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

Cancer Cell. 2014 Jul 14;26(1):48-60. doi: 10.1016/j.ccr.2014.05.001.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Neurofibromin 2
  • Phosphoproteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • YAP1 protein, human
  • Ubiquitin-Protein Ligases
  • LATS1 protein, human
  • LATS2 protein, human
  • DCAF1 protein, human
  • Hippo protein, human
  • Protein-Serine-Threonine Kinases
  • Proteasome Endopeptidase Complex