Insulin and insulin-like growth factor I receptors utilize different G protein signaling components.
We examined the role of heterotrimeric G protein signaling components in insulin and insulin-like growth factor I (IGF-I) action. In HIRcB cells and in 3T3L1 adipocytes, treatment with the Galpha(i) inhibitor (pertussis toxin) or microinjection of the Gbetagamma inhibitor (glutathione S-transferase-betaARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogenesis but had no effect on epidermal growth factor (EGF) or insulin action. In basal state, Galpha(i) and Gbeta were associated with the IGF-I receptor (IGF-IR), and after ligand stimulation the association of IGF-IR with Galpha(i) increased concomitantly with a decrease in Gbeta association. No association of Galpha(i) was found with either the insulin or EGF receptor. Microinjection of anti-beta-arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. beta-Arrestin-1 was associated with the receptors for IGF-I, insulin, and EGF in a ligand-dependent manner. We demonstrated that Galpha(i), betagamma subunits, and beta-arrestin-1 all play a critical role in IGF-I mitogenic signaling. In contrast, neither metabolic, such as GLUT4 translocation, nor mitogenic signaling by insulin is dependent on these protein components. These results suggest that insulin receptors and IGF-IRs can function as G protein-coupled receptors and engage different G protein partners for downstream signaling.
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093-0673, USA.
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S
Dalle
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Ricketts
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Imamura
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Vollenweider
J M
JM
Olefsky
D016475:3T3 Cells; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts; D005982:Glutathione Transferase / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D037342:Pertussis Toxin; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000187:drug effects / Q000502:physiology*; D011972:Receptor, Insulin / Q000187:drug effects / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D051552:beta-Adrenergic Receptor Kinases; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D000906:Antibodies; C000605255:Arrb1 protein, mouse; C000605256:Arrb1 protein, rat; D019390:Arrestins; D007328:Insulin; D011993:Recombinant Fusion Proteins; D010566:Virulence Factors, Bordetella; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D007334:Insulin-Like Growth Factor I; D037342:Pertussis Toxin; D005982:Glutathione Transferase; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D020962:Heterotrimeric GTP-Binding Proteins