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Molecular and Cellular Biology, August 2009, p. 4250-4261, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01581-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

NF2/Merlin Is a Novel Negative Regulator of mTOR Complex 1, and Activation of mTORC1 Is Associated with Meningioma and Schwannoma Growth{triangledown} ,{dagger}

Marianne F. James,1 Sangyeul Han,1 Carolyn Polizzano,1 Scott R. Plotkin,2 Brendan D. Manning,3 Anat O. Stemmer-Rachamimov,4 James F. Gusella,1 and Vijaya Ramesh1*

Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Building, 185 Cambridge Street, Boston, Massachusetts 02114,1 Department of Neurology,2 Molecular Neuro-Oncology Laboratory, Division of Neuropathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts,4 Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 021153

Received 8 October 2008/ Returned for modification 7 January 2009/ Accepted 12 May 2009

Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.

* Corresponding author. Mailing address: Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Building, 185 Cambridge St., Boston, MA 02114. Phone: (617) 724-9733. Fax: (617) 726-3655. E-mail: ramesh{at}helix.mgh.harvard.edu

{triangledown} Published ahead of print on 18 May 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2009, p. 4250-4261, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.01581-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lopez-Lago, M. A., Okada, T., Murillo, M. M., Socci, N., Giancotti, F. G. (2009). Loss of the Tumor Suppressor Gene NF2, Encoding Merlin, Constitutively Activates Integrin-Dependent mTORC1 Signaling. Mol. Cell. Biol. 29: 4235-4249 [Abstract] [Full Text]  


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