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Molecular and Cellular Biology, March 2007, p. 2103-2119, Vol. 27, No. 6
0270-7306/07/$08.00+0     doi:10.1128/MCB.00572-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification and Characterization of Putative Tumor Suppressor NGB, a GTP-Binding Protein That Interacts with the Neurofibromatosis 2 Protein

Hansoo Lee ,^1,, Donghwa Kim,^1, Han C. Dan,¹ Eric L. Wu,¹ Tatiana M. Gritsko,¹ Chuanhai Cao,¹ Santo V. Nicosia,¹ Erica A. Golemis,² Wanguo Liu,³ Domenico Coppola,¹ Steven S. Brem,¹ Joseph R. Testa,^2* and Jin Q. Cheng^1*

Departments of Pathology and Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida and College of Medicine, Tampa, Florida 33612,¹ Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,² Department of Experimental Pathology and Medicine, Mayo Foundation, 200 First Street SW, Rochester, Minnesota 55905³

Received 31 March 2006/ Returned for modification 17 July 2006/ Accepted 20 December 2006

Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene have frequently been detected not only in schwannomas and other central nervous system tumors of NF2 patients but also in their sporadic counterparts and malignant tumors unrelated to the NF2 syndrome such as malignant mesothelioma, indicating a broader role for the NF2 gene in human tumorigenesis. However, the mechanisms by which the NF2 product, merlin or schwannomin, is regulated and controls cell proliferation remain elusive. Here, we identify a novel GTP-binding protein, dubbed NGB (referring to NF2-associated GTP binding protein), which binds to merlin. NGB is highly conserved between Saccharomyces cerevisiae, Caenorhabditis elegans, and human cells, and its GTP-binding region is very similar to those found in R-ras and Rap2. However, ectopic expression of NGB inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwanomma cells. Down-regulation and infrequent mutation of NGB were detected in human glioma cell lines and primary tumors. The interaction of NGB with merlin impairs the turnover of merlin, yet merlin does not affect the GTPase nor GTP-binding activity of NGB. Finally, the tumor suppressor functions of NGB require merlin and are linked to its ability to suppress cyclin D1 expression. Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation.

Published ahead of print on 8 January 2007.

Contributed equally to this work.

Present address: Division of Life Sciences, Kangwon National University, Chuncheon, South Korea.

This article has been cited by other articles:

• Lau, Y.-K. I., Murray, L. B., Houshmandi, S. S., Xu, Y., Gutmann, D. H., Yu, Q. (2008). Merlin Is a Potent Inhibitor of Glioma Growth. Cancer Res. 68: 5733-5742 [Abstract] [Full Text]