Role of the carboxyl-terminal domains of the insulin and insulin-like growth factor I receptors in receptor function.
The insulin and insulin-like growth factor I receptors (IR and IGF-IR, respectively) are heterotetrameric tyrosine kinases consisting of two extracellular ligand-binding alpha subunits and two transmembrane catalytic beta subunits. A number of lines of evidence have suggested that the IR and IGF-IR differ with respect to their ability to elicit mitogenic versus metabolic events upon activation by cognate ligands. To ascertain the contribution of the poorly conserved carboxyl-terminal domains to the differential functioning of the IR and IGF-IR, we have constructed receptor chimeras in which the carboxyl-terminal domain of one receptor was fused to the remainder of the heterologous receptor. The responses of a number of parameters after ligand stimulation were examined in stably transfected NIH-3T3 cells expressing the chimeric receptors or the analogous wild-type receptor sequence. Replacement of the IR carboxyl terminus with that of the IGF-IR severely affected insulin-stimulated responses, whereas substitution of the carboxyl terminus of the IGF-IR with that of the IR had a minimal effect. These data suggest that the carboxyl-terminal domains of the IR and IGF-IR are not interchangeable and that the mitogenic activity of the IR can be influenced by sequences present in the carboxyl-terminal domain. The analogous functions of the IGF-IR, on the other hand, do not appear to be greatly affected by the presence of the IR carboxyl-terminal domain.
Faria
T N
TN
Section on Molecular and Cellular Physiology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892.
Blakesley
V A
VA
Kato
H
H
Stannard
B
B
LeRoith
D
D
Roberts
C T
CT
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010446:Peptide Fragments / Q000502:physiology; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D011972:Receptor, Insulin / Q000378:metabolism / Q000502:physiology*; D013936:Thymidine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D017931:DNA Primers; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D014443:Tyrosine; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D009955:Ornithine Decarboxylase; D005947:Glucose; D013936:Thymidine