Figure 7.

A model for double-negative feedback loop between two cellular kinases AMPK and Akt. We show that detachment-triggered AMPK concomitantly inactivates Akt through the phosphatase PHLPP2, resulting in a pAMPK^high/pAkt^low catabolic state that facilitates stress-survival in matrix-deprived cells. In contrast, adhesion-triggered Akt keeps AMPK under check by the phosphatase PP2C-α, maintaining a pAkt^high/pAMPK^low anabolic state, which is conducive for cell growth and proliferation. Thus, between attachment and detachment, AMPK and Akt constitute a reversible double-negative feedback loop, maintaining stable pAkt^high/pAMPK^low and pAMPK^high/pAkt^low states, yet retaining the ability to switch between these two cellular states.