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

Overview

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 date

  • July 14, 2014

Research

keywords

  • Carrier Proteins
  • Cell Nucleus
  • Neurofibromatosis 2
  • Neurofibromin 2
  • Protein Serine-Threonine Kinases
  • Tumor Suppressor Proteins

Identity

PubMed Central ID

  • PMC4126592

Scopus Document Identifier

  • 84904266769

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2014.05.001

PubMed ID

  • 25026211

Additional Document Info

volume

  • 26

issue

  • 1