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Autosomal dominant polycystic kidney disease b Catenin binds to transcription factors (ADPKD) is caused by mutations in several genes. Two of these genes, PKD1 and PKD2, have been Cytoplasmic b catenin interacts with members of cloned and sequenced. PKD1 codes for an integral the LEF/TCF family of transcription factors [4]. membrane protein, polycystin-1, with a large extracelInteraction with LEF translocates b catenin to the lular amino terminal domain and a carboxyl terminal nucleus, where the complex activates gene transcripdomain that spans the lipid bilayer 11 times. The tion. Targets of this pathway include the genes for mechanism of polycystin-1 signal transduction is cyclin D1 and the c-myc proto-oncogene [5–7]. unknown. A potential target is the b catenin signal transduction pathway. This cytoplasmic protein is a key player in the regulation of cell polarity, proliferPolycystin-1 interacts with b catenin ation, and morphogenesis, processes that are all affected in ADPKD. We recently found that polycystin-1 interacts with the E-cadherin–catenin complex containing b catenin [8]. This discovery raises the question of whether E-cadherin complexes contain b catenin and polycystin-1 modulates signalling by b catenin. Several determine cell polarity lines of evidence implicate b catenin in the pathogenesis of polycystic kidney disease. First, expression of the E-cadherin is a calcium dependent cell adhesion molcarboxyl terminal tail of polycystin-1 protected b catecule. The cytoplasmic domain of E-cadherin binds b enin from degradation by the proteasome and activated catenin, which binds in turn to a second cytoplasmic transcription of a known b catenin target, the Siamois protein, a catenin. a Catenin is required for cadherin gene [6 ]. Second, expression of c-myc, a likely b catenin mediated cell–cell adhesion and links the E-cadherin– target, is found in the cysts of both human ADPKD catenin complex to the actin cytoskeleton via a actinin. and two rodent forms of polycystic kidney disease The E-cadherin–catenin complex is required for mor[10–13]. Transgenic mice that overexpress c-myc in phogenesis during embryonic development. Assembly renal epithelial cells develop fatal polycystic kidney of the E-cadherin–catenin complex is the first step in disease, demonstrating that c-myc is in the pathway to the formation of a polarized epithelium [1,2]. cyst formation [14]. Third, nuclear catenin staining is found in the bcl-2 null mouse model of polycystic kidney disease [15]. These data suggest that aberrant b Catenin degradation is regulated by the APC b catenin signalling could be a common feature of complex polycystic kidney diseases. This hypothesis predicts that the half-life of b catenin will be prolonged in cystlining epithelial cells and that expression of other b b Catenin binds to a cytoskeletal, microtubule associcatenin target genes, for example cyclin D1, will be ated complex that contains APC (the adenomatous up-regulated in these cells. polyposis coli gene product), axin and GSK (glycogen synthase kinase). b Catenin, which interacts with this complex, is targeted for degradation by the proReferences teasome. E-cadherin and APC complexes compete for b catenin and thus determine the levels of free b catenin 1. van Adelsberg JS. Protein targeting: the molecular basis of in the cytoplasm [3,4]. vectorial transport in the kidney. Semin Nephrol 1998; 18: 152–166 2. Yeaman C, Grindstaff KK, Nelson WJ. New perspectives on Correspondence and offprint requests to: Janet van Adelsberg, Assistant Professor of Medicine, Columbia University, 630 W168th mechanisms involved in generating epithelial cell polarity. Physiol Rev 1999; 79: 73–98 St, Box 84, P&S 10-501, New York, NY 10032, USA.

Polycystin-1 interacts with E-cadherin and the catenins—clues to the pathogenesis of cyst formation in ADPKD?