当前位置： SCI文献检索 > JOURNAL OF MOLECULAR BIOLOGY期刊下所有文献 > A unique FGF23 with the ability to activate FGFR signaling through both αKlotho and βKlotho.

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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Wu X,Weiszmann J,Ge H,Baribault H,Stevens J,Hawkins N,Vonderfecht S,Gardner J,Gupte J,Sheng J,Wang M,Li Y

doi

10.1016/j.jmb.2012.02.027

subject

Has Abstract

pub_date

2012-04-20 00:00:00

pages

82-9

issue

1-2

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(12)00184-2

journal_volume

418

pub_type

杂志文章

在线工具

A unique FGF23 with the ability to activate FGFR signaling through both αKlotho and βKlotho.