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Sci Signal. 2019 Jan 1;12(562). pii: eaau9048. doi: 10.1126/scisignal.aau9048.

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

Author information

1
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK.
2
Norwegian PSC Research Center, Department of Transplantation Medicine and Institute of Clinical Medicine, Oslo University Hospital and University of Oslo, 0027 Oslo, Norway.
3
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
4
Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
5
MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London SE1 9RT, UK.
6
Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge CB2 0QQ, UK. nk428@cam.ac.uk.

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.

PMID:
30600262
DOI:
10.1126/scisignal.aau9048

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