Deubiquitylating enzyme USP9x regulates hippo pathway activity by controlling angiomotin protein turnover

被引：37

作者：

Hung Thanh Nguyen ^{[1
]}

Andrejeva, Diana ^{[1
]}

Gupta, Rajat ^{[2
]}

Choudhary, Chunaram ^{[2
]}

Hong, Xin ^{[3
]}

Eichhorn, Pieter J. A. ^{[4
,5
]}

Loya, Anand C. ^{[6
]}

Cohen, Stephen M. ^{[1
]}

机构：

[1] Univ Copenhagen, Dept Cellular & Mol Med, Copenhagen, Denmark

[2] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Copenhagen, Denmark

[3] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Charlestown, MA USA

[4] Natl Univ Singapore, Yong Loo Lin Sch Med, Canc Sci Inst Singapore, Singapore, Singapore

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Pharmacol, Singapore, Singapore

[6] Rigshosp, Dept Pathol, Copenhagen, Denmark

来源：

CELL DISCOVERY | 2016年 / 2卷

基金：

英国医学研究理事会;

关键词：

Hippo pathway; LATS; protein degradation; YAP; ubiquitin; ACTIN-BINDING; YAP PATHWAY; ORGAN SIZE; IN-VIVO; PHOSPHORYLATION; INHIBITION; IDENTIFICATION; SUPPRESSES; ACTIVATION; FAM/USP9X;

D O I：

10.1038/celldisc.2016.1

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The Hippo pathway has been identified as a key barrier for tumorigenesis, acting through downregulation of YAP/TAZ activity. Elevated YAP/TAZ activity has been documented in many human cancers. Ubiquitylation has been shown to play a key role in regulating YAP/TAZ activity through downregulation of a number of Hippo pathway components. Several ubiquitin ligase complexes have been implicated in this process, however, little is known about the deubiquitylating enzymes that counteract these activities to regulate YAP/TAZ. Here we identify the deubiquitylating enzyme USP9x as a regulator of YAP/TAZ activity. We demonstrate that USPx regulates ubiquitin-mediated turnover of the YAP inhibitor, Angiomotin. USP9x acts to deubiquitylate Angiomotin at lysine 496, resulting in stabilization of Angiomotin and lower YAP/TAZ activity. USP9x mRNA levels were reduced in several cancers. Clinically, USP9x mRNA levels were reduced in several cancers with low USPx expression correlating with poor prognosis in renal clear cell carcinoma. Our data indicate that USP9x may be a useful biomarker for renal clear cell carcinoma.

引用

页数：13

共 60 条

[1] Amot130 Adapts Atrophin-1 Interacting Protein 4 to Inhibit Yes-associated Protein Signaling and Cell Growth [J].

Adler, Jacob J. ;

Heller, Brigitte L. ;

Bringman, Lauren R. ;

Ranahan, William P. ;

Cocklin, Ross R. ;

Goebl, Mark G. ;

Oh, Misook ;

Lim, Hyun-Suk ;

Ingham, Robert J. ;

Wells, Clark D. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (21) :15181-15193

[2] The Hippo superhighway: signaling crossroads converging on the Hippo/Yap pathway in stem cells and development [J].

Barry, Evan R. ;

Camargo, Fernando D. .

CURRENT OPINION IN CELL BIOLOGY, 2013, 25 (02) :247-253

[3] Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes [J].

Biankin, Andrew V. ;

Waddell, Nicola ;

Kassahn, Karin S. ;

Gingras, Marie-Claude ;

Muthuswamy, Lakshmi B. ;

Johns, Amber L. ;

Miller, David K. ;

Wilson, Peter J. ;

Patch, Ann-Marie ;

Wu, Jianmin ;

Chang, David K. ;

Cowley, Mark J. ;

Gardiner, Brooke B. ;

Song, Sarah ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Nourse, Craig ;

Nourbakhsh, Ehsan ;

Manning, Suzanne ;

Wani, Shivangi ;

Gongora, Milena ;

Pajic, Marina ;

Scarlett, Christopher J. ;

Gill, Anthony J. ;

Pinho, Andreia V. ;

Rooman, Ilse ;

Anderson, Matthew ;

Holmes, Oliver ;

Leonard, Conrad ;

Taylor, Darrin ;

Wood, Scott ;

Xu, Qinying ;

Nones, Katia ;

Fink, J. Lynn ;

Christ, Angelika ;

Bruxner, Tim ;

Cloonan, Nicole ;

Kolle, Gabriel ;

Newell, Felicity ;

Pinese, Mark ;

Mead, R. Scott ;

Humphris, Jeremy L. ;

Kaplan, Warren ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chou, Angela ;

Chin, Venessa T. ;

Chantrill, Lorraine A. .

NATURE, 2012, 491 (7424) :399-405

[4] Identification of the familial cylindromatosis tumour-suppressor gene [J].

Bignell, GR ;

Warren, W ;

Seal, S ;

Takahashi, M ;

Rapley, E ;

Barfoot, R ;

Green, H ;

Brown, C ;

Biggs, PJ ;

Lakhani, SR ;

Jones, C ;

Hansen, J ;

Blair, E ;

Hofmann, B ;

Siebert, R ;

Turner, G ;

Evans, DG ;

Schrander-Stumpel, C ;

Beemer, FA ;

van den Ouweland, A ;

Halley, D ;

Delpech, B ;

Cleveland, MG ;

Leigh, I ;

Leisti, J ;

Rasmussen, S ;

Wallace, MR ;

Fenske, C ;

Banerjee, P ;

Oiso, N ;

Chaggar, R ;

Merrett, S ;

Leonard, N ;

Huber, M ;

Hohl, D ;

Chapman, P ;

Burn, J ;

Swift, S ;

Smith, A ;

Ashworth, A ;

Stratton, MR .

NATURE GENETICS, 2000, 25 (02) :160-165

[5] A system for stable expression of short interfering RNAs in mammalian cells [J].

Brummelkamp, TR ;

Bernards, R ;

Agami, R .

SCIENCE, 2002, 296 (5567) :550-553

[6] Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-κB [J].

Brummelkamp, TR ;

Nijman, SMB ;

Dirac, AMG ;

Bernards, R .

NATURE, 2003, 424 (6950) :797-801

[7] Actin-binding and Cell Proliferation Activities of Angiomotin Family Members Are Regulated by Hippo Pathway-mediated Phosphorylation [J].

Chan, Siew Wee ;

Lim, Chun Jye ;

Guo, Fusheng ;

Tan, Ivan ;

Leung, Thomas ;

Hong, Wanjin .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2013, 288 (52) :37296-37307

[8] Hippo Pathway-independent Restriction of TAZ and YAP by Angiomotin [J].

Chan, Siew Wee ;

Lim, Chun Jye ;

Chong, Yaan Fun ;

Pobbati, Ajaybabu V. ;

Huang, Caixia ;

Hong, Wanjin .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (09) :7018-7026

[9]

Chen M., Oncotarget

[10] Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers [J].

Cottini, Francesca ;

Hideshima, Teru ;

Xu, Chunxiao ;

Sattler, Martin ;

Dori, Martina ;

Agnelli, Luca ;

ten Hacken, Elisa ;

Bertilaccio, Maria Teresa ;

Antonini, Elena ;

Neri, Antonino ;

Ponzoni, Maurilio ;

Marcatti, Magda ;

Richardson, Paul G. ;

Carrasco, Ruben ;

Kimmelman, Alec C. ;

Wong, Kwok-Kin ;

Caigaris-Cappio, Federico ;

Blandino, Giovanni ;

Kuehl, W. Michael ;

Anderson, Kenneth C. ;

Tonon, Giovanni .

NATURE MEDICINE, 2014, 20 (06) :599-606

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