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

Rutherford, C. et al. (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. (doi: 10.1126/scisignal.aaf8566) (PMID:27919027)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Speirs, Miss Claire and Palmer, Dr Timothy and Mancini, Dr Sarah and Salt, Dr Ian and Delles, Professor Christian and Williams, Dr Jamie and Rutherford, Dr Claire
Authors: 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., and Palmer, T. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Science Signaling
Publisher:American Association for the Advancement of Science
ISSN (Online):1937-9145
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Science Signaling 9(453): ra109
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
641891Inhibition of endothelial mitogen-activated protein kinases by amp-activated protein kinaseIan SaltBritish Heart Foundation (BHF)PG/13/82/30483RI CARDIOVASCULAR & MEDICAL SCIENCES
588611cAMP phosphodiesterase-4: signalling complexes, regulation and potential therapeutic targets.George BaillieMedical Research Council (MRC)MR/J007412/1RI CARDIOVASCULAR & MEDICAL SCIENCES
605941Extracellular signal-regulated kinase 5 (ERK5) and regulation of neuroendocrine differentiation in prostate cancerTimothy PalmerScottish Executive Health Department (SEHHD-CSO)ETM/226RI CARDIOVASCULAR & MEDICAL SCIENCES
580311The sensitive assessment of the activity of cellular signalling pathways regulating insulin action and the cardiovascular complications of diabetesIan SaltDiabetes UK (DIABETESUK)11/0004309RI CARDIOVASCULAR & MEDICAL SCIENCES
531051Regulation of inflammatory signalling in adipocytes by AMP-activated protein kinaseIan SaltDiabetes UK (DIABETESUK)09/0003948RI CARDIOVASCULAR & MEDICAL SCIENCES