ABSTRACT
Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (γ-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin because DGC-insulin receptor dissociation by plakoglobin downregulation reduced insulin signaling and caused atrophy. Furthermore, impaired insulin receptor function in muscles from diabetic mice reduced plakoglobin-DGC-insulin receptor content on the plasma membrane; however, plakoglobin overexpression alone restored DGC association with the insulin receptor, and stimulated glucose uptake. Our findings establish DGC as a signaling hub, containing plakoglobin as an auxiliary subunit, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.