Fibrocystin is a type I membrane protein that undergoes regulated proteolysis. Many proteolytic cleavages occur on the ectodomain whereas at least one cleavage occurs on the cytoplasmic portion of Fibrocystin. The latter gener- ates a C-terminal intracellular fragment that localizes to the nucleus. This proteolysis requires activation of protein kinase C (PKC) and release of intra- cellular calcium. Fibrocystin is expressed in the cilia of the bile duct epitheli- um and leads to abnormalities in the rubric of the ductal plate malformation. The intracellular C-terminus of Fibrocystin interacts with calcium modulating cyclophilin ligand (CAML), a protein implicated in calcium signaling. Fibro- cystin may participate in the mediation of intracellular calcium in the distal nephron in a manner similar to PKD1 and PKD2. Mutations in the PKHD1 gene, which encodes Fibrocystin, result in autosomal recessive polycystic kidney disease (ARPKD), a severe form of polycystic kidney disease characterized by enlarged kidneys and congenital hepatic fibrosis.