title: Moesin is a glioma progression marker that induces proliferation and Wnt/β-catenin pathway activation via interaction with CD44.
abstract: Moesin is an ERM family protein that connects the actin cytoskeleton to transmembrane receptors. With the identification of the ERM family protein NF2 as a tumor suppressor in glioblastoma, we investigated roles for other ERM proteins in this malignancy. Here, we report that overexpression of moesin occurs generally in high-grade glioblastoma in a pattern correlated with the stem cell marker CD44. Unlike NF2, moesin acts as an oncogene by increasing cell proliferation and stem cell neurosphere formation, with its ectopic overexpression sufficient to shorten survival in an orthotopic mouse model of glioblastoma. Moesin was the major ERM member activated by phosphorylation in glioblastoma cells, where it interacted and colocalized with CD44 in membrane protrusions. Increasing the levels of moesin competitively displaced NF2 from CD44, increasing CD44 expression in a positive feedback loop driven by the Wnt/β-catenin signaling pathway. Therapeutic targeting of the moesin-CD44 interaction with the small-molecule inhibitor 7-cyanoquinocarcinol (DX-52-1) or with a CD44-mimetic peptide specifically reduced the proliferation of glioblastoma cells overexpressing moesin, where the Wnt/β-catenin pathway was activated. Our findings establish moesin and CD44 as progression markers and drugable targets in glioblastoma, relating their oncogenic effects to activation of the Wnt/β-catenin pathway.
authors.affiliation: Department of Neuro-Oncology and Veterinary Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 75390, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhu
authors.forename: Fabiana C
authors.initials: FC
authors.lastname: Morales
authors.forename: Nitin Kumar
authors.initials: NK
authors.lastname: Agarwal
authors.forename: Turgut
authors.initials: T
authors.lastname: Dogruluk
authors.forename: Mihai
authors.initials: M
authors.lastname: Gagea
authors.forename: Maria-Magdalena
authors.initials: MM
authors.lastname: Georgescu
mesh_terms: D000595:Amino Acid Sequence; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003598:Cytoskeletal Proteins / Q000502:physiology; D018450:Disease Progression; D005910:Glioma / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D008840:Microfilament Proteins / Q000032:analysis / Q000502:physiology*; D008969:Molecular Sequence Data; D025581:Neurofibromin 2 / Q000378:metabolism; D010766:Phosphorylation; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D025581:Neurofibromin 2; D051176:beta Catenin; D000099149:Ezrin; C497483:CD44 protein, human; C495270:CTNNB1 protein, human; C071058:moesin; C071776:radixin