Signal transduction by a chimeric insulin-like growth factor-1 (IGF-1) receptor having the carboxyl-terminal domain of the insulin receptor.
Insulin-like growth factor-1 receptors (IGF-1R) and insulin receptors (IR) are closely related tyrosine kinases. However, the IR plays a major role in metabolism control, whereas the IGF-1R is mainly involved in growth and differentiation. With these observations in mind, we wished to define the regions of IR and IGF-1R responsible for generation of biological specificity. We constructed a chimeric IGF-1R in which the carboxyl-terminal domain was replaced by that of IR. This receptor (IGF/CTIR) was expressed in NIH3T3 cells, and we compared its biological activity with that of wild-type receptors. The IGF/CTIR was fully functional regarding kinase activity and biological properties. Comparison of insulin and IGF-1 effects on IR and IGF-1R cells, respectively, indicated that the IR is more efficient in stimulating glycogen synthesis and p44mapk activity than is the IGF-1R. Interestingly, in IGF/CTIR16 cells expressing only 250,000 receptors glycogen synthesis was better stimulated than in IGF-1R cells with 600,000 receptors. Similarly, p44mapk activation was slightly higher in IGF/CTIR16 cells than in IGF-1R cells. These results suggest that the carboxyl-terminal domain of IR is more tightly coupled to the stimulation of glycogen synthesis and to the p44mapk pathway than is that of IGF-1R. We propose that this domain plays a crucial role in the transmission of biological effects and could account, at least in part, for receptor specificity.
Tartare
S
S
Unité 145, Institut National de la Santé et de la Recherche Médicale, Faculté de Médecine, Nice, France.
Mothe
I
I
Kowalski-Chauvel
A
A
Breittmayer
J P
JP
Ballotti
R
R
Van Obberghen
E
E
D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D003545:Cysteine / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007700:Kinetics; D008715:Methionine / Q000378:metabolism; D051379:Mice; D010957:Plasmids; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000502:physiology*; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D015183:Restriction Mapping; D015398:Signal Transduction; D013462:Sulfur Radioisotopes; D014162:Transfection
D018076:DNA, Complementary; D007328:Insulin; D011993:Recombinant Fusion Proteins; D013462:Sulfur Radioisotopes; D007334:Insulin-Like Growth Factor I; D006003:Glycogen; D008715:Methionine; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005947:Glucose; D003545:Cysteine