Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DcAF1-Mediated Inhibition of the Hippo Pathway Kinases Latsl and 2 in the Nucleus

被引：190

作者：

Li, Wei ^{[1
]}

Cooper, Jonathan ^{[1
,2
]}

Zhou, Lu ^{[3
]}

Yang, Chenyi ^{[4
]}

Erdjument-Bromage, Hediye ^{[5
]}

Zagzag, David ^{[6
,7
]}

Snuderl, Matija ^{[6
,7
]}

Ladanyi, Marc ^{[8
,9
]}

Hanemann, C. Oliver ^{[3
]}

Zhou, Pengbo ^{[4
]}

Karajannis, Matthias A. ^{[6
,10
]}

Giancotti, Filippo G. ^{[1
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst Canc Res, Cell Biol Program, New York, NY 10065 USA

[2] Cornell Univ, Weill Grad Sch Med Sci, Sloan Kettering Div, New York, NY 10065 USA

[3] Univ Plymouth, Peninsula Sch Med & Dent, Plymouth PL6 8BU, Devon, England

[4] Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10065 USA

[5] Mem Sloan Kettering Canc Ctr, Sloan Kettering Inst Canc Res, Program Mol Biol, New York, NY 10065 USA

[6] NYU Langone Med Ctr, NYU Canc Inst, New York, NY 10016 USA

[7] NYU Langone Med Ctr, Dept Pathol, New York, NY 10016 USA

[8] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA

[9] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[10] NYU Langone Med Ctr, Dept Pediat, New York, NY 10016 USA

来源：

CANCER CELL | 2014年 / 26卷 / 01期

关键词：

TUMOR-SUPPRESSOR GENES; YAP ONCOPROTEIN; PLASMA-MEMBRANE; SIZE-CONTROL; PHOSPHORYLATION; GROWTH; UBIQUITIN; MST2; INACTIVATION; DESTRUCTION;

D O I：

10.1016/j.ccr.2014.05.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

It is currently unclear whether Merlin/NF2 suppresses tumorigenesis by activating upstream components of the Hippo pathway at the plasma membrane or by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. We found that derepressed CRL4(DCAF1) promotes YAP- and TEAD-dependent transcription by ubiquitylating and, thereby, inhibiting Lats1 and 2 in the nucleus. Genetic epistasis experiments and analysis of tumor-derived missense mutations indicate that this signaling connection sustains the oncogenicity of Merlin-deficient tumor cells. Analysis of clinical samples confirms that this pathway operates in NF2-mutant tumors. We conclude that derepressed CRL4(DCAF1) promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.

引用

页码：48 / 60

页数：13

共 41 条

[1] Molecular architecture and assembly of the DDB1-CUL4A ubiquitin ligase machinery [J].

Angers, Stephane ;

Li, Ti ;

Yi, Xianhua ;

MacCoss, Michael J. ;

Moon, Randall T. ;

Zheng, Ning .

NATURE, 2006, 443 (7111) :590-593

[2] An evolutionary shift in the regulation of the Hippo pathway between mice and flies [J].

Bossuyt, W. ;

Chen, C-L ;

Chen, Q. ;

Sudol, M. ;

McNeill, H. ;

Pan, D. ;

Kopp, A. ;

Halder, G. .

ONCOGENE, 2014, 33 (10) :1218-1228

[3] The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma [J].

Bott, Matthew ;

Brevet, Marie ;

Taylor, Barry S. ;

Shimizu, Shigeki ;

Ito, Tatsuo ;

Wang, Lu ;

Creaney, Jenette ;

Lake, Richard A. ;

Zakowski, Maureen F. ;

Reva, Boris ;

Sander, Chris ;

Delsite, Robert ;

Powell, Simon ;

Zhou, Qin ;

Shen, Ronglai ;

Olshen, Adam ;

Rusch, Valerie ;

Ladanyi, Marc .

NATURE GENETICS, 2011, 43 (07) :668-U81

[4] The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data [J].

Cerami, Ethan ;

Gao, Jianjiong ;

Dogrusoz, Ugur ;

Gross, Benjamin E. ;

Sumer, Selcuk Onur ;

Aksoy, Buelent Arman ;

Jacobsen, Anders ;

Byrne, Caitlin J. ;

Heuer, Michael L. ;

Larsson, Erik ;

Antipin, Yevgeniy ;

Reva, Boris ;

Goldberg, Arthur P. ;

Sander, Chris ;

Schultz, Nikolaus .

CANCER DISCOVERY, 2012, 2 (05) :401-404

[5] The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1 [J].

Chan, EH ;

Nousiainen, M ;

Chalamalasetty, RB ;

Schafër, A ;

Nigg, EA ;

Silljé, HHW .

ONCOGENE, 2005, 24 (12) :2076-2086

[6] Nonproteolytic Functions of Ubiquitin in Cell Signaling [J].

Chen, Zhijian J. ;

Sun, Lijun J. .

MOLECULAR CELL, 2009, 33 (03) :275-286

[7] Regulation of mammalian STE20-like kinase 2 (MST2) by protein phophorylation/dephosphorylation and proteolysis [J].

Deng, Y ;

Pang, A ;

Wang, JH .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (14) :11760-11767

[8] Elucidation of a universal size-control mechanism in Drosophila and mammals [J].

Dong, Jixin ;

Feldmann, Georg ;

Huang, Jianbin ;

Wu, Shian ;

Zhang, Nailing ;

Comerford, Sarah A. ;

Gayyed, Mariana F. ;

Anders, Robert A. ;

Maitra, Anirban ;

Pan, Duojia .

CELL, 2007, 130 (06) :1120-1133

[9] Regulation of Cre recombinase activity by mutated estrogen receptor ligand-binding domains [J].

Feil, R ;

Wagner, J ;

Metzger, D ;

Chambon, P .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1997, 237 (03) :752-757

[10] Kibra Is a Regulator of the Salvador/Warts/Hippo Signaling Network [J].

Genevet, Alice ;

Wehr, Michael C. ;

Brain, Ruth ;

Thompson, Barry J. ;

Tapon, Nicolas .

DEVELOPMENTAL CELL, 2010, 18 (02) :300-308

← 1 2 3 4 5 →