New Insights into the Mechanism of Action of Soluble Klotho.
New Insights into the Mechanism of Action of Soluble Klotho.
复制标题
对可溶性Klotho作用机制的新见解。
DOI：
10.3389/fendo.2017.00323
复制
发表时间：
2017
影响因子：
5.2
通讯作者：
Huang CL
中科院分区：
文献类型：
--
作者：
Dalton GD;Xie J;An SW;Huang CL
klotho 基因编码 I 型单次跨膜蛋白，其包含大的胞外结构域、跨膜片段和短的胞内结构域。 Klotho 蛋白以多种形式存在，包括全长膜形式 (mKl) 和可溶性循环形式 [可溶性 klotho (sKl)]。 mK1与成纤维细胞生长因子受体复合形成FGF23的辅助受体，这使其能够参与FGF23介导的信号转导以及磷酸盐和钙稳态的调节。 sKL 存在于血液、尿液和脑脊液中，发挥多种功能，包括调节离子通道/转运蛋白和生长因子信号传导。 sKl 如何发挥这些多效性功能尚不清楚。理解 sKl 作为“激素”的作用机制的一个障碍是无法识别介导其作用的受体。在体内，肾脏是 sKl 的主要来源，肾脏疾病期间 sKl 水平会下降。慢性肾病中的 sKL 缺乏使心脏容易受到压力引起的损伤。在这里，我们总结了目前对 mKl 作用机制的了解，以及 sKl 对心脏具有不依赖于 FGF23 的保护作用的机制基础，并提供了对 sKl 作用机制的新见解，重点关注最近发现的 sKl 结合膜脂筏中的唾液酸神经节苷脂以调节生长因子信号传导。
The klotho gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full-length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for FGF23, which allows it to participate in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl’s mechanism of action as a “hormone” has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl’s mechanism of action, the mechanistic basis of sKl’s protective, FGF23-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling.