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J. Biol. Chem., Vol. 283, Issue 46, 31559-31566, November 14, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/46/31559    most recent M805452200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kim, I. Articles by Wu, G. Search for Related Content PubMed PubMed Citation Articles by Kim, I. Articles by Wu, G. Social Bookmarking                      What's this?

Polycystin-2 Expression Is Regulated by a PC2-binding Domain in the Intracellular Portion of Fibrocystin^*

Ingyu Kim, Cunxi Li, Dan Liang, Xing-Zhen Chen^¶, Robert J. Coffy, Jie Ma^||, Ping Zhao^||, and Guanqing Wu^||1

From the Departments of Medicine and Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37232, the ^¶Department of Physiology, University of Alberta, Edmonton T6G 2H7, Canada, and the ^||Division of Translational Cancer Research and Therapy, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing 100021, China

Autosomal dominant (ADPKD) and autosomal recessive (ARPKD) polycystic kidney disease are caused by mutations in Pkd1/Pkd2 and Pkhd1, which encode polycystins (PCs) and fibrocystin/polyductin (FPC). Our recent study reported that a deficiency in FPC increases the severity of cystic disease in Pkd2 mutants and down-regulates PC2 in vivo, but the precise molecular mechanism of these effects is unknown (Kim, I., Fu, Y., Hui, K., Moeckel, G., Mai, W., Li, C., Liang, D., Zhao, P., Ma, J., Chen, X.-Z., George, A. L., Jr., Coffey, R. J., Feng, Z. P., and Wu, G. (2008) J. Am. Soc. Nephrol. 19, 455–468). In this study, through the use of deletion and mutagenesis strategies, we identified a PC2-binding domain in the intracellular C terminus of FPC and an FPC-binding domain in the intracellular N terminus of PC2. These binding domains provide a molecular basis for the physical interaction between PC2 and FPC. In addition, we also found that physical interaction between the binding domains of PC2 and FPC is able to prevent down-regulation of PC2 induced by loss of FPC. In vivo, we generated a mouse model of ADPKD with hypomorphic Pkd2 alleles (Pkd2^nf3/nf3) and show that PC2 down-regulation is accompanied by a phenotype similar to that of Pkhd1^–/– mice. These findings demonstrate a common mechanism underlying cystogenesis in ADPKD and ARPKD and provide insight into the molecular relationship between PC2 and FPC.

Received for publication, July 16, 2008 , and in revised form, September 9, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK062373 and DK071090. This work was also supported by a Yangzhi scholarship, China (to G. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Vanderbilt University, 539 Light Hall, 2215 Garland Ave., Nashville, TN 37232. Fax: 615-936-2661; E-mail: guanqing.wu{at}vanderbilt.edu.

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