Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Dev Cell. 2010 Jul 20;19(1):27-38. doi: 10.1016/j.devcel.2010.06.015.
The conserved Hippo signaling pathway regulates organ size in Drosophila and mammals. While a core kinase cascade leading from the protein kinase Hippo (Hpo) (Mst1 and Mst2 in mammals) to the transcription coactivator Yorkie (Yki) (YAP in mammals) has been established, upstream regulators of the Hippo kinase cascade are less well defined, especially in mammals. Using conditional knockout mice, we demonstrate that the Merlin/NF2 tumor suppressor and the YAP oncoprotein function antagonistically to regulate liver development. While inactivation of Yap led to loss of hepatocytes and biliary epithelial cells, inactivation of Nf2 led to hepatocellular carcinoma and bile duct hamartoma. Strikingly, the Nf2-deficient phenotypes in multiple tissues were largely suppressed by heterozygous deletion of Yap, suggesting that YAP is a major effector of Merlin/NF2 in growth regulation. Our studies link Merlin/NF2 to mammalian Hippo signaling and implicate YAP activation as a mediator of pathologies relevant to Neurofibromatosis 2.
保守的 Hippo 信号通路调节果蝇和哺乳动物的器官大小。虽然已经建立了从蛋白激酶 Hippo（Hpo）（哺乳动物中的 Mst1 和 Mst2）到转录共激活因子 Yorkie（Yki）（哺乳动物中的 YAP）的核心激酶级联，但 Hippo 激酶级联的上游调节剂定义不太明确，尤其是在哺乳动物中。使用条件性敲除小鼠，我们证明 Merlin/NF2 肿瘤抑制因子和 YAP 癌蛋白拮抗作用调节肝脏发育。虽然 Yap 的失活导致肝细胞和胆管上皮细胞丢失，但 Nf2 的失活导致肝细胞癌和胆管错构瘤。引人注目的是， Yap 杂合缺失在很大程度上抑制了多种组织中的 Nf2 缺陷表型，表明 YAP 是 Merlin/NF2 在生长调节中的主要效应物。我们的研究将 Merlin/NF2 与哺乳动物 Hippo 信号通路联系起来，并暗示 YAP 激活是与神经纤维瘤病 2 相关的病理学的介导物。
