LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control.,Nature Cell Biology

当前位置： X-MOL 学术 › Nat. Cell Biol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control.
Nature Cell Biology ( IF 17.3 ) Pub Date : 2020-02-03 , DOI: 10.1038/s41556-020-0463-6
Wenjian Gan _{1,

2} , Xiaoming Dai ₁ , Xiangpeng Dai ₁ , Jun Xie ₃ , Shasha Yin ₂ , Junjie Zhu ₄ , Chen Wang ₄ , Yuchen Liu ₅ , Jianping Guo ₁ , Min Wang _{1,

6} , Jing Liu ₁ , Jia Hu _{1,

7} , Ryan J Quinton _{8,

9} , Neil J Ganem _{8,

9} , Pengda Liu ₁₀ , John M Asara ₁₁ , Pier Paolo Pandolfi ₁₂ , Yingzi Yang ₅ , Zhigang He ₄ , Guangping Gao ₃ , Wenyi Wei ₁

Affiliation

Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
Li Weibo Institute for Rare Diseases Research and Horae Gene Therapy Center and Vector Core, University of Massachusetts Medical School, Worcester, MA, USA.
F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurology, Harvard Medical School, Boston, MA, USA.
Department of Developmental Biology, Harvard Stem Cell Institute, Harvard School of Dental Medicine, Boston, MA, USA.
Departments of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Departments of Urology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
The Laboratory of Cancer Cell Biology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
Division of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

The Hippo and mammalian target of rapamycin complex 1 (mTORC1) pathways are the two predominant growth-control pathways that dictate proper organ development. We therefore explored potential crosstalk between these two functionally relevant pathways to coordinate their growth-control functions. We found that the LATS1 and LATS2 kinases, the core components of the Hippo pathway, phosphorylate S606 of Raptor, an essential component of mTORC1, to attenuate mTORC1 activation by impairing the interaction of Raptor with Rheb. The phosphomimetic Raptor-S606D knock-in mutant led to a reduction in cell size and proliferation. Compared with Raptor+/+ mice, RaptorD/D knock-in mice exhibited smaller livers and hearts, and a significant inhibition of elevation in mTORC1 signalling induced by Nf2 or Lats1 and Lats2 loss. Thus, our study reveals a direct link between the Hippo and mTORC1 pathways to fine-tune organ growth.

中文翻译：

LATS 抑制 mTORC1 活性以在生长控制中直接协调 Hippo 和 mTORC1 通路。

河马和哺乳动物雷帕霉素复合物 1 (mTORC1) 通路的靶点是决定适当器官发育的两条主要生长控制通路。因此，我们探索了这两种功能相关途径之间的潜在串扰，以协调它们的生长控制功能。我们发现 LATS1 和 LATS2 激酶（Hippo 通路的核心成分）磷酸化 Raptor（mTORC1 的重要成分）的 S606，通过削弱 Raptor 与 Rheb 的相互作用来减弱 mTORC1 的激活。拟磷 Raptor-S606D 敲入突变体导致细胞大小和增殖的减少。与 Raptor+/+ 小鼠相比，RaptorD/D 敲入小鼠的肝脏和心脏更小，并且显着抑制了由 Nf2 或 Lats1 和 Lats2 缺失诱导的 mTORC1 信号传导的升高。因此，

更新日期：2020-02-03

点击分享查看原文

点击收藏

公开下载

阅读更多本刊最新论文本刊介绍/投稿指南11