Vincent S. Tagliabracci1, J Engel2,3, Sandra E. Wiley2,3, Junyu Xiao2,3, David J. Gonzalez2,4,3, Hitesh Appaiah5, Antonius Koller6, Victor Nizet4,7, Kenneth E. White5, Jack E. Dixon8,9,2,3
1Departments of Pharmacology, Pediatrics, Cellular and Molecular Medicine, and Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093.
2Departments of aPharmacology,
3University of california at San Diego
4Pediatrics
5cDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202; and
6Stony Brook University Proteomics Center, School of Medicine, Stony Brook University, Stony Brook, NY 11794
7Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093
8¶Cellular and Molecular Medicine, and
9Chemistry and Biochemistry and
Tóm tắt
Significance
The family with sequence similarity 20, member C (Fam20C) is a secretory pathway-specific kinase that phosphorylates secreted proteins on Ser-x-Glu/pSer motifs. Mutations in human
FAM20C
cause a devastating childhood disorder known as Raine syndrome. Some patients with
FAM20C
mutations as well as
Fam20C
KO mice develop hypophosphatemia due to elevated levels of the phosphate-regulating hormone FGF23. In this paper, we show that Fam20C phosphorylates FGF23 on a Ser-x-Glu motif that lies within a critical region of the hormone. The phosphorylation promotes FGF23 proteolysis by furin by blocking O-glycosylation by polypeptide
N
-acetylgalactosaminyltransferase 3. Our results have important implications for patients with abnormalities in phosphate homeostasis.
