LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control

Wenjian Gan; Xiaoming Dai; Xiangpeng Dai; Jun Xie; Shasha Yin; Junjie Zhu; Chen Wang; Yuchen Liu; Jianping Guo; Min Wang; Jing Liu; Jia Hu; Ryan J Quinton; Neil J Ganem; Pengda Liu; John M Asara; Pier Paolo Pandolfi; Yingzi Yang; Zhigang He; Guangping Gao; Wenyi Wei

doi:10.1038/s41556-020-0463-6

LATS suppresses mTORC1 activity to directly coordinate Hippo and mTORC1 pathways in growth control

Nat Cell Biol. 2020 Feb;22(2):246-256. doi: 10.1038/s41556-020-0463-6. Epub 2020 Feb 3.

Authors

Wenjian Gan^#^{1

2}, Xiaoming Dai^#³, Xiangpeng Dai³, Jun Xie⁴, Shasha Yin⁵, Junjie Zhu⁶, Chen Wang⁶, Yuchen Liu⁷, Jianping Guo³, Min Wang^{3

8}, Jing Liu³, Jia Hu^{3

9}, Ryan J Quinton^{10

11}, Neil J Ganem^{10

11}, Pengda Liu¹², John M Asara¹³, Pier Paolo Pandolfi¹⁴, Yingzi Yang⁷, Zhigang He⁶, Guangping Gao⁴, Wenyi Wei¹⁵

Affiliations

¹ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].
² Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA. [email protected].
³ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
⁴ Li Weibo Institute for Rare Diseases Research and Horae Gene Therapy Center and Vector Core, University of Massachusetts Medical School, Worcester, MA, USA.
⁵ Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
⁶ F.M. Kirby Neurobiology Center, Boston Children's Hospital and Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁷ Department of Developmental Biology, Harvard Stem Cell Institute, Harvard School of Dental Medicine, Boston, MA, USA.
⁸ Departments of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁹ Departments of Urology, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
¹⁰ The Laboratory of Cancer Cell Biology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.
¹¹ Division of Hematology and Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
¹² Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹³ Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁴ Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
¹⁵ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [email protected].

^# Contributed equally.

Abstract

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, Raptor^D/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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
CRISPR-Cas Systems
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology
Female
Gene Editing
Gene Expression Regulation, Developmental*
HCT116 Cells
HEK293 Cells
HeLa Cells
Heterografts
Hippo Signaling Pathway
Humans
Liver / abnormalities
Liver / metabolism
MCF-7 Cells
Mechanistic Target of Rapamycin Complex 1 / genetics*
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Mice, Nude
Mice, Transgenic
Myocardium / metabolism
Myocardium / pathology
Neurofibromin 2 / deficiency
Neurofibromin 2 / genetics
Organ Size
Protein Serine-Threonine Kinases / deficiency
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
Ras Homolog Enriched in Brain Protein / genetics*
Ras Homolog Enriched in Brain Protein / metabolism
Regulatory-Associated Protein of mTOR / genetics*
Regulatory-Associated Protein of mTOR / metabolism
Signal Transduction
Tumor Suppressor Proteins / deficiency
Tumor Suppressor Proteins / genetics*

Substances

Neurofibromin 2
Ras Homolog Enriched in Brain Protein
Regulatory-Associated Protein of mTOR
Rheb protein, mouse
Rptor protein, mouse
Tumor Suppressor Proteins
Lats1 protein, mouse
LATS2 protein, mouse
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding