AMPK: A Target for Drugs and Natural Products With Effects on Both Diabetes and Cancer

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FIG. 1.
FIG. 1.

Tripartite mechanism by which AMPK is activated by changes in cellular energy status. Displacement of ATP by ADP and/or AMP at one or more of the sites on the AMPK-γ subunit causes a conformational change in the heterotrimeric complex that 1) promotes phosphorylation, and 2) inhibits dephosphorylation of Thr-172, causing a large (up to 100-fold) increase in kinase activity. Binding of AMP, but not ADP, causes 3) further activation of the phosphorylated kinase of up to 10-fold. The upstream kinase LKB1 appears to be constitutively active, and increased Thr-172 phosphorylation in response to energy stress does not normally occur in tumor cells lacking LKB1. However, AMPK can also be activated by Thr-172 phosphorylation catalyzed by CaMKKβ via a mechanism that requires an increase in intracellular Ca2+ but can be independent of changes in AMP and/or ADP.

This Article

  1. Diabetes vol. 62 no. 7 2164-2172