Overexpression of ezrin inactivates NF2 tumor suppressor in glioblastoma.
Glioblastoma is a frequent brain malignancy with a dismal prognosis. The molecular changes causing its aggressive phenotype are under investigation. We report that the cytoskeletal-related proteins neurofibromatosis type 2 (NF2) and ezrin have opposite yet interdependent activities in glioblastoma growth. We show that NF2 is absent in approximately one-third of glioblastoma cell lines and tumors, and that it suppresses growth when expressed in cells. Although ezrin overexpression was previously observed in glioblastoma, we show here that ezrin enhanced cell proliferation and anchorage-independent growth but only in cells expressing NF2. Ezrin interacted and delocalized NF2 from the cortical compartment releasing its inhibition on Rac1. By using swap NF2-ezrin molecules, we identified that the opposite effects on cell growth of NF2 and ezrin depend on their amino-terminal FERM domain. The subcellular cortical localization appeared important for NF2 suppressive activity. In contrast, the ability of ezrin to enhance growth or complex NF2 did not depend on the molecular conformation or subcellular localization. In conclusion, these studies show 2 mechanisms for NF2 inactivation in glioblastoma: (i) decreased protein expression and (ii) increasing dosages of ezrin that disable NF2 by intermolecular association and aberrant intracellular recruitment.
Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 6767 Bertner Avenue, Houston, TX 77030, USA.
Fabiana C
FC
Morales
Jennifer R
JR
Molina
Yuho
Y
Hayashi
Maria-Magdalena
MM
Georgescu
D000818:Animals; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D025581:Neurofibromin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D025581:Neurofibromin 2; D000099149:Ezrin