Phosphorylation by Akt within the ST loop of AMPK-{alpha}1 down-regulates its activation in tumour cells

The insulin/IGF1-activated protein kinase Akt phosphorylates Ser487 in the “ST loop” within the C-terminal domain of AMPK-α1, leading to inhibition of phosphorylation by upstream kinases at the activating site, Thr172. Surprisingly, the equivalent site on AMPK-α2, Ser491, is not an Akt target and is modified instead by autophosphorylation. Prior stimulation of HEK-293 cells with IGF1 caused reduced subsequent Thr172 phosphorylation and activation of AMPK-α1 in response to the activator A769662 and the Ca2+ ionophore A23187, effects we show to be dependent on Akt activation and Ser487 phosphorylation. Consistent with this, in three PTEN-null tumour cell lines (in which the lipid phosphatase PTEN that normally restrains the Akt pathway is absent and Akt thus hyper-activated), AMPK was resistant to activation by A769662. However, full AMPK activation could be restored by pharmacological inhibition of Akt, or by re-expression of active PTEN. We also show that inhibition of Thr172 phosphorylation is due to interaction of the phosphorylated ST loop with basic side chains within the αC-helix of the kinase domain. Our findings reveal that a previously unrecognized effect of hyper-activation of Akt in tumour cells is to restrain activation of the LKB1-AMPK pathway, which would otherwise inhibit cell growth and proliferation.

Source: BJ Signal - January 27, 2014 Category: Biochemistry Authors: S A. Hawley, F A. Ross, G J. Gowans, P Tibarewal, N R. Leslie, D Grahame Hardie Tags: BJ Signal Source Type: research