NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth.
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.
James
Marianne F
MF
Center for Human Genetic Research, Massachusetts General Hospital, Richard B. Simches Research Building, 185 Cambridge St., Boston, MA 02114, USA.
Han
Sangyeul
S
Polizzano
Carolyn
C
Plotkin
Scott R
SR
Manning
Brendan D
BD
Stemmer-Rachamimov
Anat O
AO
Gusella
James F
JF
Ramesh
Vijaya
V
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001099:Arachnoid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D000076222:Mechanistic Target of Rapamycin Complex 1; D008579:Meningioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D025581:Neurofibromin 2; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors