RT Journal Article
SR Electronic
T1 Novel signaling hub of insulin receptor, dystrophin glycoprotein complex and plakoglobin regulates muscle size
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 517789
DO 10.1101/517789
A1 Yara Eid Mutlak
A1 Dina Aweida
A1 Alexandra Volodin
A1 Bar Ayalon
A1 Nitsan Dahan
A1 Anna Parnis
A1 Shenhav Cohen
YR 2019
UL http://biorxiv.org/content/early/2019/01/13/517789.abstract
AB 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.