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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, M-A. Mancini, S.J. Hawley, S.A. Delles, C. Viollet, B. Costa-Pereira, A.P. Baillie, G.S.
Rutherford, C.
Speirs, C.
Williams, Jamie J.L.
Ewart, M-A.
Mancini, S.J.
Hawley, S.A.
Delles, C.
Viollet, B.
Costa-Pereira, A.P.
Baillie, G.S.
Publication Date
08/11/2016
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© 2016 The Authors. Reproduced in accordance with the publisher's self-archiving policy.
This manuscript has been accepted for publication in Science Signaling. This version has not undergone final editing. Please refer to the complete version of record at http://dx.doi.org/10.1126/scisignal.aaf8566. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.
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21/10/2016
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Abstract
AMP-activated protein kinase (AMPK) is a pivotal regulator of metabolism at the
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 SH2 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 which required the presence of Ser515 and Ser518 and was abolished
in cells lacking AMPK catalytic subunits. Mutation of Ser515 and Ser518 abolished AMPKmediated
inhibition of JAK-STAT signaling stimulated either by the sIL-6Rα/IL-6 complex or
by 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.
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Citation
Rutherford C, Speirs C, Williams JJL, Ewart MA, Mancini SJ, Hawley SA, Delles C, Viollet B, Costa-Pereira AP, Baillie GS, Salt IP and Palmer TM (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.
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