The Polycystic Kidney Disease 1 Gene Product Modulates Wnt Signaling

doi:10.1074/jbc.274.8.4947

The Polycystic Kidney Disease 1 Gene Product Modulates Wnt Signaling*

From the ^‡Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, the ^¶Renal Division and the ^‖Department of Molecular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, and the ^**Renal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114

Abstract

Two distinct signaling pathways, involving Wnt signaling and polycystin, have been found to be critical for normal kidney development. Renal tubulogenesis requires the presence of certain Wnt proteins, whereas mutations in polycystin impede the terminal differentiation of renal tubular epithelial cells, causing the development of large cystic kidneys that characterize autosomal dominant polycystic kidney disease. Polycystin is an integral membrane protein, consisting of several extracellular motifs indicative of cell-cell and cell-matrix interactions, coupled through multiple transmembrane domains to a functionally active cytoplasmic domain. We report here that expression of the C-terminal cytoplasmic domain of polycystin stabilizes soluble endogenous β-catenin and stimulates TCF-dependent gene transcription in human embryonic kidney cells. Microinjection of the polycystin C-terminal cytoplasmic domain induces dorsalization in zebrafish. Our findings suggest that polycystin has the capacity to modulate Wnt signaling during renal development.

Footnotes

↵* This work was supported by a grant from the Polycystic Kidney Research Foundation (to G.W.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵§ Supported by Public Health Service Grant MH-01147.
↵‡ To whom correspondence should be addressed. Fax: 617-667-1610; E-mail: gwalz{at}bidmc.harvard.edu.
Abbreviations:

GSK

glycogen synthase kinase

PKD

polycystic kidney disease

HEK

human embryonic kidney cells

PAGE

polyacrylamide gel electrophoresis

AP-1

activation protein-1

GST

glutathione S-transferase

F.gfp

Flag-tagged green fluorescent protein

EGF

epidermal growth factor

HA

hemagglutinin

hpf

hours post-fertilization
- Received October 2, 1998.
- Revision received November 10, 1998.
The American Society for Biochemistry and Molecular Biology, Inc.