite the reduction in autophosphorylation and receptor internalization, IGF-I-induced thymidine incorporation and cellular proliferation were unaffected. Thus, the extent of receptor autophosphorylation and internalization does not appear to be a limiting factor for IGF-I-stimulated mitogenesis.
Stannard
B
B
Section on Molecular and Cellular Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Blakesley
V
V
Kato
H
H
Roberts
C T
CT
LeRoith
D
D
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002455:Cell Division / Q000502:physiology*; D004247:DNA / Q000096:biosynthesis; D051379:Mice; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010649:Phenylalanine; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D014443:Tyrosine; D010649:Phenylalanine; D000255:Adenosine Triphosphate; D004247:DNA; D017526:Receptor, IGF Type 1