Retention of membrane-localized beta-catenin in cells lacking functional polycystin-1 and tuberin.

The tuberous sclerosis (TSC) 2 tumor suppressor gene encodes the protein tuberin, which has recently been shown to play a crucial role in the intracellular trafficking of polycystin-1, the product of the polycystic kidney disease (PDK) 1 gene. PKD1 is responsible for most cases of autosomal dominant polycystic kidney disease, which has been described as "neoplasia in disguise." Polycystin-1 is a membrane protein localized to adherens junctions in a complex containing E-cadherin and alpha-, beta-, and gamma-catenins. To determine whether loss of membrane localization of polycystin-1 and E-cadherin affects the function of beta-catenin, beta-catenin localization and signaling were characterized in tuberin-null EKT2 and ERC15 cells and in tuberin-positive TRKE2 cells derived from polycystic, neoplastic, and normal rat kidney epithelial cells, respectively. EKT2 cells lacking tuberin because of inactivation of the Tsc2 gene fail to localize polycystin-1 and E-cadherin appropriately to these junctions. However, beta-catenin was retained at lateral cell membranes in both tuberin-null and tuberin-positive cells. Moreover, gene transcription mediated by beta-catenin T-cell--specific transcription factor complexes showed no differences among EKT2, ERC15, and TRKE2 cells. Thus, beta-catenin was stably retained at the lateral cell membrane in tuberin-null renal cells lacking membrane-localized polycystin-1 and E-cadherin. These data suggest that, although loss of Tsc2 tumor suppressor gene function disrupts normal polycystin-1 function and membrane localization of E-cadherin, normal beta-catenin signaling is retained in tuberin-null cells.