Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis.
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.
['Tagliabracci|Vincent S|VS|', 'Engel|James L|JL|', 'Wiley|Sandra E|SE|', 'Xiao|Junyu|J|', 'Gonzalez|David J|DJ|', 'Nidumanda Appaiah|Hitesh|H|', 'Koller|Antonius|A|', 'Nizet|Victor|V|', 'White|Kenneth E|KE|', 'Dixon|Jack E|JE|']
D000595:Amino Acid Sequence D001483:Base Sequence D047389:Casein Kinase I D017931:DNA Primers D016326:Extracellular Matrix Proteins D000089703:Fibroblast Growth Factor-23 D005346:Fibroblast Growth Factors D045683:Furin D006031:Glycosylation D057809:HEK293 Cells D006801:Humans D015151:Immunoblotting D047468:Immunoprecipitation D013058:Mass Spectrometry D008969:Molecular Sequence Data D017350:N-Acetylgalactosaminyltransferases D010766:Phosphorylation D059748:Proteolysis D017422:Sequence Analysis, DNA D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization D053719:Tandem Mass Spectrometry
Fam20 chronic kidney disease familial tumoral calcinosis phosphate homeostasis rickets