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

Claire Rutherford, Claire Speirs, Jamie J L Williams, Marie Ann Ewart, Sarah J. Mancini, Simon A. Hawley, Christian Delles, Benoit Viollet, Ana P. Costa-Pereira, George S. Baillie, Ian P. Salt (Lead / Corresponding author), Timothy M. Palmer (Lead / Corresponding author)

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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-6Ra/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. 2016

Original languageEnglish
Article numberra109
Pages (from-to)1-10
Number of pages10
JournalScience Signaling
Volume9
Issue number453
DOIs
Publication statusPublished - 8 Nov 2016

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    Rutherford, C., Speirs, C., Williams, J. J. L., 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), 1-10. [ra109]. https://doi.org/10.1126/scisignal.aaf8566