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Human Molecular Genetics Advance Access published online on March 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl070
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 5, 2006
Revised February 17, 2006
Accepted March 15, 2006

Article

Identification of an N-terminal glycogen synthase kinase 3 phosphorylation site which regulates the functional localisation of polycystin-2 in vivo and in vitro

Andrew J Streets 1, David J Moon 1, Michelle E Kane 2, Tomoko Obara 2, and Albert CM Ong 3 *

1 Academic Nephrology Unit, Sheffield Kidney Institute, Division of Clinical Sciences (North), University of Sheffield, Sheffield, United Kingdom.
2 Department of Medicine, Metrohealth Medical Center, Case Western Reserve University, Cleveland, USA
3 Academic Nephrology Unit, Sheffield Kidney Institute, Division of Clinical Sciences (North), University of Sheffield, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, United Kingdom

* To whom correspondence should be addressed.
Albert CM Ong, E-mail: a.ong{at}sheffield.ac.uk


  Abstract

PKD2 is mutated in 15% of patients with autosomal dominant polycystic kidney disease (ADPKD). Polycystin-2 (PC2), the PKD2 protein, is a nonselective Ca2 + -permeable cation channel which may function at the cell surface and ER. Nevertheless, the factors that regulate the dynamic translocation of PC2 between the ER and other compartments are not well understood. Constitutive phosphorylation of PC2 at a single C-terminal site (Ser812) has been previously reported. Since we were unable to abolish phospholabelling of PC2 in HEK293 cells by site-directed mutagenesis of Ser812 or all 5 predicted phosphorylation sites in the C-terminus, we hypothesised that PC2 could also be phosphorylated at the N-terminus. In this paper, we report the identification of a new phosphorylation site for PC2 within its N-terminal domain (Ser76) and demonstrate that this residue is phosphorylated by glycogen synthase kinase 3 (GSK-3). The consensus recognition sequence for GSK-3 (Ser76/Ser80) is evolutionarily conserved down to lower vertebrates. In the presence of specific GSK-3 inhibitors, the lateral plasma membrane pool of endogenous PC2 redistributes into an intracellular compartment in MDCK cells without a change in primary cilia localization. Finally, co-injection of wild-type but not a S76A/S80A mutant PKD2 capped mRNA could rescue the cystic phenotype induced by an antisense morpholino oligonucleotide to pkd2 in zebrafish pronephric kidney. We conclude that surface localization of PC2 is regulated by phosphorylation at a unique GSK-3 site in its N-terminal domain in vivo and in vitro. This site is functionally significant for the maintenance of normal glomerular and tubular morphology.


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