Insulin and Insulin-like Growth Factor I Receptors Utilize Different G Protein Signaling Components

Abstract

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 Gαi inhibitor (pertussis toxin) or microinjection of the Gβγ inhibitor (glutathione S-transferase-βARK) inhibited IGF-I and lysophosphatidic acid-stimulated mitogenesis but had no effect on epidermal growth factor (EGF) or insulin action. In basal state, Gαi and Gβ were associated with the IGF-I receptor (IGF-IR), and after ligand stimulation the association of IGF-IR with Gαi increased concomitantly with a decrease in Gβ association. No association of Gαi was found with either the insulin or EGF receptor. Microinjection of anti-β-arrestin-1 antibody specifically inhibited IGF-I mitogenic action but had no effect on EGF or insulin action. β-Arrestin-1 was associated with the receptors for IGF-I, insulin, and EGF in a ligand-dependent manner. We demonstrated that Gαi, βγ subunits, and β-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.