title: Fibroblast growth factor 23 reduces expression of type IIa Na+/Pi co-transporter by signaling through a receptor functionally distinct from the known FGFRs in opossum kidney cells.
abstract: Fibroblast growth factor (FGF) 23 is an important phosphaturic factor that inhibits inorganic phosphate (Pi) reabsorption from the renal proximal tubule. Its overproduction and proteolysis-resistant mutation such as R179Q cause tumor-induced osteomalacia and autosomal dominant hypophosphatemic rickets, respectively. To clarify the signaling mechanisms of FGF23 that mediate the reduction of Pi reabsorption, we inhibited the function of the known FGFRs in opossum kidney (OK-E) cells by expressing a dominant-negative (DN) form of FGFR. OK-E cells, which represent the renal proximal tubular cells, expressed all four known FGFRs. FGF23(R179Q) bound to and activated FGFR2, a prominent FGFR expressed in OK-E cells. The activated receptor transmitted a signal to increase the expression of type IIa Na(+)/Pi co-transporter and the Pi uptake. Expression of FGFR2(DN), which suppresses the major FGFR-mediated signal through the FRS2alpha-ERK pathway, reversed the function of FGF23(R179Q). When FGF23(R179Q) was applied to the basolateral side of polarized OK-E cells, regardless of the FGFR2(DN) expression, the apical Pi uptake decreased significantly. The apical application of FGF23(R179Q) in the polarized cells did not show such decrease but increase. The exogenously expressed FGFR2 was detectable only at the apical membrane. These results suggest that an FGF23 receptor, which is functionally distinct from the known FGFRs, is expressed at the basolateral membrane of OK-E cells.
authors.affiliation: Department of Molecular Cell Biology, Institute of Advanced Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Yan
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yokote
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Jing
authors.forename: Li
authors.initials: L
authors.lastname: Yao
authors.forename: Takahiro
authors.initials: T
authors.lastname: Sawada
authors.forename: Yueqiang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sitai
authors.initials: S
authors.lastname: Liang
authors.forename: Kazushige
authors.initials: K
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D009893:Opossums; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C000717427:FGF23 protein, human; D017468:Receptors, Fibroblast Growth Factor; C493554:SLC34A1 protein, human; D050608:Sodium-Phosphate Cotransporter Proteins; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D027981:Symporters; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23