QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (41) Citing Articles via Google Scholar Google Scholar Articles by Wick, W. Articles by Weller, M. Search for Related Content PubMed PubMed Citation Articles by Wick, W. Articles by Weller, M.

 Previous Article  |  Next Article 

The Journal of Neuroscience, May 15, 2001, 21(10):3360-3368

Ezrin-Dependent Promotion of Glioma Cell Clonogenicity, Motility, and Invasion Mediated by BCL-2 and Transforming Growth Factor-₂

Wolfgang Wick¹, Cornelia Grimmel¹, Christine Wild-Bode¹, Michael Platten¹, Monique Arpin², and Michael Weller¹

¹ Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Tübingen, Germany, and ² Laboratoire de Morphogenese et Signalisation Cellulaires, Unité Mixte de Recherche, 144 Centre National de la Recherche Scientifique/Institut Curie, 75248 Paris Cedex 05, France

Ezrin belongs to the ezrin-radixin-moesin family proteins, which cross-link actin cytoskeleton and plasma membrane. Malignant glioma cells are paradigmatic for their strong migratory and invasive properties. Here, we report that the expression of dominant-negative ezrins inhibits clonogenicity, migration, and invasiveness of human malignant glioma cells. Furthermore, dominant-negative ezrins block hepatocyte growth factor (HGF)-mediated stimulation of clonogenicity and migration, without altering HGF-induced protein kinase B/Akt and focal adhesion kinase phosphorylation. Glioma cells expressing dominant-negative ezrins exhibit a shift of the BCL-2/BAX rheostat toward apoptosis, reduced _V3 integrin expression and reduced matrix metalloproteinase (MMP) expression and activity. These changes are associated with a dramatic loss of transforming growth factor ₂ (TGF-₂) release. Exogenous supplementation of TGF-₂ overcomes the inhibitory effects of dominant-negative ezrins on migration and clonogenicity. A neutralizing TGF-₂ antibody mimics the effects of dominant-negative ezrins on clonogenicity and migration. Exogenous HGF markedly induces TGF-₂ protein levels, and a neutralizing TGF-₂ antibody abolishes the HGF-mediated increase in glioma cell motility. Finally, TGF-₂ does not modulate BCL-2 or BAX expression, but BCL-2 gene transfer increases the levels of latent and active TGF-₂. Intracranial xenografts of U87MG glioma cells transfected with the dominant-negative ezrins in athymic mice grow to significantly smaller volumes, and the median survival of these mice is 50 d compared with 28 d in the control group. These data define a novel pathway for HGF-induced glioma cell migration and invasion, which requires ezrin, changes in the BCL-2/BAX rheostat, and the induction of TGF-₂ expression in vitro, and underscore the important role of HGF signaling in vivo.

Key words: brain tumor; ERM proteins; motility; TGF-; BCL-2; metalloproteinases; HGF; athymic mice

---

Copyright © 2001 Society for Neuroscience  0270-6474/01/21103360-09$05.00/0

This article has been cited by other articles:

				F. Baumann, P. Leukel, A. Doerfelt, C. P. Beier, K. Dettmer, P. J. Oefner, M. Kastenberger, M. Kreutz, T. Nickl-Jockschat, U. Bogdahn, et al. Lactate promotes glioma migration by TGF-{beta}2-dependent regulation of matrix metalloproteinase-2 Neuro-oncol, January 1, 2009; 11(4): 368 - 380. [Abstract] [Full Text] [PDF]

				H. Osawa, C. A. Smith, Y. S. Ra, P. Kongkham, and J. T. Rutka The role of the membrane cytoskeleton cross-linker ezrin in medulloblastoma cells Neuro-oncol, January 1, 2009; 11(4): 381 - 393. [Abstract] [Full Text] [PDF]

				J. Austermann, A. R. Nazmi, C. Muller-Tidow, and V. Gerke Characterization of the Ca2+-regulated Ezrin-S100P Interaction and Its Role in Tumor Cell Migration J. Biol. Chem., October 24, 2008; 283(43): 29331 - 29340. [Abstract] [Full Text] [PDF]

				J.-T. Chen, C.-Y. Huang, Y.-Y. Chiang, W.-H. Chen, S.-H. Chiou, C.-Y. Chen, and K.-C. Chow HGF Increases Cisplatin Resistance via Down-Regulation of AIF in Lung Cancer Cells Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 559 - 565. [Abstract] [Full Text] [PDF]

				F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment Genes & Dev., November 1, 2007; 21(21): 2683 - 2710. [Abstract] [Full Text] [PDF]

				T.-T. Tran, M. Uhl, J. Y. Ma, L. Janssen, V. Sriram, S. Aulwurm, I. Kerr, A. Lam, H. K. Webb, A. M. Kapoun, et al. Inhibiting TGF-{beta} signaling restores immune surveillance in the SMA-560 glioma model Neuro-oncol, July 1, 2007; 9(3): 259 - 270. [Abstract] [Full Text] [PDF]

				R. Coras, A. Holsken, S. Seufert, J. Hauke, I. Y. Eyupoglu, M. Reichel, C. Trankle, F. A. Siebzehnrubl, R. Buslei, I. Blumcke, et al. The peroxisome proliferator-activated receptor-{gamma} agonist troglitazone inhibits transforming growth factor-{beta}-mediated glioma cell migration and brain invasion Mol. Cancer Ther., June 1, 2007; 6(6): 1745 - 1754. [Abstract] [Full Text] [PDF]

				A. J. LaGier, S. H. Yoo, E. C. Alfonso, S. Meiners, and M. E. Fini Inhibition of Human Corneal Epithelial Production of Fibrotic Mediator TGF-{beta}2 by Basement Membrane-Like Extracellular Matrix Invest. Ophthalmol. Vis. Sci., March 1, 2007; 48(3): 1061 - 1071. [Abstract] [Full Text] [PDF]

				G. Tabatabai, O. Bahr, R. Mohle, I. Y. Eyupoglu, A. M. Boehmler, J. Wischhusen, J. Rieger, I. Blumcke, M. Weller, and W. Wick Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells Brain, September 1, 2005; 128(9): 2200 - 2211. [Abstract] [Full Text] [PDF]

				L. Heiska and O. Carpen Src Phosphorylates Ezrin at Tyrosine 477 and Induces a Phosphospecific Association between Ezrin and a Kelch-Repeat Protein Family Member J. Biol. Chem., March 18, 2005; 280(11): 10244 - 10252. [Abstract] [Full Text] [PDF]

				V. Firlej, B. Bocquet, X. Desbiens, Y. de Launoit, and A. Chotteau-Lelievre Pea3 Transcription Factor Cooperates with USF-1 in Regulation of the Murine bax Transcription without Binding to an Ets-binding Site J. Biol. Chem., January 14, 2005; 280(2): 887 - 898. [Abstract] [Full Text] [PDF]

				M. Uhl, S. Aulwurm, J. Wischhusen, M. Weiler, J. Y. Ma, R. Almirez, R. Mangadu, Y.-W. Liu, M. Platten, U. Herrlinger, et al. SD-208, a Novel Transforming Growth Factor {beta} Receptor I Kinase Inhibitor, Inhibits Growth and Invasiveness and Enhances Immunogenicity of Murine and Human Glioma Cells In vitro and In vivo Cancer Res., November 1, 2004; 64(21): 7954 - 7961. [Abstract] [Full Text] [PDF]

				P. M. Smith, A. Cowan, and B. A. White The Low-Density Lipoprotein Receptor Is Regulated by Estrogen and Forms a Functional Complex with the Estrogen-Regulated Protein Ezrin in Pituitary GH3 Somatolactotropes Endocrinology, July 1, 2004; 145(7): 3075 - 3083. [Abstract] [Full Text] [PDF]

				J. Nylandsted, W. Wick, U. A. Hirt, K. Brand, M. Rohde, M. Leist, M. Weller, and M. Jaattela Eradication of Glioblastoma, and Breast and Colon Carcinoma Xenografts by Hsp70 Depletion Cancer Res., December 15, 2002; 62(24): 7139 - 7142. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help