Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis.

Abstract

The family with sequence similarity 20, member C (Fam20C) has recently been identified as the Golgi casein kinase. Fam20C phosphorylates secreted proteins on Ser-x-Glu/pSer motifs and loss-of-function mutations in the kinase cause Raine syndrome, an often-fatal osteosclerotic bone dysplasia. Fam20C is potentially an upstream regulator of the phosphate-regulating hormone fibroblast growth factor 23 (FGF23), because humans with FAM20C mutations and Fam20C KO mice develop hypophosphatemia due to an increase in full-length, biologically active FGF23. However, the mechanism by which Fam20C regulates FGF23 is unknown. Here we show that Fam20C directly phosphorylates FGF23 on Ser(180), within the FGF23 R(176)XXR(179)/S(180)AE subtilisin-like proprotein convertase motif. This phosphorylation event inhibits O-glycosylation of FGF23 by polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-T3), and promotes FGF23 cleavage and inactivation by the subtilisin-like proprotein convertase furin. Collectively, our results provide a molecular mechanism by which FGF23 is dynamically regulated by phosphorylation, glycosylation, and proteolysis. Furthermore, our findings suggest that cross-talk between phosphorylation and O-glycosylation of proteins in the secretory pathway may be an important mechanism by which secreted proteins are regulated.

• Authors: Vincent S Tagliabracci, James L Engel, Sandra E Wiley, Junyu Xiao, David J Gonzalez, Hitesh Nidumanda Appaiah, Antonius Koller, Victor Nizet, Kenneth E White, Jack E Dixon
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 15 Pg. 5520-5 (Apr 15 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24706917 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA Primers
• Extracellular Matrix Proteins
• FGF23 protein, human
• Fgf23 protein, mouse
• Fibroblast Growth Factors
• Fibroblast Growth Factor-23
• N-Acetylgalactosaminyltransferases
• polypeptide N-acetylgalactosaminyltransferase
• Casein Kinase I
• FAM20C protein, human
• Furin

Topics

• Amino Acid Sequence
• Base Sequence
• Casein Kinase I
• DNA Primers (genetics)
• Extracellular Matrix Proteins (immunology, metabolism)
• Fibroblast Growth Factor-23
• Fibroblast Growth Factors (metabolism)
• Furin (metabolism)
• Glycosylation
• HEK293 Cells
• Humans
• Immunoblotting
• Immunoprecipitation
• Mass Spectrometry
• Molecular Sequence Data
• N-Acetylgalactosaminyltransferases (metabolism)
• Phosphorylation
• Proteolysis
• Sequence Analysis, DNA
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• Tandem Mass Spectrometry