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J. Biol. Chem., Vol. 281, Issue 27, 18370-18377, July 7, 2006

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Polypeptide GalNAc-transferase T3 and Familial Tumoral Calcinosis

SECRETION OF FIBROBLAST GROWTH FACTOR 23 REQUIRES O-GLYCOSYLATION^*

Kentaro Kato, Charlotte Jeanneau, Mads Agervig Tarp, Anna Benet-Pagès, Bettina Lorenz-Depiereux, Eric Paul Bennett^¶, Ulla Mandel^¶, Tim M. Strom^||, and Henrik Clausen¹

From the Department of Medical Biochemistry and Genetics, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark, the Institute of Human Genetics, GSF National Research Center, Ingolstädter Landstrasse 1, 85764 Munich-Neuherberg, Germany, the ^¶Faculty of Health Sciences, School of Dentistry, University of Copenhagen, Nørre Alle 20 DK-2200 Copenhagen N, Denmark, the ^||Institute of Human Genetics, Klinikum rechts der Isar, Technical University, Ismaningerstrasse 22, 81675 Munich, Germany

Mutations in the gene encoding the glycosyltransferase polypeptide GalNAc-T3, which is involved in initiation of O-glycosylation, were recently identified as a cause of the rare autosomal recessive metabolic disorder familial tumoral calcinosis (OMIM 211900). Familial tumoral calcinosis is associated with hyperphosphatemia and massive ectopic calcifications. Here, we demonstrate that the secretion of the phosphaturic factor fibroblast growth factor 23 (FGF23) requires O-glycosylation, and that GalNAc-T3 selectively directs O-glycosylation in a subtilisin-like proprotein convertase recognition sequence motif, which blocks processing of FGF23. The study suggests a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation and protease processing to produce intact FGF23.

Received for publication, March 16, 2006 , and in revised form, April 21, 2006.

^* This work was supported by the Danish Cancer Society, the Danish Medical Council, EU Biotech 5th Framework CT-2002-01980, CT-2002-02010, and the Deutsche Forschungsgemeinschaft (STR304/2-2). 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: Dept. of Medical Biochemistry and Genetics, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. Tel.: 45-35327797; Fax: 45-35367980; E-mail: hc{at}imbg.ku.dk.

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