Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling.
Polycystin-1 (PC1), the product of the PKD1 gene mutated in the majority of autosomal dominant polycystic kidney disease (ADPKD) cases, undergoes a cleavage resulting in the intracellular release of its C-terminal tail (CTT). Here, we demonstrate that the PC1 CTT co-localizes with and binds to beta-catenin in the nucleus. This interaction requires a nuclear localization motif present in the PC1 CTT as well as the N-terminal portion of beta-catenin. The PC1 CTT inhibits the ability of both beta-catenin and Wnt ligands to activate T-cell factor (TCF)-dependent gene transcription, a major effector of the canonical Wnt signaling pathway. The PC1 CTT may produce this effect by reducing the apparent affinity of the interaction between beta-catenin and the TCF protein. DNA microarray analysis reveals that the canonical Wnt signaling pathway is activated in ADPKD patient cysts. Our results suggest a novel mechanism through which PC1 cleavage may impact upon Wnt-dependent signaling and thereby modulate both developmental processes and cystogenesis.
Lal
Mark
M
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Song
Xuewen
X
Pluznick
Jennifer L
JL
Di Giovanni
Valeria
V
Merrick
David M
DM
Rosenblum
Norman D
ND
Chauvet
Veronique
V
Gottardi
Cara J
CJ
Pei
York
Y
Caplan
Michael J
MJ
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008024:Ligands; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016891:Polycystic Kidney, Autosomal Dominant / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D049490:Systems Biology; D051820:TCF Transcription Factors / Q000235:genetics; D050396:TRPP Cation Channels / Q000737:chemistry* / Q000378:metabolism*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
D008024:Ligands; D010446:Peptide Fragments; D011994:Recombinant Proteins; D051820:TCF Transcription Factors; D050396:TRPP Cation Channels; D051153:Wnt Proteins; D051176:beta Catenin; C495270:CTNNB1 protein, human