The carboxyl-terminal domain of the insulin receptor: its potential role in growth-promoting effects.
The role of the insulin receptor carboxyl-terminal domain in regulation of insulin signal transduction was studied with antipeptide antibodies against the sequence 1321-1338, which contains two autophosphorylation sites, tyrosine 1328 and tyrosine 1334. The antibodies were introduced by electroporation in murine fibroblasts transfected with an expression plasmid encoding the human insulin receptor. We found that introduction of these antipeptides into cells stimulated cellular proliferation, compared to cells loaded with nonimmune Ig. In contrast, neither glucose transport nor amino acid transport was stimulated by the antibodies. Despite its stimulatory effect on cell growth, the injected antipeptide did not enhance phosphorylation of ribosomal protein S6. In vitro, anti-C1 antipeptide stimulated insulin receptor autophosphorylation but did not increase receptor-mediated phosphorylation of the copolymer (glutamate/tyrosine, 4/1), while histone phosphorylation was increased. We interpret our results to mean that perturbation of the receptor C-terminus could lead to phosphorylation of selected substrates, which may be involved in cell growth regulation. Taken together, our data suggest that (i) insulin receptor mediated stimulation of cell growth and stimulation of ribosomal protein S6 phosphorylation result from divergent signaling pathways and (ii) the insulin receptor C-terminal domain exerts an inhibition on the growth signal mediated by the receptor. This inhibition appears to be released upon insulin binding to receptor or by interaction of the antipeptide with the receptor.
Baron
V
V
INSERM U 145, Faculté de Médecine, Nice, France.
Gautier
N
N
Kaliman
P
P
Dolais-Kitabgi
J
J
Van Obberghen
E
E
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002455:Cell Division; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007158:Immunologic Techniques; D066298:In Vitro Techniques; D051379:Mice; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000737:chemistry / Q000502:physiology*; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins / Q000378:metabolism; D015398:Signal Transduction
D000596:Amino Acids; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005947:Glucose