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.
Kugoh
Hiroyuki
H
Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Kleymenova
Elena
E
Walker
Cheryl Lyn
CL
D000818:Animals; D015820:Cadherins / Q000032:analysis; D002292:Carcinoma, Renal Cell / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000032:analysis* / Q000502:physiology; D017353:Gene Deletion; D017930:Genes, Reporter; D007668:Kidney / Q000737:chemistry / Q000378:metabolism; D007680:Kidney Neoplasms / Q000737:chemistry / Q000378:metabolism; D008856:Microscopy, Fluorescence; D007690:Polycystic Kidney Diseases / Q000737:chemistry* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D050396:TRPP Cation Channels; D015534:Trans-Activators; D015533:Transcriptional Activation; D000077005:Tuberous Sclerosis Complex 2 Protein; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D011506:Proteins; D012097:Repressor Proteins; D050396:TRPP Cation Channels; D015534:Trans-Activators; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; C495268:Ctnnb1 protein, rat; C000624655:Tsc2 protein, rat