Research ArticleCancer

GPR35 promotes glycolysis, proliferation, and oncogenic signaling by engaging with the sodium potassium pump

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Science Signaling  01 Jan 2019:
Vol. 12, Issue 562, eaau9048
DOI: 10.1126/scisignal.aau9048

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Altering membrane potential for cancer

Disease-associated polymorphisms can give insight into protein function, particularly for receptors whose ligands are unknown or controversial. Polymorphisms in the G protein–coupled receptor GPR35 are associated with increased risk for certain inflammatory diseases of the bile duct and large intestine that have increased cancer risk. Schneditz et al. found that GPR35 promoted the activity of Na/K-ATPase, a ubiquitous and essential transmembrane pump that sets the membrane potential in cells, in a manner that did not rely on its proposed ligands. A disease-associated variant of GPR35 induced a more pronounced increase in Na/K-ATPase activity. This stimulation of Na/K-ATPase activity enhanced glycolysis and proliferation in intestinal epithelial cells. Deficiency in Na/K-ATPase or treatment with a pepducin targeting Gpr35 decreased tumor burden in mouse models of intestinal cancer. Thus, GPR35 coordinates regulation of membrane potential by Na/K-ATPase with metabolism and proliferation.