ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells

Marie Jo Halaby, Jody C. Hibma, Jinghua He, Da Qing Yang

Research output: Contribution to journalArticlepeer-review

102 Scopus citations

Abstract

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia and oculocutaneous telangiectasias. Patients with A-T also have high incidences of type 2 diabetes mellitus. The gene mutated in this disease, ATM (A-T, mutated), encodes a protein kinase. Previous studies have demonstrated that cytoplasmic ATM is an insulin-responsive protein and a major upstream activator of Akt following insulin treatment. To further investigate the function of ATM in insulin signal transduction, insulin resistance was induced in rats by feeding them a high-fat diet. Muscle tissue of rats with insulin resistance had both dramatically reduced ATM levels and substantially decreased Akt phosphorylation at Ser473 in comparison to that of regular chow-fed controls. The decreased ATM expression suggests that ATM is involved in the development of insulin resistance through down-regulation of Akt activity. The role of ATM in activation of Akt was further confirmed in mouse embryonic fibroblast (MEF) A29 (ATM+/+) and A38 (ATM-/-) cells. In addition, insulin-mediated Akt phosphorylation in mouse L6 muscle cells was greatly reduced by KU-55933, a specific inhibitor of ATM. A 2-deoxyglucose incorporation assay showed that this inhibitor also caused a significant reduction in insulin-mediated glucose uptake in L6 cells. An immunofluorescence experiment demonstrated that in L6 cells transfected with wild-type (WT) ATM, insulin caused a dramatic increase of the cell surface glucose transporter 4 (GLUT4), while in cells transfected with kinase-dead (KD) ATM, translocation of GLUT4 to the cell surface in response to insulin was markedly inhibited.

Original languageEnglish (US)
Pages (from-to)1555-1563
Number of pages9
JournalCellular Signalling
Volume20
Issue number8
DOIs
StatePublished - Aug 2008

Bibliographical note

Funding Information:
We are grateful to Dr. Amira Klip (The Hospital for Sick Children, Toronto) for her kindness in providing us with the GLUT4myc plasmid and L6 muscle cells, as well as detailed experimental protocols for our GLUT4-related experiments. We are also grateful to Dr. Graeme Smith (KuDos Pharmaceuticals) for providing us with the ATM inhibitor KU-55933. We would also like to thank Dr. Doug Martin and Dr. Keith Miskimins (University of South Dakota) for their critical reading of this manuscript and Dr. Rabelais Tatchum-Talom (University of South Dakota) for his technical assistance. In addition, we thank Dr. Evelyn Schlenker (University of South Dakota) for her help with the statistical analysis of the results. This project is supported by an Innovation Award received by DQ Yang from the American Diabetes Association.

Keywords

  • ATM protein kinase
  • Akt
  • Glucose uptake
  • Insulin resistance
  • Insulin signaling
  • Muscle

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