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New uses for AMPK activators
Inflammatory cytokines stimulate the JAK-STAT pathway and promote cell survival and migration in hematopoietic cells. Chronic or excessive inflammation also contributes to diseases. Drugs that activate the kinase AMPK, such as salicylate and the diabetes drug metformin, have anti-inflammatory effects. Rutherford et al. found that AMPK phosphorylates JAK, inhibiting JAK-mediated STAT activation in vascular endothelial cells exposed to IL-6. Pharmacological activation of AMPK suppressed JAK-STAT signaling in cells expressing a JAK1 mutant associated with acute lymphoblastic leukemia (ALL). JAK inhibitors have had limited success in patients. Thus, the findings not only identify JAK1 as a substrate for AMPK in its anti-inflammatory function but also suggest that metformin might be repurposed to inhibit JAK-STAT signaling in patients with ALL and, perhaps, other inflammatory diseases.
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.
