A Unique FGF23 with the Ability to Activate FGFR Signaling through Both ¦ÁKlotho and ¦ÂKlotho

详细信息    查看全文

• 作者：Xinle Wu¹ ; ^&dagger ; ; Jennifer Weiszmann¹ ; ^&dagger ; ; Hongfei Ge¹ ; ^&dagger ; ; Helene Baribault¹ ; Jennitte Stevens² ; Nessa Hawkins² ; Steven Vonderfecht² ; Jonitha Gardner¹ ; Jamila Gupte¹ ; Jackie Sheng² ; Minghan Wang² ; Yang Li¹ ; ^{yangl@amgen.com}
• 关键词：FGF19 ; FGF21 ; FGF23 ; Klotho ; ¦ÂKlotho
• 刊名：Journal of Molecular Biology
• 出版年：2012
• 出版时间：20 April, 2012
• 年：2012
• 卷：418
• 期：1-2
• 页码：82-89
• 全文大小：578 K

文摘

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 ¦ÂKlotho 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 ¦ÂKlotho/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 ¦ÁKlotho. 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.