Evidence for a regulatory role of Cullin-RING E3 ubiquitin ligase 7 in insulin signaling |
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| Institution: | 1. Institute of Pharmacology and Toxicology, Technische Universität München, Biedersteiner Straße 29, 80802 Munich, Germany;2. German Institute of Human Nutrition Potsdam-Rehbrücke, Department of Clinical Nutrition, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany;3. Walther-Straub-Institute of Pharmacology and Toxicology, Ludwig-Maximilians-University, Goethestraße 33, 80336 Munich, Germany;4. Department of Endocrinology, Diabetes and Nutrition, Charité University Medicine, 10117 Berlin, Germany;5. Krannert Institute of Cardiology, University of Indiana, Indianapolis, IN 46202, USA;6. Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA;7. Department of Medicine (Endocrinology), Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA;8. Department of Obstetrics & Gynecology and Women''s Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA;9. Mount Sinai School of Medicine, Icahn Medical Institute, Department of Oncological Sciences, 1425 Madison Avenue, New York, NY 10029, USA;10. DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, 80802 Munich, Germany;2. Clinical Nutrition and Food Service, Higashi-Sumiyoshi Morimoto Hospital, Osaka, Japan;3. Clinical Nutrition and Food Service, Kokuho Central Hospital, Shiki, Japan;4. Department of Neurosurgery, Osaka Medical College, Takatsuki, Japan |
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| Abstract: | Dysfunctional regulation of signaling pathways downstream of the insulin receptor plays a pivotal role in the pathogenesis of insulin resistance and type 2 diabetes. In this study we report both in vitro and in vivo experimental evidence for a role of Cullin-RING E3 ubiquitin ligase 7 (CRL7) in the regulation of insulin signaling and glucose homeostasis. We show that Cul7?/? mouse embryonic fibroblasts displayed enhanced AKT and Erk MAP kinase phosphorylation upon insulin stimulation. Depletion of CUL7 by RNA interference in C2C12 myotubes led to increased activation of insulin signaling pathways and cellular glucose uptake, as well as a reduced capacity of these cells to execute insulin-induced degradation of insulin receptor substrate 1 (IRS1). In vivo, heterozygosity of either Cul7 or Fbxw8, both key components of CRL7, resulted in elevated PI3 kinase/AKT activation in skeletal muscle tissue upon insulin stimulation when compared to wild-type controls. Finally, Cul7+/? or Fbxw8+/? mice exhibited enhanced insulin sensitivity and plasma glucose clearance. Collectively, our findings point to a yet unrecognized role of CRL7 in insulin-mediated control of glucose homeostasis by restraining PI3 kinase/AKT activities in skeletal muscle cells. |
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