| Polycystin 1 (PC1), encoded by the PKD1 gene, is a large transmembrane protein that functions as a mechanosensitive receptor in epithelial cells of renal tubules, liver, and pancreas, where it regulates cell–matrix adhesion, lumen architecture, and mechanotransduction. Its extended extracellular domain integrates multiple structural motifs that engage mechanical strain and ligand dependent cues at the cell surface and couples through the membrane to polycystin 2 (PC2), assembling a calcium permeable channel complex that localizes to primary cilia and apical membranes and converts luminal flow and shear stress into graded intracellular calcium signals. These PC1–PC2 dependent calcium fluxes intersect with calcineurin, mTORC1, ERK, and JAK–STAT pathways to modulate cell proliferation, differentiation, fluid secretion, and cytoskeletal remodeling, while PC1 simultaneously engages Wnt–planar cell polarity and integrin linked signaling to coordinate planar orientation of mitotic spindles, apicobasal polarization, and extracellular matrix organization across the tubular epithelium. In autosomal dominant polycystic kidney disease, germline or somatic inactivating PKD1 mutations impair PC1–PC2 complex formation, trafficking, or channel gating, leading to sustained suppression of calcium dependent growth inhibitory signals and aberrant activation of mTORC1 and proliferative kinase cascades that drive epithelial hyperplasia and misoriented divisions. This altered signaling environment promotes progressive tubular dilation, mislocalized fluid secretion, and matrix remodeling, resulting in cyst expansion in kidneys and liver, and analogous PC2 lesions produce a comparable phenotype, demonstrating the essential interdependence of both polycystins in maintaining tubular integrity, such that PC1 dependent signaling is ultimately dysregulated in the cystic epithelium. |
