Curtailing FGF19’s mitogenicity by suppressing its receptor dimerization ability
Jianlou Niu, Jing Zhao, Jiamin Wu, Guanting Qiao, Junlian Gu, Chuanren Zhou, Qi Li, Ying Lei, Dezhong Wang, Huan Lin, Xiaokun Li, Moosa Mohammadi, Zhifeng Huang
Abstract
Significance In this study, we posited that the metabolic and mitogenic activities of enterokine FGF19 are reflections of different thresholds of FGF19-induced FGF receptor (FGFR) dimerization. To test our hypothesis, we engineered three FGF19 variants that have progressively reduced FGFR dimerization capacity. We show that these variants have progressively reduced cell proliferative/tumorigenic activity but maintain FGF19 WT -like metabolic activities. These observations substantiate our model in which FGF signaling specificity is regulated by different thresholds in FGF-induced FGFR dimer stability and longevity, and provide a simple stratagem to engineer safer agonists of FGF19—or indeed any other FGF—for the treatment of a range of metabolic diseases.