Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis

Hongtan Wu; Luyao Wei; Fuqin Fan; Suyuan Ji; Shihao Zhang; Jing Geng; Lixin Hong; Xin Fan; Qinghua Chen; Jing Tian; Mingting Jiang; Xiufeng Sun; Changnan Jin; Zhen Yu Yin; Qingxu Liu; Jinjia Zhang; Funiu Qin; Kwang Huei Lin; Jau Song Yu; Xianming Deng; Hong Rui Wang; Bin Zhao; Randy L. Johnson; Lanfen Chen; Dawang Zhou

doi:10.1038/ncomms7239

Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis

Hongtan Wu, Luyao Wei, Fuqin Fan, Suyuan Ji, Shihao Zhang, Jing Geng, Lixin Hong, Xin Fan, Qinghua Chen, Jing Tian, Mingting Jiang, Xiufeng Sun, Changnan Jin, Zhen Yu Yin, Qingxu Liu, Jinjia Zhang, Funiu Qin, Kwang Huei Lin, Jau Song Yu, Xianming DengHong Rui Wang, Bin Zhao, Randy L. Johnson, Lanfen Chen, Dawang Zhou

Research output: Contribution to journal › Article › peer-review

133 Scopus citations

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.

Original language	English (US)
Article number	6239
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7239
State	Published - Feb 2015

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

MD Anderson CCSG core facilities

Genetically Engineered Mouse Facility
Research Animal Support Facility

Access to Document

10.1038/ncomms7239

Cite this

Wu, H., Wei, L., Fan, F., Ji, S., Zhang, S., Geng, J., Hong, L., Fan, X., Chen, Q., Tian, J., Jiang, M., Sun, X., Jin, C., Yin, Z. Y., Liu, Q., Zhang, J., Qin, F., Lin, K. H., Yu, J. S., ... Zhou, D. (2015). Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis. Nature communications, 6, Article 6239. https://doi.org/10.1038/ncomms7239

Wu, H, Wei, L, Fan, F, Ji, S, Zhang, S, Geng, J, Hong, L, Fan, X, Chen, Q, Tian, J, Jiang, M, Sun, X, Jin, C, Yin, ZY, Liu, Q, Zhang, J, Qin, F, Lin, KH, Yu, JS, Deng, X, Wang, HR, Zhao, B, Johnson, RL, Chen, L & Zhou, D 2015, 'Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis', Nature communications, vol. 6, 6239. https://doi.org/10.1038/ncomms7239

@article{e56f9e2630bb40ceb385e4520650f2f7,

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.",

author = "Hongtan Wu and Luyao Wei and Fuqin Fan and Suyuan Ji and Shihao Zhang and Jing Geng and Lixin Hong and Xin Fan and Qinghua Chen and Jing Tian and Mingting Jiang and Xiufeng Sun and Changnan Jin and Yin, {Zhen Yu} and Qingxu Liu and Jinjia Zhang and Funiu Qin and Lin, {Kwang Huei} and Yu, {Jau Song} and Xianming Deng and Wang, {Hong Rui} and Bin Zhao and Johnson, {Randy L.} and Lanfen Chen and Dawang Zhou",

year = "2015",

month = feb,

doi = "10.1038/ncomms7239",

language = "English (US)",

volume = "6",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis

AU - Wu, Hongtan

AU - Wei, Luyao

AU - Fan, Fuqin

AU - Ji, Suyuan

AU - Zhang, Shihao

AU - Geng, Jing

AU - Hong, Lixin

AU - Fan, Xin

AU - Chen, Qinghua

AU - Tian, Jing

AU - Jiang, Mingting

AU - Sun, Xiufeng

AU - Jin, Changnan

AU - Yin, Zhen Yu

AU - Liu, Qingxu

AU - Zhang, Jinjia

AU - Qin, Funiu

AU - Lin, Kwang Huei

AU - Yu, Jau Song

AU - Deng, Xianming

AU - Wang, Hong Rui

AU - Zhao, Bin

AU - Johnson, Randy L.

AU - Chen, Lanfen

AU - Zhou, Dawang

PY - 2015/2

Y1 - 2015/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923362350&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923362350&partnerID=8YFLogxK

U2 - 10.1038/ncomms7239

DO - 10.1038/ncomms7239

M3 - Article

C2 - 25695629

AN - SCOPUS:84923362350

SN - 2041-1723

VL - 6

JO - Nature communications

JF - Nature communications

M1 - 6239

ER -

Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

Other files and links

Fingerprint

Cite this