Impaired formation of desmosomal junctions in ADPKD epithelia

Abstract

Mutations in polycystin-1 (PC-1) are responsible for autosomal dominant polycystic kidney disease (ADPKD), characterized by formation of fluid-filled tubular cysts. The PC-1 is a multifunctional protein essential for tubular differentiation and maturation found in desmosomal junctions of epithelial cells where its primary function is to mediate cell-cell adhesion. To address the impact of mutated PC-1 on intercellular adhesion, we have analyzed the structure/function of desmosomal junctions in primary cells derived from ADPKD cysts. Primary epithelial cells from normal kidney showed co-localization of PC-1 and desmosomal proteins at cell-cell contacts. A striking difference was seen in ADPKD cells, where PC-1 and desmosomal proteins were lost from the intercellular junction membrane, despite unchanged protein expression levels. Instead, punctate intracellular expression for PC-1 and desmosomal proteins was detected. The N-cadherin, but not E-cadherin was expressed in adherens junctions of ADPKD cells. These data together with co-sedimentation analysis demonstrate that, in the absence of functional PC-1, desmosomal junctions cannot be properly assembled and remain sequestered in cytoplasmic compartments. Taken together, our results demonstrate that PC-1 is crucial for formation of intercellular contacts. We propose that abnormal expression of PC-1 causes disregulation of cellular adhesion complexes leading to increased proliferation, loss of polarity and, ultimately, cystogenesis.

Targeting Dysregulated Cell Cycle and Apoptosis for Polycystic Kidney Disease Therapy

“…[14][15][16] Importantly, disruption of desmosomal and adherens cell-cell junctions were detected in cystic ADPKD epithelia, suggesting that mutations in polycystin-1 lead to perturbation of intercellular adhesion complexes and cystogenesis. 17,18 In addition, polycystin-1 was found in focal adhesion complexes suggesting its role in cell-matrix adhesion. 19,20 These data clearly suggest that mutation in polycystin-1 results in the disruption of cell-cell/matrix adhesion, which, in turn leads to increased proliferation, de-differentiation and cystic transformation.…”

Homophilic and heterophilic polycystin 1 interactions regulate E-cadherin recruitment and junction assembly in MDCK cells

“…In MDCK cells, we found that PC1 was 1411 PC1 and junction assembly coimmunoprecipitate with E-cadherin and the catenins in human pancreatic adenocarcinoma cells (Huan and van Adelsberg, 1999). In human cystic cells, the absence of surface PC1 is associated with concomitant loss of surface E-cadherin expression and its replacement by N-cadherin (Streets et al, 2003;Roitbak et al, 2004;Russo et al, 2005). A putative role for PC1 in desmosome function has also been postulated because of its immunolocalisation to desmosomal junctions, the mislocalisation of desmosome junction proteins in cystic cells and the reported interaction of the PC1 C-terminus with intermediate filaments (Scheffers et al, 2000;Xu et al, 2001;Russo et al, 2005;Silberberg et al, 2005).…”

Polycystins and mechanotransduction: From physiology to disease

“…In ADPKD cysts, these desmosomal elements are severely disoriented [42] . Finally, cytoskeletal proteins such as actinbinding proteins, cardiac troponin and tropomysin have been directly associated with PC2 channel activity upon stimulation by osmotic or hydrostatic pressure [43,44] .…”