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.
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: liw@mskcc.org.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Sloan Kettering Division, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cooper
authors.affiliation: Plymouth University Peninsula School of Medicine and Dentistry, Plymouth PL6 8BU, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Chenyi
authors.initials: C
authors.lastname: Yang
authors.affiliation: Molecular Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.affiliation: NYU Cancer Institute and Department of Pathology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.affiliation: NYU Cancer Institute and Department of Pathology, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Matija
authors.initials: M
authors.lastname: Snuderl
authors.affiliation: Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Plymouth University Peninsula School of Medicine and Dentistry, Plymouth PL6 8BU, UK.
authors.forename: C Oliver
authors.initials: CO
authors.lastname: Hanemann
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
authors.affiliation: NYU Cancer Institute and Department of Pediatrics, NYU Langone Medical Center, New York, NY 10016, USA.
authors.forename: Matthias A
authors.initials: MA
authors.lastname: Karajannis
authors.affiliation: Cell Biology Program, Sloan Kettering Institute for Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: f-giancotti@ski.mskcc.org.
authors.forename: Filippo G
authors.initials: FG
authors.lastname: Giancotti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002648:Child; D004843:Epistasis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D020125:Mutation, Missense; D016518:Neurofibromatosis 2 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D000091102:YAP-Signaling Proteins; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D025581:Neurofibromin 2; D010750:Phosphoproteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D044767:Ubiquitin-Protein Ligases; C092745:LATS1 protein, human; C406449:LATS2 protein, human; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex