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

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Title: Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling
Authors: Rutherford, C
Speirs, C
Williams, JJL
Ewart, MA
Mancini, SJ
Hawley, SA
Delles, C
Viollet, B
Costa-Pereira, AP
Baillie, GS
Salt, IP
Palmer, TM
Item Type: Journal Article
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.
Issue Date: 8-Nov-2016
Date of Acceptance: 21-Oct-2016
URI: http://hdl.handle.net/10044/1/43027
DOI: http://dx.doi.org/10.1126/scisignal.aaf8566
ISSN: 1945-0877
Publisher: American Association for the Advancement of Science
Journal / Book Title: Science Signaling
Volume: 9
Issue: 453
Copyright Statement: © American Association for the Advancement of Science. This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signalling in Vol 9. Issue 453 08 Nov 2016, DOI: 10.1126/scisignal.aaf8566
Sponsor/Funder: Cancer Research UK
Cancer Research UK
Funder's Grant Number: C42671 / A12991
C42671 / A12993
Keywords: 0601 Biochemistry And Cell Biology
Publication Status: Published
Article Number: ra109
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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