Research ArticleCancer

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

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Sci. Signal.  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.

Abstract

The sodium potassium pump (Na/K-ATPase) ensures the electrochemical gradient of a cell through an energy-dependent process that consumes about one-third of regenerated ATP. We report that the G protein–coupled receptor GPR35 interacted with the α chain of Na/K-ATPase and promotes its ion transport and Src signaling activity in a ligand-independent manner. Deletion of Gpr35 increased baseline Ca2+ to maximal levels and reduced Src activation and overall metabolic activity in macrophages and intestinal epithelial cells (IECs). In contrast, a common T108M polymorphism in GPR35 was hypermorphic and had the opposite effects to Gpr35 deletion on Src activation and metabolic activity. The T108M polymorphism is associated with ulcerative colitis and primary sclerosing cholangitis, inflammatory diseases with a high cancer risk. GPR35 promoted homeostatic IEC turnover, whereas Gpr35 deletion or inhibition by a selective pepducin prevented inflammation-associated and spontaneous intestinal tumorigenesis in mice. Thus, GPR35 acts as a central signaling and metabolic pacesetter, which reveals an unexpected role of Na/K-ATPase in macrophage and IEC biology.

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