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

Research output: Contribution to journalArticlepeer-review

127 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 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.

Original languageEnglish (US)
Pages (from-to)48-60
Number of pages13
JournalCancer Cell
Volume26
Issue number1
DOIs
StatePublished - Jul 14 2014

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cell Biology
  • Cancer Research

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