| First Author | Dite TA | Year | 2017 |
| Journal | Nat Commun | Volume | 8 |
| Issue | 1 | Pages | 571 |
| PubMed ID | 28924239 | Mgi Jnum | J:254767 |
| Mgi Id | MGI:5925737 | Doi | 10.1038/s41467-017-00628-y |
| Citation | Dite TA, et al. (2017) The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nat Commun 8(1):571 |
| abstractText | AMP-activated protein kinase (AMPK) is a metabolic stress-sensing enzyme responsible for maintaining cellular energy homeostasis. Activation of AMPK by salicylate and the thienopyridone A-769662 is critically dependent on phosphorylation of Ser108 in the beta1 regulatory subunit. Here, we show a possible role for Ser108 phosphorylation in cell cycle regulation and promotion of pro-survival pathways in response to energy stress. We identify the autophagy initiator Unc-51-like kinase 1 (ULK1) as a beta1-Ser108 kinase in cells. Cellular beta1-Ser108 phosphorylation by ULK1 was dependent on AMPK beta-subunit myristoylation, metabolic stress associated with elevated AMP/ATP ratio, and the intrinsic energy sensing capacity of AMPK; features consistent with an AMP-induced myristoyl switch mechanism. We further demonstrate cellular AMPK signaling independent of activation loop Thr172 phosphorylation, providing potential insight into physiological roles for Ser108 phosphorylation. These findings uncover new mechanisms by which AMPK could potentially maintain cellular energy homeostasis independently of Thr172 phosphorylation.AMPK is involved in sensing of metabolic stress. The authors show that the autophagy initiator ULK1 phosphorylates beta1-Ser108 on the regulatory beta1-subunit, sensitizing AMPK to allosteric drugs, and activates signaling pathways that appear independent of Thr172 phosphorylation in the kinase activation loop. |
