The AMPK signalling pathway coordinates cell growth, autophagy and metabolism

Abstract

One of the central regulators of cellular and organismal metabolism in eukaryotes is AMP-activated protein kinase (AMPK), which is activated when intracellular ATP production decreases. AMPK has critical roles in regulating growth and reprogramming metabolism, and has recently been connected to cellular processes such as autophagy and cell polarity. Here we review a number of recent breakthroughs in the mechanistic understanding of AMPK function, focusing on a number of newly identified downstream effectors of AMPK.

Figure 1. The AMPK signaling pathway

AMPK is activated when AMP and ADP levels in the cells rise due to variety of physiological stresses, as well as pharmacological inducers. LKB1 is the upstream kinase activating it in response to AMP increase, whereas CAMKK2 activates AMPK in response to calcium increase. Activated AMPK directly phosphorylates a number of subtrates to acutely impact metabolism and growth, as well as phosphorylating a number of transcriptional regulators that mediate long term metabolic reprogramming. Shown are all the best-established substrates to date-those needing further in vivo examination are italicized. Question marks denote candidate substrates whose identified phosphorylation sites diverge from the established optimal substrate motif (which all the others conform to). A full lineup of the identified AMPK phosphorylation sites in these substrates in Supplemental Table 1. Substrates in red have been reported to serve as substrates of other AMPK family members (SIK1, SIK2, MARKs, SADs) in vivo in addition to being substrates of AMPK.

Figure 2. The Ras/ PI3K/ mTOR pathways intersect the LKB1/AMPK pathway at multiple points

LKB1, the upstream kinase for AMPK, is the tumor suppressor gene mutated in Peutz–Jeghers syndrome (PJS), as well a significant fraction of sporadic lung cancers and cervical cancers. PJS patients share a number of clinical features with patients inheriting defective PTEN or TSC tumor suppressors, perhaps due to their control of common biochemical pathways, best understood currently being the mammalian target of rapamycin complex 1 (mTORC1) pathway. Extensive cross-regulation of the LKB1/AMPK pathway by the oncogenic Ras and PI3K pathways has been discovered, which may explain how these commonly mutated oncogenes also try to circumvent this endogenous tumor suppressor pathway. The ULK1/hATG1 kinase complex has emerged recently as a central node receiving inputs from both AMPK and mTORC1. A number of kinases that can phosphorylate specific residues in LKB1 or AMPK have been identified (upper inset), though the contexts in which most of these regulatory events occur is poorly defined at present, as is the functional impact of these phosphorylation events on AMPK signaling. The BHD tumor suppressor and its partner FNIP1, as well as the sestrin family of proteins, have also been implicated as being upstream or downstream of AMPK and mTOR depending on the context.

Figure 3. AMPK acts as a mitochondrial “Cash for Clunkers”

Activated AMPK acutely triggers the destruction of existing defective mitochondria via ULK1-dependent mitophagy and simultaneously triggers the biogenesis of new mitochondria via effects on PGC-1a dependent transcription. These dual processes controlled by AMPK have the net effect of replacing existing defective mitochondria with new functional mitochondria. This two-pronged control of mitochondria homeostasis by AMPK will have a number of physiological and pathological conditions where it plays a critical role, and a few are illustrated here.

Figure 4. AMPK control of transcription

AMPK regulates several physiological processes through phosphorylation of transcription factors and co-activators. It shares substrates with its AMPK family related kinases to negatively regulate gluconeogenesis in the liver by phosphorylation and inhibition of the CRCT2 and Class IIa HDACs. These phosphorylation events induce binding to 14-3-3 scaffold proteins and sequestration of these transcription regulators into the cytoplasm. AMPK also regulates transcription factors via inducing their degradation (Cry1), preventing their proteolytic activation and translocation to nucleus (Srebp1), and by disrupting protein-protein (p300) or protein-DNA interactions (Arebp, HNF4a). AMPK has also been shown to directly control phosphorylation of Histone 2B on Serine 36 as well as indirectly controlling SIRT1 activity via increasing NAD+ levels.