期刊
SCIENCE SIGNALING
卷 9, 期 453, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaf8566
关键词
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资金
- British Heart Foundation [PG/12/1/29276, PG/13/82/30483]
- Medical Research Council [MR/J007412/1]
- Chief Scientist Office [ETM/226]
- Diabetes UK [BDA11/0004309]
- National Health Service Greater Glasgow and Clyde Research Endowment Fund [2011REFCH08]
- Chest Heart and Stroke Scotland [R10/A131]
- Experimental Cancer Medicine Centres
- Cancer Research U.K. Centre at Imperial College London, U.K.
- Diabetes U.K. [BDA11/0004403, BDA09/0003948]
- British Heart Foundation [PG/14/32/30812, PG/13/82/30483, PG/12/1/29276] Funding Source: researchfish
- Chief Scientist Office [ETM/226] Funding Source: researchfish
- Medical Research Council [MR/J007412/1] Funding Source: researchfish
- MRC [MR/J007412/1] Funding Source: UKRI
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 (Ser(515) and Ser(518)) 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 Ser(515) and Ser(518) and was abolished in cells lacking AMPK catalytic subunits. Mutation of Ser(515) and Ser(518) abolished AMPK-mediated inhibition of JAK-STAT signaling stimulated by either the sIL-6R alpha/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.
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