AMPK Signaling Pathway

Adenosine monophosphate-activated protein kinase (AMPK) consists of three major segments or “modules”: the catalytic module, the CBM, and the nucleotide-binding module (also called “regulatory fragment”). AMPK exists as a trimetric complex consisting of a catalytic subunit (α subunit) and two regulatory subunits (β and γ subunits). The activation loop of the α subunit resides at the interface between the catalytic and nucleotide-binding modules, in close proximity to the C terminus of the β subunit and the CBS repeats of the γ subunit.

The active form of AMPK, i.e. phosphorylated AMP-activated protein kinase (p-AMPK), can down regulate the energy consuming process as well as increase adenosine triphosphate (ATP) generation through stimulating ATP-producing catabolic pathways, such as fatty acid oxidation, and inhibiting ATP consuming processes, such as lipogenesis. In the case of nucleotides, the regulation of AMPK as a sensor of changes in intracellular levels of AMP, ADP, and ATP, which is often mediated by energy stress, is significantly understood and is well established as the canonical regulation of AMPK. Accordingly, the ability of the γ subunit to bind AMP, ADP, and ATP confers AMPK with its exquisite ability to sense the energy state of the cell. Specifically, AMPK becomes fully activated through a three-pronged mechanism. First of all, binding of AMP or ADP to the γ subunit promotes Thr172 phosphorylation in the activation loop in the kinase domain (KD) by upstream kinases. The main upstream kinase responsible for Thr172 phosphorylation in response to energy stress is the serine/threonine kinase LKB1 (liver-kinase-B1). Phosphorylation of Thr172 in the α subunit can increase AMPK activity up to 100-fold in vitro, although fold activation in intact cells is usually more modest. Second, a conformational change that protects against Thr172 dephosphorylation by protein phosphatases will be induced by this binding of AMP or ADP to the γ subunit. Lastly, binding of AMP, but not ADP, results in up to 10-fold allosteric activation of AMPK. Of note, ATP inhibits all these above three mechanisms.

In addition to nucleotide-dependent regulation of AMPK, some other non-canonical modes of AMPK regulation have become increasingly clear. They are critical for the regulation of many aspects of whole-body metabolism by AMPK. For example, AMPK is activated by LKB1 and CAMKK2 in response to stimuli that increase AMP/ADP levels (energy stress) or Ca2+ flux, respectively. AMPK then induces metabolic changes via the phosphorylation of substrates.

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