title: Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis.
abstract: The role of the unfolded protein response (UPR) in tissue homeostasis remains largely unknown. Here we find that loss of Mst1/2, the mammalian Hippo orthologues, or their regulator WW45, leads to a remarkably enlarged endoplasmic reticulum (ER) size-associated UPR. Intriguingly, attenuation of the UPR by tauroursodeoxycholic acid (TUDCA) diminishes Mst1/2 mutant-driven liver overgrowth and tumorigenesis by promoting nuclear exit and degradation of Hippo downstream effector Yap. Yap is required for UPR activity and ER expansion to alleviate ER stress. During the adaptive stage of the UPR, PERK kinase-eIF2α axis activates Yap, while prolonged ER stress-induced Hippo signalling triggers assembly of the GADD34/PP1 complex in a negative feedback loop to inhibit Yap and promote apoptosis. Significantly, the deregulation of UPR signals associated with Yap activation is found in a substantial fraction of human hepatocellular carcinoma (HCC). Thus, we conclude Yap integrates Hippo and UPR signalling to control liver size and tumorigenesis.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Hongtan
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Luyao
authors.initials: L
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Fuqin
authors.initials: F
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Suyuan
authors.initials: S
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Shihao
authors.initials: S
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Geng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Lixin
authors.initials: L
authors.lastname: Hong
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Mingting
authors.initials: M
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Hepatology, Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian 361001, China.
authors.forename: Changnan
authors.initials: C
authors.lastname: Jin
authors.affiliation: Department of Hepatobiliary Surgery, Zhongshan Hospital of Xiamen University, Xiamen, Fujian 361004, China.
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Qingxu
authors.initials: Q
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Jinjia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Funiu
authors.initials: F
authors.lastname: Qin
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yang 333, Taiwan.
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
authors.affiliation: College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yang 333, Taiwan.
authors.forename: Jau-Song
authors.initials: JS
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Hong-Rui
authors.initials: HR
authors.lastname: Wang
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Lanfen
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiang'An district, Xiamen, Fujian 361102, China.
authors.forename: Dawang
authors.initials: D
authors.lastname: Zhou
mesh_terms: D051702:Activating Transcription Factor 6 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects / Q000473:pathology*; D018797:Cell Cycle Proteins; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D056945:Hep G2 Cells; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D008099:Liver / Q000254:growth & development* / Q000473:pathology*; D008113:Liver Neoplasms / Q000201:enzymology / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D010750:Phosphoproteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D015398:Signal Transduction / Q000187:drug effects; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D051702:Activating Transcription Factor 6; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D010750:Phosphoproteins; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000090742:Serine-Threonine Kinase 3; D013655:Taurochenodeoxycholic Acid; D000091102:YAP-Signaling Proteins; C497112:Atf6 protein, mouse; C486223:Yap1 protein, mouse; C082332:macrophage stimulating protein; C031655:ursodoxicoltaurine; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases