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.