title: Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling.
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 (Ser515and 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 Ser515and Ser518and was abolished in cells lacking AMPK catalytic subunits. Mutation of Ser515and Ser518abolished 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.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors.forename: Claire
authors.initials: C
authors.lastname: Rutherford
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors.forename: Claire
authors.initials: C
authors.lastname: Speirs
authors.affiliation: School of Pharmacy, University of Bradford, Bradford BD7 1DP, U.K.
authors.forename: Jamie J L
authors.initials: JJ
authors.lastname: Williams
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Mancini
authors.affiliation: Division of Cell Signaling and Immunology, University of Dundee, Dundee DD1 5EH, U.K.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hawley
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors.forename: Christian
authors.initials: C
authors.lastname: Delles
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.|CNRS, UMR8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Faculty of Medicine, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, U.K.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Costa-Pereira
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K.
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K. t.palmer1@bradford.ac.uk ian.salt@glasgow.ac.uk.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Salt
authors.affiliation: School of Pharmacy, University of Bradford, Bradford BD7 1DP, U.K. t.palmer1@bradford.ac.uk ian.salt@glasgow.ac.uk.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Palmer
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048948:14-3-3 Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D055372:AMP-Activated Protein Kinases