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

• Published in: Nature cell biology Vol. 22; no. 2; pp. 246 - 256
• Main Authors: Gan, Wenjian, Dai, Xiaoming, Dai, Xiangpeng, Xie, Jun, Yin, Shasha, Zhu, Junjie, Wang, Chen, Liu, Yuchen, Guo, Jianping, Wang, Min, Liu, Jing, Hu, Jia, Quinton, Ryan J., Ganem, Neil J., Liu, Pengda, Asara, John M., Pandolfi, Pier Paolo, Yang, Yingzi, He, Zhigang, Gao, Guangping, Wei, Wenyi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2020; Nature Publishing Group
• Subjects: 13/106; 13/109; 13/51; 13/95; 14/19; 631/80/458/1733; 631/80/83/2359; 631/80/83/2360; 82/1; 82/83; 96/63; Activation; Animals; Biomedical and Life Sciences; Cancer Research; Cell Biology; Cell size; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; CRISPR-Cas Systems; Crosstalk; Developmental Biology; Female; Gene Editing; Gene Expression Regulation, Developmental; Gene mutations; Genetic aspects; Growth; HCT116 Cells; Health aspects; HEK293 Cells; HeLa Cells; Heterografts; Humans; Kinases; Life Sciences; 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; Mutants; Myocardium - metabolism; Myocardium - pathology; Neurofibromin 2 - deficiency; Neurofibromin 2 - genetics; Organ Size; Phosphorylation; Protein-Serine-Threonine Kinases - deficiency; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Rapamycin; 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; Stem Cells; TOR protein; Tumor Suppressor Proteins - deficiency; Tumor Suppressor Proteins - genetics; United States
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-020-0463-6

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. The Hippo and mTORC1 pathways regulate growth control for proper organ development. Here, Gan et al. find that the Hippo pathway kinases LATS1 and LATS2 phosphorylate the mTORC1 component Raptor to attenuate mTORC1 activation.