Klotho converts canonical FGF receptor into a specific receptor for FGF23
Klotho converts canonical FGF receptor into a specific receptor for FGF23
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DOI：
10.1038/nature05315
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发表时间：
2006-12-07
期刊：
影响因子：
64.8
通讯作者：
Yamashita, Takeyoshi
中科院分区：
文献类型：
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作者：
Urakawa, Itaru;Yamazaki, Yuji;Yamashita, Takeyoshi
FGF 23是成纤维细胞生长因子（FGF）家族的独特成员，因为它作为源自骨的激素并调节肾功能，而大多数其他家族成员被认为在局部水平调节各种细胞功能（1-5）。循环FGF 23的促肾活性表明肾脏中可能存在FGF 23特异性受体（6）。在这里，我们表明，Klotho（一种衰老相关分子）先前未描述的受体转换产生了FGF 23受体。使用肾匀浆，我们发现Klotho与FGF 23结合。Klotho的强制表达使FGF 23能够高亲和力结合到细胞表面，并恢复肾细胞系响应FGF 23处理的能力。此外，通过向野生型小鼠注射抗Klotho单克隆抗体诱导FGF 23无能。因此，Klotho对于内源性FGF 23功能是必需的。由于Klotho单独似乎不能进行细胞内信号传导，我们寻找了FGF 23受体的其他组分，并发现了FGFR 1（IIIc），它被Klotho直接转化为FGF 23受体。因此，Klotho和FGFR 1（IIIc）的协同作用重建了FGF 23受体。这些发现提供了深入了解FGF和FGF受体之间相互作用的多样性和特异性。
FGF23 is a unique member of the fibroblast growth factor (FGF) family because it acts as a hormone that derives from bone and regulates kidney functions, whereas most other family members are thought to regulate various cell functions at a local level(1-5). The renotropic activity of circulating FGF23 indicates the possible presence of an FGF23-specific receptor in the kidney(6). Here we show that a previously undescribed receptor conversion by Klotho, a senescence-related molecule(7), generates the FGF23 receptor. Using a renal homogenate, we found that Klotho binds to FGF23. Forced expression of Klotho enabled the high-affinity binding of FGF23 to the cell surface and restored the ability of a renal cell line to respond to FGF23 treatment. Moreover, FGF23 incompetence was induced by injecting wild-type mice with an anti-Klotho monoclonal antibody. Thus, Klotho is essential for endogenous FGF23 function. Because Klotho alone seemed to be incapable of intracellular signalling, we searched for other components of the FGF23 receptor and found FGFR1(IIIc), which was directly converted by Klotho into the FGF23 receptor. Thus, the concerted action of Klotho and FGFR1( IIIc) reconstitutes the FGF23 receptor. These findings provide insights into the diversity and specificity of interactions between FGF and FGF receptors.