Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling

Rutherford, C.; Speirs, C.; Williams, Jamie J.L.; Ewart, Marie Ann; Mancini, S. J.; Hawley, S. A.; Delles, C.; Viollet, B.; Costa-Pereira, A. P.; Baillie, G. S.; Salt, I. P.; Palmer, T. M.

Abstract

Adenosine 5′-monophosphate–activated protein kinase (AMPK) is a pivotal regulator of metabolism at cellular and organismal levels. AMPK also suppresses inflammation. We found that pharmacological activation of AMPK rapidly inhibited the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway in various cells. In vitro kinase assays revealed that AMPK directly phosphorylated two residues (Ser515 and Ser518) within the Src homology 2 domain of JAK1. Activation of AMPK enhanced the interaction between JAK1 and 14-3-3 proteins in cultured vascular endothelial cells and fibroblasts, an effect that required the presence of Ser515 and Ser518 and was abolished in cells lacking AMPK catalytic subunits. Mutation of Ser515 and Ser518 abolished AMPK-mediated inhibition of JAK-STAT signaling stimulated by either the sIL-6Rα/IL-6 complex or the expression of a constitutively active V658F-mutant JAK1 in human fibrosarcoma cells. Clinically used AMPK activators metformin and salicylate enhanced the inhibitory phosphorylation of endogenous JAK1 and inhibited STAT3 phosphorylation in primary vascular endothelial cells. Therefore, our findings reveal a mechanism by which JAK1 function and inflammatory signaling may be suppressed in response to metabolic stress and provide a mechanistic rationale for the investigation of AMPK activators in a range of diseases associated with enhanced activation of the JAK-STAT pathway.

Citation

Rutherford, C., Speirs, C., Williams, J. J., Ewart, M. A., Mancini, S. J., Hawley, S. A., Delles, C., Viollet, B., Costa-Pereira, A. P., Baillie, G. S., Salt, I. P., & Palmer, T. M. (2016). Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling. Science Signaling, 9(453), ra109. https://doi.org/10.1126/scisignal.aaf8566

• Journal Article Type: Article
• Acceptance Date: Oct 21, 2016
• Online Publication Date: Nov 8, 2016
• Publication Date: Nov 8, 2016
• Deposit Date: Oct 30, 2018
• Publicly Available Date: Oct 30, 2018
• Journal: Science Signaling
• Print ISSN: 1945-0877
• Publisher: American Association for the Advancement of Science
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 453
• Pages: ra109
• DOI: https://doi.org/10.1126/scisignal.aaf8566
• Public URL: https://hull-repository.worktribe.com/output/1137101
• Publisher URL: http://stke.sciencemag.org/content/9/453/ra109
• Related Public URLs: https://bradscholars.brad.ac.uk/handle/10454/10881?show=full
• Contract Date: Oct 30, 2018