The browser you are using is not supported by this website. All versions of Internet Explorer are no longer supported, either by us or Microsoft (read more here: https://www.microsoft.com/en-us/microsoft-365/windows/end-of-ie-support).

Please use a modern browser to fully experience our website, such as the newest versions of Edge, Chrome, Firefox or Safari etc.

Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase

På svenska

Author

  • Olga Göransson
  • Andrew McBride
  • Simon A. Hawley
  • Fiona A. Ross
  • Natalia Shpiro
  • Marc Foretz
  • Benoit Viollet
  • D. Grahame Hardie
  • Kei Sakamoto

Summary, in English

We have studied the mechanism of A- 769662, a new activator of AMP- activated protein kinase ( AMPK). Unlike other pharmacological activators, it directly activates native rat AMPK by mimicking both effects of AMP, i. e. allosteric activation and inhibition of dephosphorylation. We found that it has no effect on the isolated alpha subunit kinase domain, with or without the associated autoinhibitory domain, or on interaction of glycogen with the beta subunit glycogen- binding domain. Although it mimics actions of AMP, it has no effect on binding of AMP to the isolated Bateman domains of the gamma subunit. The addition of A- 769662 to mouse embryonic fibroblasts or primary mouse hepatocytes stimulates phosphorylation of acetyl- CoA carboxylase ( ACC), effects that are completely abolished in AMPK- alpha 1(-/-) alpha 2(-/-) cells but not in TAK1(-/-) mouse embryonic fibroblasts. Phosphorylation of AMPK and ACC in response to A- 769662 is also abolished in isolated mouse skeletal muscle lacking LKB1, a major upstream kinase for AMPK in this tissue. However, in HeLa cells, which lack LKB1 but express the alternate upstream kinase calmodulin- dependent protein kinase kinase-beta, phosphorylation of AMPK and ACC in response to A- 769662 still occurs. These results show that in intact cells, the effects of A- 769662 are independent of the upstream kinase utilized. We propose that this direct and specific AMPK activator will be a valuable experimental tool to understand the physiological roles of AMPK.

Publishing year

2007

Language

English

Pages

32549-32560

Publication/Series

Journal of Biological Chemistry

Volume

282

Issue

45

Document type

Journal article

Publisher

American Society for Biochemistry and Molecular Biology

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Insulin Signal Transduction

ISBN/ISSN/Other

  • ISSN: 1083-351X