Conversion of a Paracrine Fibroblast Growth Factor into an Endocrine Fibroblast Growth Factor
Conversion of a Paracrine Fibroblast Growth Factor into an Endocrine Fibroblast Growth Factor
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DOI：
10.1074/jbc.m112.342980
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发表时间：
2012-08-17
影响因子：
4.8
通讯作者：
Mohammadi, Moosa
中科院分区：
文献类型：
--
作者：
Goetz, Regina;Ohnishi, Mutsuko;Mohammadi, Moosa
FGF 19、21 和 23 是以 Klotho 共受体依赖性方式调节主要代谢过程的激素，例如葡萄糖和脂质代谢 (FGF21) 以及磷酸盐和维生素 D 稳态 (FGF23)。硫酸乙酰肝素糖胺聚糖在内分泌 FGF 细胞表面信号复合物形成中的作用仍不清楚。在这里，我们证明硫酸乙酰肝素不是 FGF19 和 FGF23 信号转导单元的组成部分。为了支持我们的模型，我们通过降低旁分泌 FGF 的硫酸乙酰肝素结合亲和力并将其 C 端尾部替换为含有 Klotho 共受体结合位点的内分泌 FGF 的 C 端尾部，将旁分泌 FGF 转化为内分泌配体，从而将配体归巢到靶组织中。除了作为概念证明之外，配体转化还为工程内分泌 FGF 样分子提供了一种新策略，用于治疗代谢性疾病，包括 2 型糖尿病和肥胖等全球流行病。
FGFs 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. Here we show that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. In support of our model, we convert a paracrine FGF into an endocrine ligand by diminishing heparan sulfate-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor-binding site to home the ligand into the target tissue. In addition to serving as a proof of concept, the ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.