Kharitonenkov Alexei, Dunbar James D, Bina Holly A, Bright Stuart, Moyers Julie S, Zhang Chen, Ding Liyun, Micanovic Radmila, Mehrbod Sean F, Knierman Michael D, Hale John E, Coskun Tamer, Shanafelt Armen B
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
J Cell Physiol. 2008 Apr;215(1):1-7. doi: 10.1002/jcp.21357.
Fibroblast growth factor-21 (FGF-21) is a metabolic regulator that can influence glucose and lipid control in diabetic rodents and primates. We demonstrate that betaKlotho is an integral part of an activated FGF-21-betaKlotho-FGF receptor (FGFR) complex thus a critical subunit of the FGF-21 receptor. Cells lacking betaKlotho did not respond to FGF-21; the introduction of betaKlotho to these cells conferred FGF-21-responsiveness and recapitulated the entire scope of FGF-21 signaling observed in naturally responsive cells. Interestingly, FGF-21-mediated effects are heparin independent suggesting that betaKlotho plays a role in FGF-21 activity similar to the one played by heparin in the signaling of conventional FGFs. Moreover, in addition to conferring specificity for FGF-21, betaKlotho appears to support FGF-19 activity and mediates the receptor selectivity profile of FGF-19. All together, these results indicate that betaKlotho and FGFRs form the cognate FGF-21 receptor complex, mediating FGF-21 cellular specificity and physiological effects.
成纤维细胞生长因子21（FGF - 21）是一种代谢调节因子，可影响糖尿病啮齿动物和灵长类动物的血糖和血脂控制。我们证明β-klotho是活化的FGF - 21 - β-klotho - 成纤维细胞生长因子受体（FGFR）复合物的一个组成部分，因此是FGF - 21受体的关键亚基。缺乏β-klotho的细胞对FGF - 21无反应；将β-klotho引入这些细胞赋予了它们对FGF - 21的反应性，并重现了在天然反应性细胞中观察到的FGF - 21信号传导的整个范围。有趣的是，FGF - 21介导的效应不依赖于肝素，这表明β-klotho在FGF - 21活性中所起的作用类似于肝素在传统FGF信号传导中所起的作用。此外，除了赋予对FGF - 21的特异性外，β-klotho似乎还支持FGF - 19的活性并介导FGF - 19的受体选择性谱。总之，这些结果表明β-klotho和FGFRs形成了同源的FGF - 21受体复合物，介导FGF - 21的细胞特异性和生理效应。
