ATM protein kinase mediates full activation of Akt and regulates glucose transporter 4 translocation by insulin in muscle cells.
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.
Halaby
Marie-Jo
MJ
Division of Basic Biomedical Sciences, University of South Dakota, Sanford School of Medicine, Vermillion, South Dakota 57069, USA.
Hibma
Jody C
JC
He
Jinghua
J
Yang
Da-Qing
DQ
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt