Polycystin-1 acts as an atypical adhesion GPCR that responds to novel Wnt signaling and mechanical stimuli

Mutations in the genes encoding Polycystin-1 and 2 cause autosomal dominant polycystic kidney disease (ADPKD). These proteins’ cellular functions and the mechanisms through which their absence causes disease are unknown. We find that the behavior of the 11 transmembrane domain polycystin-1 protein resembles that of an adhesion G protein-coupled receptor when activated by Wnt ligands. Exposure to Wnt ligands causes shedding of the polycystin-1 N terminal region, exposing a tethered agonist that activates G protein-dependent functions of the membrane-associated C terminal fragment. Activated polycystin-1 communicates through G_α13to activate RhoA, leading in turn to the ROCK-dependent phosphorylation and inactivation of GSK3β. Activated polycystin-1 traffics out of the primary cilium through an arrestin-dependent mechanism, and arrestin involvement is required for signaling to occur. These data elaborate a function for polycystin-1 that is structurally non-canonical and that is directly connected to pathways whose perturbation results in cystic disease.