Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

Wei Li; Jonathan Cooper; Lu Zhou; Chenyi Yang; Hediye Erdjument-Bromage; David Zagzag; Matija Snuderl; Marc Ladanyi; C. Oliver Hanemann; Pengbo Zhou; Matthias A. Karajannis; Filippo G. Giancotti

doi:10.1016/j.ccr.2014.05.001

Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4^DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

Wei Li, Jonathan Cooper, Lu Zhou, Chenyi Yang, Hediye Erdjument-Bromage, David Zagzag, Matija Snuderl, Marc Ladanyi, C. Oliver Hanemann, Pengbo Zhou, Matthias A. Karajannis, Filippo G. Giancotti

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

172 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	48-60
Number of pages	13
Journal	Cancer Cell
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2014.05.001
State	Published - Jul 14 2014

All Science Journal Classification (ASJC) codes

Oncology
Cell Biology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccr.2014.05.001

Cite this

Li, W., Cooper, J., Zhou, L., Yang, C., Erdjument-Bromage, H., Zagzag, D., Snuderl, M., Ladanyi, M., Hanemann, C. O., Zhou, P., Karajannis, M. A., & Giancotti, F. G. (2014). Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4^DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus. Cancer Cell, 26(1), 48-60. https://doi.org/10.1016/j.ccr.2014.05.001

@article{0cd13466963c43ba80da507e335d245a,

title = "Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus",

abstract = "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 CRL4DCAF1 in the nucleus. We found that derepressed CRL4DCAF1 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 CRL4DCAF1 promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.",

author = "Wei Li and Jonathan Cooper and Lu Zhou and Chenyi Yang and Hediye Erdjument-Bromage and David Zagzag and Matija Snuderl and Marc Ladanyi and Hanemann, {C. Oliver} and Pengbo Zhou and Karajannis, {Matthias A.} and Giancotti, {Filippo G.}",

note = "Funding Information: We thank I. Farrance, M. Giovannini, K. Guan, S. Jhanwar, D. Lim, M. Pagano, and D. Pan for reagents, R. Mukherjee and N. Antao for experimental assistance, the core facilities of MSKCC and NYU-Langone Medical Center for sample processing and analysis, and members of the F.G.G. laboratory for discussions. This work was supported by CTF Young Investigator Award 2009-01-013 (to W.L.) and NIH grants R01 CA152975 (to F.G.G.), S10 OD010591 (to the Microchemistry and Proteomics Core Laboratory of MSKCC), UL1 TR000038 (to the BioRepository and Immunohistochemistry Core Laboratory of NYU-Langone Medical Center), and P30 CA08748 (to MSKCC). ",

year = "2014",

month = jul,

day = "14",

doi = "10.1016/j.ccr.2014.05.001",

language = "English (US)",

volume = "26",

pages = "48--60",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "1",

}

Li, W, Cooper, J, Zhou, L, Yang, C, Erdjument-Bromage, H, Zagzag, D, Snuderl, M, Ladanyi, M, Hanemann, CO, Zhou, P, Karajannis, MA & Giancotti, FG 2014, 'Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4^DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus', Cancer Cell, vol. 26, no. 1, pp. 48-60. https://doi.org/10.1016/j.ccr.2014.05.001

TY - JOUR

T1 - Merlin/NF2 Loss-Driven Tumorigenesis Linked to CRL4DCAF1-Mediated Inhibition of the Hippo Pathway Kinases Lats1 and 2 in the Nucleus

AU - Li, Wei

AU - Cooper, Jonathan

AU - Zhou, Lu

AU - Yang, Chenyi

AU - Erdjument-Bromage, Hediye

AU - Zagzag, David

AU - Snuderl, Matija

AU - Ladanyi, Marc

AU - Hanemann, C. Oliver

AU - Zhou, Pengbo

AU - Karajannis, Matthias A.

AU - Giancotti, Filippo G.

N1 - Funding Information: We thank I. Farrance, M. Giovannini, K. Guan, S. Jhanwar, D. Lim, M. Pagano, and D. Pan for reagents, R. Mukherjee and N. Antao for experimental assistance, the core facilities of MSKCC and NYU-Langone Medical Center for sample processing and analysis, and members of the F.G.G. laboratory for discussions. This work was supported by CTF Young Investigator Award 2009-01-013 (to W.L.) and NIH grants R01 CA152975 (to F.G.G.), S10 OD010591 (to the Microchemistry and Proteomics Core Laboratory of MSKCC), UL1 TR000038 (to the BioRepository and Immunohistochemistry Core Laboratory of NYU-Langone Medical Center), and P30 CA08748 (to MSKCC).

PY - 2014/7/14

Y1 - 2014/7/14

N2 - 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 CRL4DCAF1 in the nucleus. We found that derepressed CRL4DCAF1 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 CRL4DCAF1 promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.

AB - 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 CRL4DCAF1 in the nucleus. We found that derepressed CRL4DCAF1 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 CRL4DCAF1 promotes activation of YAP by inhibiting Lats1 and 2 in the nucleus.

UR - http://www.scopus.com/inward/record.url?scp=84904266769&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84904266769&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2014.05.001

DO - 10.1016/j.ccr.2014.05.001

M3 - Article

C2 - 25026211

AN - SCOPUS:84904266769

SN - 1535-6108

VL - 26

SP - 48

EP - 60

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -