Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability
Curtailing FGF19's mitogenicity by suppressing its receptor dimerization ability
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通过抑制 FGF19 受体二聚化能力来减少 FGF19 的有丝分裂能力
DOI：
10.1073/pnas.2010984117
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发表时间：
2020-11-17
影响因子：
11.1
通讯作者：
Huang, Zhifeng
中科院分区：
文献类型：
--
作者：
Niu, Jianlou;Zhao, Jing;Huang, Zhifeng
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 FGF19WT-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. As a physiological regulator of bile acid homeostasis, FGF19 is also a potent insulin sensitizer capable of normalizing plasma glucose concentration, improving lipid profile, ameliorating fatty liver disease, and causing weight loss in both diabetic and diet-induced obesity mice. There is therefore a major interest in developing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease. However, the known tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its clinical potential. Here, we show that nonmitogenic FGF19 variants that retain the full beneficial glucose-lowering and bile acid regulatory activities of WT FGF19 (FGF19WT) can be engineered by diminishing FGF19’s ability to induce dimerization of its cognate FGF receptors (FGFR). As proof of principle, we generated three such variants, each with a partial defect in binding affinity to FGFR (FGF19ΔFGFR) and its coreceptors, i.e., βklotho (FGF19ΔKLB) or heparan sulfate (FGF19ΔHBS). Pharmacological assays in WT and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control and regulating bile acid synthesis. This approach provides a robust framework for the development of safer and more efficacious FGF19 analogs.
