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

Research output: Contribution to journalArticle

Georg Schneditz, Joshua E. Elias, Ester Pagano, M. Zaeem Cader, Svetlana Saveljeva, Kathleen Long, Subhankar Mukhopadhyay, Maryam Arasteh, Trevor D. Lawley, Gordon Dougan, Andrew Bassett, Tom H. Karlsen, Arthur Kaser, Nicole C. Kaneider

Original languageEnglish
JournalScience Signaling
Volume12
Issue number562
DOIs
StatePublished - 1 Jan 2019

King's Authors

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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