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J. Biol. Chem., Vol. 281, Issue 47, 36044-36051, November 24, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/47/36044    most recent M604787200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mochida, Y. Articles by Yamauchi, M. Search for Related Content PubMed PubMed Citation Articles by Mochida, Y. Articles by Yamauchi, M. Social Bookmarking                      What's this?

Nephrocan, a Novel Member of the Small Leucine-rich Repeat Protein Family, Is an Inhibitor of Transforming Growth Factor- Signaling^*

Yoshiyuki Mochida, Duenpim Parisuthiman, Masaru Kaku, Jun-ichi Hanai, Vikas P. Sukhatme, and Mitsuo Yamauchi¹

From the Dental Research Center, University of North Carolina, Chapel Hill, North Carolina 27599-7455 and Divisions of Nephrology and Hematology-Oncology, Departments of Medicine and Pathology, Center for Study of the Tumor Microenvironment, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215

In a search of new, small leucine-rich repeat proteoglycan/protein (SLRP) family members, a novel gene, nephrocan (NPN), has been identified. The gene consists of three exons, and based on the deduced amino acid sequence, NPN has 17 leucine-rich repeat motifs and unique cysteine-rich clusters both in the N and C termini, indicating that this gene belongs to a new class of SLRP family. NPN mRNA was predominantly expressed in kidney in adult mice, and during mouse embryogenesis, the expression was markedly increased in 11-day-old embryos at a time when early kidney development takes place. In the adult mouse kidney, NPN protein was located in distal tubules and collecting ducts. When NPN was overexpressed in cell culture, the protein was detected in the cultured medium, and upon treatment with N-glycosidase F, the molecular mass was lowered by 14 kDa, indicating that NPN is a secreted N-glycosylated protein. Furthermore, transforming growth factor- (TGF-)-responsive 3TP promoter luciferase activity was down-regulated, and TGF--induced Smad3 phosphorylation was also inhibited by NPN, suggesting that NPN suppresses TGF-/Smad signaling. Taken together, NPN is a novel member of the SLRP family that may play important roles in kidney development and pathophysiology by functioning as an endogenous inhibitor of TGF- signaling.

Received for publication, May 18, 2006 , and in revised form, August 29, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY938536 [GenBank] , DQ233647 [GenBank] , and DQ166815 [GenBank] .

^* This work was supported by National Institutes of Health Grants NIDCR DE10489 (to M. Y.) and NIAMS AR052824 (to M. Y.) and NASA Grant NAG2-1596 (to M. Y.). 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.

¹ To whom correspondence should be addressed: CB 7455, Dental Research Center, University of North Carolina, Chapel Hill, NC 27599-7455. Tel.: 919-966-3441; Fax: 919-966-1231; E-mail: Mitsuo_Yamauchi{at}dentistry.unc.edu.

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