Gα_i2 Enhances Insulin Signaling via Suppression of Protein-tyrosine Phosphatase 1B

Suppression of the expression of the heterotrimeric G-protein Gα _i2 in vivo has been shown to provoke insulin resistance, whereas enhanced insulin signaling is observed when Gα_i2 is overexpressed in vivo. The basis for Gα_i2 regulation of insulin signaling was explored in transgenic mice with targeted expression of the GTPase-deficient, constitutively active Q205L Gα_i2 in fat and skeletal muscle. Phosphorylation of insulin receptor and IRS-1 in response to insulin challenge in vivo was markedly amplified in fat and skeletal muscle expressing Q205L Gα_i2. The expression and activity of the protein-tyrosine phosphatase 1B (PTP1B), but not protein-tyrosine phosphatases SHP-1, SHP-2, and LAR, were constitutively decreased in tissues expressing the Q205L Gα_i2, providing a direct linkage between insulin signaling and Gα_i2. The loss of PTP1B expression may explain, in part, the loss of PTP1B activity in the iQ205L transgenic mice. Activation of Gα_i2 in mouse adipocytes with lysophosphatidic acid was shown to decrease PTP1B activity, whereas pertussis toxin inactivates Gα_i2, blocks lysophosphatidic acid-stimulated inhibition of PTP1B activity, and blocks tonic suppression of PTP1B activity by Gα _i2. Elevation of intracellular cAMP in fat cells is shown to increase PTP1B activity, whereas either depression of cAMP levels or direct activation of Gα_i2 suppresses PTP1B. These data provide the first molecular basis for the interplay between Gα_i2 and insulin signaling, i.e. activation of Gα_i2 can suppress both the expression and activity of PTP1B in insulin-sensitive tissues.