Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates
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Cellular and Molecular Life Sciences
REVIEW
Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates Latha Ramalingam • Eunjin Oh • Debbie C. Thurmond
Received: 16 April 2012 / Revised: 21 August 2012 / Accepted: 18 September 2012 / Published online: 10 October 2012 Ó Springer Basel 2012
Abstract The insulin signaling pathway regulates wholebody glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/ longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan.
L. Ramalingam Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA E. Oh Department of Pediatrics, Herman B Wells Center, Indiana University School of Medicine, Indianapolis, IN, USA D. C. Thurmond (&) Departments of Pediatrics, Biochemistry and Molecular Biology, and Cellular and Integrative Physiology, Herman B Wells Center, Indiana University School of Medicine, 635 Barnhill Drive MS 2031, Indianapolis, IN 46202, USA e-mail: [email protected]
Keywords Insulin receptor Skeletal muscle Adipose tissue Insulin signaling Insulin receptor substrate Metabolism Mitogenesis Longevity Abbreviations Akt Protein kinase B aP2 Adipocyte protein 2 APS Adapter protein with pleckstrin homology and Src homology domain Arp2/3 Actin-related protein 2/3 AS160 Akt substrate of 160 kDa BAIRKO Brown adipocyte-specific insulin receptor knockout CAP c-Cbl-associated protein Cav-1 Caveolin-1 Cav-3 Caveolin-3 CHO Chinese hamster ovary cells CIP4 Cdc42-interacting protein CrkII CT10-related kinase Erk1/2 Extracellular signal regulated kinases 1 or 2 FIRKO Fat-specific muscle insulin receptor knockout FOXO Forkhead box protein O-1 Gab-1 Grb2-associated binding protein GIRKI GLUT4-expressing tissues insulin receptor knock-in mouse GIRKO GLUT4-expressing tissues insulin receptor knockout GLUT4 Glucose transporter 4 Grb2 Growth factor receptor bound 2 Grb10 Growth factor receptor bound 10 HR Hybrid receptor IGF Insulin-like growth factor IGFR Insulin-like growth factor receptor IR Insulin receptor IRS-1/2 Insulin receptor substrate-1 or 2
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