Metabolic Regulator βKlotho Interacts with Fibroblast Growth Factor Receptor 4 (FGFR4) to Induce Apoptosis and Inhibit Tumor Cell Proliferation
Metabolic Regulator βKlotho Interacts with Fibroblast Growth Factor Receptor 4 (FGFR4) to Induce Apoptosis and Inhibit Tumor Cell Proliferation
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DOI：
10.1074/jbc.m110.148288
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发表时间：
2010-09-24
影响因子：
4.8
通讯作者：
McKeehan, Wallace L.
中科院分区：
文献类型：
--
作者：
Luo, Yongde;Yang, Chaofeng;McKeehan, Wallace L.
在参与代谢稳态的器官中，跨膜 α 和 β klothos 引导 FGFR 信号传导来控制代谢途径。 β klotho 和 FGFR4 的协调表达是成熟肝细胞的一个特性。小鼠 FGFR4 或 β klotho 的基因缺失会扰乱肝脏胆固醇/胆汁酸和脂质代谢。 FGFR4的缺失对肝损伤后肝细胞的增殖反应没有影响。然而，它的缺失会导致二甲基亚硝胺引发的肝细胞癌加速进展，表明 FGFR4 抑制肝癌增殖。 FGFR4 介导的肝癌抑制的机制尚未得到解决。在这里，我们发现 β klotho 表达在人和小鼠肝癌中比 FGFR4 更一致地下调。 FGFR4 激酶的内分泌 FGF19 或细胞 FGF1 在与 β klotho 复合物中的共表达和激活通过诱导肝细胞和非肝细胞中的凋亡细胞死亡来限制细胞群生长。 β klotho-FGFR4 伙伴关系导致激活的 AKT 和雷帕霉素哺乳动物靶标的抑制，同时激活 ERK1/2，这可能是促凋亡作用的基础。我们的结果表明，β klotho 不仅与硫酸乙酰肝素-FGFR4 相互作用形成对内分泌 FGF19 具有高亲和力的复合物，而且还影响由 FGF19 或经典 FGF1 激活的下游信号传导和生物终点的质量。因此，介导肝脏代谢内分泌控制的相同β-klotho-硫酸乙酰肝素-FGFR4伙伴关系通过促凋亡信号传导介导的细胞群生长的负控制在细胞稳态和肝癌抑制中发挥作用。
In organs involved in metabolic homeostasis, transmembrane alpha and beta klothos direct FGFR signaling to control of metabolic pathways. Coordinate expression of beta klotho and FGFR4 is a property of mature hepatocytes. Genetic deletion of FGFR4 or beta klotho in mice disrupts hepatic cholesterol/bile acid and lipid metabolism. The deletion of FGFR4 has no effect on the proliferative response of hepatocytes after liver injury. However, its absence results in accelerated progression of dimethynitrosamine- initiated hepatocellular carcinomas, indicating that FGFR4 suppresses hepatoma proliferation. The mechanism underlying the FGFR4-mediated hepatoma suppression has not been addressed. Here we show that beta klotho expression is more consistently down-regulated in human and mouse hepatomas than FGFR4. Co-expression and activation by either endocrine FGF19 or cellular FGF1 of the FGFR4 kinase in a complex with beta klotho restricts cell population growth through induction of apoptotic cell death in both hepatic and nonhepatic cells. The beta klotho-FGFR4 partnership caused a depression of activated AKT and mammalian target of rapamycin while activating ERK1/2 that may underlie the pro-apoptotic effect. Our results show that beta klotho not only interacts with heparan sulfate-FGFR4 to form a complex with high affinity for endocrine FGF19 but also impacts the quality of downstream signaling and biological end points activated by either FGF19 or canonical FGF1. Thus the same beta klotho-heparan sulfate-FGFR4 partnership that mediates endocrine control of hepatic metabolism plays a role in cellular homeostasis and hepatoma suppression through negative control of cell population growth mediated by pro-apoptotic signaling.