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; L Zhou; Chenyi Yang; Hediye Erdjument-Bromage; David Zagzag; Matija Snuderl; Marc Ladanyi; C. Oliver Hanemann; P 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
, L Zhou
, Chenyi Yang
, Hediye Erdjument-Bromage
, David Zagzag
, Matija Snuderl
, Marc Ladanyi
, C. Oliver Hanemann
, P Zhou
, Matthias A. Karajannis
, Filippo G. Giancotti

^*Corresponding author for this work

Peninsula Medical School

Memorial Sloan-Kettering Cancer Center
Cornell University
New York University

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

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
Pages (from-to)	48-60
Number of pages	0
Journal	Cancer Cell
Volume	26
Issue number	1
DOIs	https://doi.org/10.1016/j.ccr.2014.05.001
Publication status	Published - 14 Jul 2014

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

Adaptor Proteins
Signal Transducing
Adolescent
Adult
Aged
80 and over
Animals
Carrier Proteins
Cell Nucleus
Cell Transformation
Neoplastic
Child
Epistasis
Genetic
Female
Gene Expression Regulation
Hep G2 Cells
Hippo Signaling Pathway
Humans
Male
Mice
Inbred C57BL
Nude
Middle Aged
Mutation
Missense
Neurofibromatosis 2
Neurofibromin 2
Phosphoproteins
Phosphorylation
Proteasome Endopeptidase Complex
Protein Serine-Threonine Kinases
RNA Interference
Signal Transduction
Time Factors
Transcription Factors
Transcription
Transfection
Tumor Cells
Cultured
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
Ubiquitination
YAP-Signaling Proteins
Young Adult

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10.1016/j.ccr.2014.05.001

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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{18e4720d8fea49ec8024da69f944fd8e,

title = "Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-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 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.",

keywords = "Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, 80 and over, Animals, Carrier Proteins, Cell Nucleus, Cell Transformation, Neoplastic, Child, Epistasis, Genetic, Female, Gene Expression Regulation, Hep G2 Cells, Hippo Signaling Pathway, Humans, Male, Mice, Inbred C57BL, Nude, Middle Aged, Mutation, Missense, Neurofibromatosis 2, Neurofibromin 2, Phosphoproteins, Phosphorylation, Proteasome Endopeptidase Complex, Protein Serine-Threonine Kinases, RNA Interference, Signal Transduction, Time Factors, Transcription Factors, Transcription, Transfection, Tumor Cells, Cultured, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Ubiquitination, YAP-Signaling Proteins, Young Adult",

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

year = "2014",

month = jul,

day = "14",

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

language = "English",

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 CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus.

AU - Li, Wei

AU - Cooper, Jonathan

AU - Zhou, L

AU - Yang, Chenyi

AU - Erdjument-Bromage, Hediye

AU - Zagzag, David

AU - Snuderl, Matija

AU - Ladanyi, Marc

AU - Hanemann, C. Oliver

AU - Zhou, P

AU - Karajannis, Matthias A.

AU - Giancotti, Filippo G.

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 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.

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 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.

KW - Adaptor Proteins

KW - Signal Transducing

KW - Adolescent

KW - Adult

KW - Aged

KW - 80 and over

KW - Animals

KW - Carrier Proteins

KW - Cell Nucleus

KW - Cell Transformation

KW - Neoplastic

KW - Child

KW - Epistasis

KW - Genetic

KW - Female

KW - Gene Expression Regulation

KW - Hep G2 Cells

KW - Hippo Signaling Pathway

KW - Humans

KW - Male

KW - Mice

KW - Inbred C57BL

KW - Nude

KW - Middle Aged

KW - Mutation

KW - Missense

KW - Neurofibromatosis 2

KW - Neurofibromin 2

KW - Phosphoproteins

KW - Phosphorylation

KW - Proteasome Endopeptidase Complex

KW - Protein Serine-Threonine Kinases

KW - RNA Interference

KW - Signal Transduction

KW - Time Factors

KW - Transcription Factors

KW - Transcription

KW - Transfection

KW - Tumor Cells

KW - Cultured

KW - Tumor Suppressor Proteins

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

KW - YAP-Signaling Proteins

KW - Young Adult

U2 - 10.1016/j.ccr.2014.05.001

DO - 10.1016/j.ccr.2014.05.001

M3 - Article

SN - 1535-6108

VL - 26

SP - 48

EP - 60

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus.

Abstract

UN SDGs

Keywords

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