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Nephrol Dial Transplant (2000) 15: 1-2
© 2000 European Renal Association-European Dialysis and Transplant Association
Editorial Comments
Polycystin-1 interacts with E-cadherin and the catenins—clues to the pathogenesis of cyst formation in ADPKD?
Department of Medicine, Division of Nephrology, Columbia University, New York, USA
Correspondence and offprint requests to: Janet van Adelsberg, Assistant Professor of Medicine, Columbia University, 630 W168th St, Box 84, P&S 10-501, New York, NY 10032, USA.
Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in several genes. Two of these genes, PKD1 and PKD2, have been cloned and sequenced. PKD1 codes for an integral membrane protein, polycystin-1, with a large extracellular amino terminal domain and a carboxyl terminal domain that spans the lipid bilayer 11 times. The mechanism of polycystin-1 signal transduction is unknown. A potential target is the ß catenin signal transduction pathway. This cytoplasmic protein is a key player in the regulation of cell polarity, proliferation, and morphogenesis, processes that are all affected in ADPKD.
E-cadherin complexes contain ß catenin and determine cell polarity
E-cadherin is a calcium dependent cell adhesion molecule. The cytoplasmic domain of E-cadherin binds ß catenin, which binds in turn to a second cytoplasmic protein, 
catenin. Catenin is required for cadherin mediated cell–cell adhesion and links the E-cadherin–catenin complex to the actin cytoskeleton via actinin. The E-cadherin–catenin complex is required for morphogenesis during embryonic development. Assembly of the E-cadherin–catenin complex is the first step in the formation of a polarized epithelium [1,2].
ß Catenin degradation is regulated by the APC complex
ß Catenin binds to a cytoskeletal, microtubule associated complex that contains APC (the adenomatous polyposis coli gene product), axin and GSK (glycogen synthase kinase). ß Catenin, which interacts with this complex, is targeted for degradation by the proteasome. E-cadherin and APC complexes compete for ß catenin and thus determine the levels of free ß catenin in the cytoplasm [3,4].
ß Catenin binds to transcription factors
Cytoplasmic ß catenin interacts with members of the LEF/TCF family of transcription factors [4]. Interaction with LEF translocates ß catenin to the nucleus, where the complex activates gene transcription. Targets of this pathway include the genes for cyclin D1 and the c-myc proto-oncogene [5–7].
Polycystin-1 interacts with ß catenin
We recently found that polycystin-1 interacts with the E-cadherin–catenin complex containing ß catenin [8]. This discovery raises the question of whether polycystin-1 modulates signalling by ß catenin. Several lines of evidence implicate ß catenin in the pathogenesis of polycystic kidney disease. First, expression of the carboxyl terminal tail of polycystin-1 protected ß catenin from degradation by the proteasome and activated transcription of a known ß catenin target, the Siamois gene [6]. Second, expression of c-myc, a likely ß catenin target, is found in the cysts of both human ADPKD and two rodent forms of polycystic kidney disease [10–13]. Transgenic mice that overexpress c-myc in renal epithelial cells develop fatal polycystic kidney disease, demonstrating that c-myc is in the pathway to 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 ß catenin signalling could be a common feature of polycystic kidney diseases. This hypothesis predicts that the half-life of ß catenin will be prolonged in cyst-lining epithelial cells and that expression of other ß catenin target genes, for example cyclin D1, will be up-regulated in these cells.
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