title: YAP Mediates Tumorigenesis in Neurofibromatosis Type 2 by Promoting Cell Survival and Proliferation through a COX-2-EGFR Signaling Axis.
abstract: 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.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida.
authors.forename: William
authors.initials: W
authors.lastname: Guerrant
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Smitha
authors.initials: S
authors.lastname: Kota
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Scott
authors.initials: S
authors.lastname: Troutman
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Vinay
authors.initials: V
authors.lastname: Mandati
authors.affiliation: Informatics Core, The Scripps Research Institute, Jupiter, Florida.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Anat
authors.initials: A
authors.lastname: Stemmer-Rachamimov
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, Jupiter, Florida. jkissil@scripps.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kissil
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D066258:Amphiregulin / Q000502:physiology; D063646:Carcinogenesis; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000502:physiology*; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D016518:Neurofibromatosis 2 / Q000209:etiology*; D010750:Phosphoproteins / Q000502:physiology*; D012583:Schwann Cells / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: C587848:AREG protein, human; D048868:Adaptor Proteins, Signal Transducing; D066258:Amphiregulin; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D051546:Cyclooxygenase 2; D066246:ErbB Receptors