|Ph.D Student||Eid Mutlak Yara|
|Subject||Novel Signaling Hub of Insulin Receptor, Dystrophin|
Glycoprotein Complex and Plakoglobin Regulates
|Department||Department of Biology||Supervisor||Professor Shenhav Cohen|
|Full Thesis text|
Skeletal muscle atrophy occurs during fasting, inactivity, naturally with aging, and in many human diseases including diabetes and cancer. During atrophy, there is a major loss of muscle mass and strength, primarily due to the accelerated destruction of the muscle’s contractile machinery, the myofibrils, by the proteasome. Signaling through the insulin receptor reduces protein breakdown and blocks atrophy. We previously demonstrated that plakoglobin, a component of cardiac desmosomes, is present in skeletal muscle and plays a critical role in maintenance of muscle mass by interacting with PI3K and the insulin receptor and inducing PI3K/Akt signaling. 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.