YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis

Cancer Res. 2016 Jun 15;76(12):3507-19. doi: 10.1158/0008-5472.CAN-15-1144. Epub 2016 May 23.


The Hippo-YAP pathway has emerged as a major driver of tumorigenesis in many human cancers. YAP is a transcriptional coactivator and while details of YAP regulation are quickly emerging, it remains unknown what downstream targets are critical for the oncogenic functions of YAP. To determine the mechanisms involved and to identify disease-relevant targets, we examined the role of YAP in neurofibromatosis type 2 (NF2) using cell and animal models. We found that YAP function is required for NF2-null Schwann cell survival, proliferation, and tumor growth in vivo Moreover, YAP promotes transcription of several targets including PTGS2, which codes for COX-2, a key enzyme in prostaglandin biosynthesis, and AREG, which codes for the EGFR ligand, amphiregulin. Both AREG and prostaglandin E2 converge to activate signaling through EGFR. Importantly, treatment with the COX-2 inhibitor celecoxib significantly inhibited the growth of NF2-null Schwann cells and tumor growth in a mouse model of NF2. Cancer Res; 76(12); 3507-19. ©2016 AACR.

MeSH terms

  • Adaptor Proteins, Signal Transducing / physiology*
  • Amphiregulin / physiology
  • Carcinogenesis
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Cyclooxygenase 2 / physiology*
  • ErbB Receptors / physiology*
  • Humans
  • Neurofibromatosis 2 / etiology*
  • Phosphoproteins / physiology*
  • Schwann Cells / physiology
  • Signal Transduction / physiology*
  • Transcription Factors
  • YAP-Signaling Proteins


  • AREG protein, human
  • Adaptor Proteins, Signal Transducing
  • Amphiregulin
  • Phosphoproteins
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Cyclooxygenase 2
  • ErbB Receptors