Research ArticlePharmacology

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

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Sci. Signal.  08 Nov 2016:
Vol. 9, Issue 453, pp. ra109
DOI: 10.1126/scisignal.aaf8566

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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.