title: Activation of Yes-Associated Protein in Low-Grade Meningiomas Is Regulated by Merlin, Cell Density, and Extracellular Matrix Stiffness.
abstract: The NF2 gene product Merlin is a protein containing ezrin, radixin, and moesin domains; it is a member of the 4.1 protein superfamily associated with the membrane cytoskeleton and also interacts with cell surface molecules. The mammalian Hippo cascade, a downstream signaling cascade of merlin, inactivates the Yes-associated protein (YAP). Yes-associated protein is activated by loss of the NF2 gene and functions as an oncogene in meningioma cells; however, the factors controlling YAP expression, phosphorylation, and subcellular localization in meningiomas have not been fully elucidated. Here, we demonstrate that merlin expression is heterogeneous in 1 NF2 gene-negative and 3 NF2 gene-positive World Health Organization grade I meningiomas. In the NF2 gene-positive meningiomas, regions with low levels of merlin (tumor rims) had greater numbers of cells with nuclear YAP versus regions with high merlin levels (tumor cores). Merlin expression and YAP phosphorylation were also affected by cell density in the IOMM-Lee and HKBMM human meningioma cell lines; nuclear localization of YAP was regulated by cell density and extracellular matrix (ECM) stiffness in IOMM-Lee cells. These results suggest that cell density and ECM stiffness may contribute to the heterogeneous loss of merlin and increased nuclear YAP expression in human meningiomas.
authors.affiliation: From the Department of Neurosurgery (KT, AN, FO, KM, AA, TW); Division of Cancer Biology, Nagoya University School of Medicine, Nagoya, Japan (TS); Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan (IT, YS); Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan (IT); Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology Department of Biomolecular Engineering, Tokyo, Japan (IH); and Division of Clinical Pathology, Konan Kosei Hospital, Aichi, Japan (RF, NS).
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Tanahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Ohka
authors.forename: Kazuya
authors.initials: K
authors.lastname: Motomura
authors.forename: Adiljan
authors.initials: A
authors.lastname: Alim
authors.forename: Ichidai
authors.initials: I
authors.lastname: Tanaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Senga
authors.forename: Ichiro
authors.initials: I
authors.lastname: Harada
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Fukuyama
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Sumiyoshi
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Wakabayashi
mesh_terms: D002452:Cell Count; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008577:Meningeal Neoplasms / Q000378:metabolism* / Q000473:pathology; D008579:Meningioma / Q000378:metabolism* / Q000473:pathology; D016518:Neurofibromatosis 2 / Q000378:metabolism*; D025581:Neurofibromin 2 / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D025581:Neurofibromin 2; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human