Phosphorylation of Janus kinase 1 (JAK1) by AMP-activated protein kinase (AMPK) links energy sensing to anti-inflammatory signaling
View/ Open
Main article (826.5Kb)
Download
Publication date
2016-11-08Author
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.
Salt, I.P.
Palmer, Timothy M.
Rights
© 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.Peer-Reviewed
yes
Metadata
Show full item recordAbstract
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.Version
Accepted ManuscriptCitation
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.Link to Version of Record
https://doi.org/10.1126/scisignal.aaf8566Type
Articleae974a485f413a2113503eed53cd6c53
https://doi.org/10.1126/scisignal.aaf8566