State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Cancer Research Center of Xiamen University, Xiamen, Fujian 361102, China.
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Dev Cell. 2019 Feb 25;48(4):460-474.e9. doi: 10.1016/j.devcel.2018.12.021. Epub 2019 Feb 7.
The external factors that modulate Hippo signaling remain elusive. Here, we report that FGF15 activates Hippo signaling to suppress bile acid metabolism, liver overgrowth, and tumorigenesis. FGF15 is induced by FXR in ileal enterocytes in response to increased amounts of intestinal bile. We found that circulating enterohepatic FGF15 stimulates hepatic receptor FGFR4 to recruit and phosphorylate NF2, which relieves the inhibitory effect of Raf on the Hippo kinases Mst1/2, thereby switching FGFR4's role from pro-oncogenic to anti-tumor signaling. The activated Mst1/2 subsequently phosphorylates and stabilizes SHP to downregulate the key bile acid-synthesis enzyme Cyp7a1 expression, thereby limiting bile acid synthesis. In contrast, Mst1/2 deficiency impairs bile acid metabolism and remarkably increases Cyp7a1 expression and bile acid production. Importantly, pharmacological depletion of intestinal bile abrogates Mst1/2-mutant-driven liver overgrowth and oncogenesis. Therefore, FGF15-Hippo signaling along the gut-liver axis acts as a sensor of bile acid availability to restrain liver size and tumorigenesis.
调节 Hippo 信号的外部因素仍然难以捉摸。在这里，我们报告 FGF15 通过激活 Hippo 信号来抑制胆汁酸代谢、肝脏过度生长和肿瘤发生。FGF15 是 FXR 在回肠肠细胞中响应增加的肠道胆汁而诱导的。我们发现循环肠肝 FGF15 刺激肝受体 FGFR4 招募和磷酸化 NF2，从而解除 Raf 对 Hippo 激酶 Mst1/2 的抑制作用，从而将 FGFR4 的作用从促癌转变为抗肿瘤信号。激活的 Mst1/2 随后磷酸化并稳定 SHP 以下调关键的胆汁酸合成酶 Cyp7a1 的表达，从而限制胆汁酸的合成。相比之下，Mst1/2 缺陷会损害胆汁酸代谢，并显著增加 Cyp7a1 的表达和胆汁酸的产生。重要的是，肠道胆汁的药理学耗竭可消除 Mst1/2 突变驱动的肝脏过度生长和肿瘤发生。因此，沿肠道-肝脏轴的 FGF15-Hippo 信号作为胆汁酸可用性的传感器，可限制肝脏大小和肿瘤发生。
