ATM and GLUT1-S490 phosphorylation regulate GLUT1 mediated transport in skeletal muscle

• Published in: PloS one 2013-06, Vol.8 (6), p.e66027-e66027
• Main Authors: Andrisse, Stanley, Patel, Gaytri D, Chen, Joseph E, Webber, Andrea M, Spears, Larry D, Koehler, Rikki M, Robinson-Hill, Rona M, Ching, James K, Jeong, Imju, Fisher, Jonathan S
• Format: Article
• Language: English
• Subjects: Activation; Adaptor Proteins, Signal Transducing - metabolism; Animals; Ataxia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Biology; C-Terminus; Cell Line; Cell surface; Design for recycling; Doxorubicin; Glucose; Glucose transport; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Immunoprecipitation; In Vitro Techniques; Inhibition; Insulin resistance; Kinases; Localization; Medicine; Mice; Muscle, Skeletal - metabolism; Muscles; Mutation; Myoblasts; Phosphorylation; Phosphorylation - genetics; Phosphorylation - physiology; Protein Binding; Protein Transport - genetics; Protein Transport - physiology; Proteins; Rats; Research design; Rodents; Skeletal muscle; Type 2 diabetes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0066027

The glucose and dehydroascorbic acid (DHA) transporter GLUT1 contains a phosphorylation site, S490, for ataxia telangiectasia mutated (ATM). The objective of this study was to determine whether ATM and GLUT1-S490 regulate GLUT1. L6 myoblasts and mouse skeletal muscles were used to study the effects of ATM inhibition, ATM activation, and S490 mutation on GLUT1 localization, trafficking, and transport activity. In myoblasts, inhibition of ATM significantly diminished cell surface GLUT1, glucose and DHA transport, GLUT1 externalization, and association of GLUT1 with Gα-interacting protein-interacting protein, C-terminus (GIPC1), which has been implicated in recycling of endosomal proteins. In contrast, ATM activation by doxorubicin (DXR) increased DHA transport, cell surface GLUT1, and the GLUT1/GIPC1 association. S490A mutation decreased glucose and DHA transport, cell surface GLUT1, and interaction of GLUT1 with GIPC1, while S490D mutation increased transport, cell surface GLUT1, and the GLUT1/GIPC1 interaction. ATM dysfunction or ATM inhibition reduced DHA transport in extensor digitorum longus (EDL) muscles and decreased glucose transport in EDL and soleus. In contrast, DXR increased DHA transport in EDL. These results provide evidence that ATM and GLUT1-S490 promote cell surface GLUT1 and GLUT1-mediated transport in skeletal muscle associated with upregulation of the GLUT1/GIPC1 interaction.