title: A unique FGF23 with the ability to activate FGFR signaling through both αKlotho and βKlotho.
abstract: Three fibroblast growth factor (FGF) molecules, FGF19, FGF21, and FGF23, form a unique subfamily that functions as endocrine hormones. FGF19 and FGF21 can regulate glucose, lipid, and energy metabolism, while FGF23 regulates phosphate homeostasis. The FGF receptors and co-receptors for these three FGF molecules have been identified, and domains important for receptor interaction and specificity determination are beginning to be elucidated. However, a number of questions remain unanswered, such as the identification of fibroblast growth factor receptor responsible for glucose regulation. Here, we have generated a variant of FGF23: FGF23-21c, where the C-terminal domain of FGF23 was replaced with the corresponding regions from FGF21. FGF23-21c showed a number of interesting and unexpected properties in vitro. In contrast to wild-type FGF23, FGF23-21c gained the ability to activate FGFR1c and FGFR2c in the presence of βKlotho and was able to stimulate glucose uptake into adipocytes in vitro and lower glucose levels in ob/ob diabetic mice model to similar extent as FGF21 in vivo. These results suggest that βKlotho/FGFR1c or FGFR2c receptor complexes are sufficient for glucose regulation. Interestingly, without the FGF23 C-terminal domain, FGF23-21c was still able to activate fibroblast growth factor receptors in the presence of αKlotho. This suggests not only that sequences outside of the C-terminal region may also contribute to the interaction with co-receptors but also that FGF23-21c may be able to regulate both glucose and phosphate metabolisms. This raises an interesting concept of designing an FGF molecule that may be able to address multiple diseases simultaneously. Further understanding of FGF/receptor interactions may allow the development of exciting opportunities for novel therapeutic discovery.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
authors.forename: Xinle
authors.initials: X
authors.lastname: Wu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Hongfei
authors.initials: H
authors.lastname: Ge
authors.forename: Helene
authors.initials: H
authors.lastname: Baribault
authors.forename: Jennitte
authors.initials: J
authors.lastname: Stevens
authors.forename: Nessa
authors.initials: N
authors.lastname: Hawkins
authors.forename: Steven
authors.initials: S
authors.lastname: Vonderfecht
authors.forename: Jonitha
authors.initials: J
authors.lastname: Gardner
authors.forename: Jamila
authors.initials: J
authors.lastname: Gupte
authors.forename: Jackie
authors.initials: J
authors.lastname: Sheng
authors.forename: Minghan
authors.initials: M
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001786:Blood Glucose; C000717428:Fgf23 protein, mouse; C418622:Klb protein, mouse; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D005966:Glucuronidase; D000090265:Klotho Proteins; D005947:Glucose