Usp7 Regulates Hippo Pathway Through Deubiquitinating the Transcriptional Coactivator Yorkie

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Jan 26

PMID 30679505

Citations 46

Authors

Xiaohan Sun

Yan Ding

Meixiao Zhan

Yan Li

Dongqing Gao

Guiping Wang

Yang Gao

Yong Li

Shian Wu

Ligong Lu

Qingxin Liu

Zizhang Zhou

Affiliations

Soon will be listed here.

Abstract

The Hippo pathway plays an important role in organ development and adult tissue homeostasis, and its deregulation has been implicated in many cancers. The Hippo signaling relies on a core kinase cascade culminating in phosphorylation of the transcription coactivator Yorkie (Yki). Although Yki is the key effector of Hippo pathway, the regulation of its protein stability is still unclear. Here, we show that Hippo pathway attenuates the binding of a ubiquitin-specific protease Usp7 to Yki, which regulates Hippo signaling through deubiquitinating Yki. Furthermore, the mammalian homolog of Usp7, HAUSP plays a conserved role in regulating Hippo pathway by modulating Yap ubiquitination and degradation. Finally, we find that the expression of HAUSP is positively correlated with that of Yap, both showing upregulated levels in clinical hepatocellular carcinoma (HCC) specimens. In summary, our findings demonstrate that Yki/Yap is stabilized by Usp7/HAUSP, and provide HAUSP as a potential therapeutic target for HCC.

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References

Shen X, Sun X, Sun B, Li T, Wu G, Li Y . ARRDC3 suppresses colorectal cancer progression through destabilizing the oncoprotein YAP. FEBS Lett. 2018; 592(4):599-609. DOI: 10.1002/1873-3468.12986. View

Ren F, Zhang L, Jiang J . Hippo signaling regulates Yorkie nuclear localization and activity through 14-3-3 dependent and independent mechanisms. Dev Biol. 2009; 337(2):303-12. PMC: 2812623. DOI: 10.1016/j.ydbio.2009.10.046. View

Li W, Cooper J, Zhou L, Yang C, Erdjument-Bromage H, Zagzag D . Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. Cancer Cell. 2014; 26(1):48-60. PMC: 4126592. DOI: 10.1016/j.ccr.2014.05.001. View

Yimlamai D, Fowl B, Camargo F . Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer. J Hepatol. 2015; 63(6):1491-501. PMC: 4654680. DOI: 10.1016/j.jhep.2015.07.008. View

Kagey J, Brown J, Moberg K . Regulation of Yorkie activity in Drosophila imaginal discs by the Hedgehog receptor gene patched. Mech Dev. 2012; 129(9-12):339-49. PMC: 3668547. DOI: 10.1016/j.mod.2012.05.007. View

Meng Z, Moroishi T, Mottier-Pavie V, Plouffe S, Hansen C, Hong A . MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway. Nat Commun. 2015; 6:8357. PMC: 4600732. DOI: 10.1038/ncomms9357. View

Mevissen T, Komander D . Mechanisms of Deubiquitinase Specificity and Regulation. Annu Rev Biochem. 2017; 86:159-192. DOI: 10.1146/annurev-biochem-061516-044916. View

Zanconato F, Battilana G, Cordenonsi M, Piccolo S . YAP/TAZ as therapeutic targets in cancer. Curr Opin Pharmacol. 2016; 29:26-33. PMC: 6175256. DOI: 10.1016/j.coph.2016.05.002. View

Yimlamai D, Christodoulou C, Galli G, Yanger K, Pepe-Mooney B, Gurung B . Hippo pathway activity influences liver cell fate. Cell. 2014; 157(6):1324-1338. PMC: 4136468. DOI: 10.1016/j.cell.2014.03.060. View

10.

Li M, Chen D, Shiloh A, Luo J, Nikolaev A, Qin J . Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature. 2002; 416(6881):648-53. DOI: 10.1038/nature737. View

11.

Harvey K, Zhang X, Thomas D . The Hippo pathway and human cancer. Nat Rev Cancer. 2013; 13(4):246-57. DOI: 10.1038/nrc3458. View

12.

Kwasna D, Abdul Rehman S, Natarajan J, Matthews S, Madden R, De Cesare V . Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability. Mol Cell. 2018; 70(1):150-164.e6. PMC: 5896202. DOI: 10.1016/j.molcel.2018.02.023. View

13.

Salah Z, Melino G, Aqeilan R . Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity. Cancer Res. 2011; 71(5):2010-20. DOI: 10.1158/0008-5472.CAN-10-3516. View

14.

Huang O, Cochran A . Regulation of deubiquitinase proteolytic activity. Curr Opin Struct Biol. 2013; 23(6):806-11. DOI: 10.1016/j.sbi.2013.07.012. View

15.

Hu M, Li P, Li M, Li W, Yao T, Wu J . Crystal structure of a UBP-family deubiquitinating enzyme in isolation and in complex with ubiquitin aldehyde. Cell. 2003; 111(7):1041-54. DOI: 10.1016/s0092-8674(02)01199-6. View

16.

Ribeiro P, Holder M, Frith D, Snijders A, Tapon N . Crumbs promotes expanded recognition and degradation by the SCF(Slimb/β-TrCP) ubiquitin ligase. Proc Natl Acad Sci U S A. 2014; 111(19):E1980-9. PMC: 4024906. DOI: 10.1073/pnas.1315508111. View

17.

Badouel C, Gardano L, Amin N, Garg A, Rosenfeld R, Le Bihan T . The FERM-domain protein Expanded regulates Hippo pathway activity via direct interactions with the transcriptional activator Yorkie. Dev Cell. 2009; 16(3):411-20. DOI: 10.1016/j.devcel.2009.01.010. View

18.

Harvey K, Tapon N . The Salvador-Warts-Hippo pathway - an emerging tumour-suppressor network. Nat Rev Cancer. 2007; 7(3):182-91. DOI: 10.1038/nrc2070. View

19.

Pantalacci S, Tapon N, Leopold P . The Salvador partner Hippo promotes apoptosis and cell-cycle exit in Drosophila. Nat Cell Biol. 2003; 5(10):921-7. DOI: 10.1038/ncb1051. View

20.

Zhang C, Robinson B, Xu W, Yang L, Yao B, Zhao H . The ecdysone receptor coactivator Taiman links Yorkie to transcriptional control of germline stem cell factors in somatic tissue. Dev Cell. 2015; 34(2):168-80. PMC: 4519380. DOI: 10.1016/j.devcel.2015.05.010. View