Orphan GPR35 controls the quintessential sodium-potassium pump (360G-Wellcome-216630_Z_19_Z)

We discovered that GPR35 interacts with the alpha1-chain of the sodium/potassium ATPase (Na/K- ATPase) and thereby controls its pump and signalling function. GPR35T108M, which confers genetic risk for ulcerative colitis and primary sclerosing cholangitis, increases Na/K-ATPase's pump function by 25%, while deletion of Gpr35 decreases it by 30%. GPR35 also activates Na/K-ATPase-dependent Src signalling, and Gpr35–/– mice are protected from developing tumours. Considering Na/K-ATPase’s quintessential role in maintaining the electrochemical gradient of a cell, we will (1) address the structural basis of GPR35’s unique interaction with Na/K-ATPase. We will use molecular biological, biochemical, and structural (cryo-EM) methods to address this. (2) We will elucidate the role of GPR35 in innate and adaptive immunity and its dependency on Na/K-ATPase. GPR35 is expressed in immune and intestinal epithelial cells. Albeit endothelial cells do not express GPR35, we observed changes in vascularisation in tumour tissue and aortic rings. This prompted us to (3) study the role of GPR35 in angiogenesis. We will test how GPR35 modulates the interaction of macrophage, fibroblasts and endothelial cells and the consequent effects on vascularisation and therefore tumour growth and size.