Role of Merlin/NF2 in mTOR Signaling and Meningioma Growth.

摘要

The scope of this research project is to mechanistically define how merlin regulates mTORC1 signaling, to examine signaling downstream of mTORC2 and to validate the efficacy of mTOR inhibitors in both in vitro and in vivo preclinical models. The results obtained during assay development of an unbiased kinome screening clearly establish that Rheb is required for mTORC1 activation mediated by NF2 loss, supporting our hypothesis that NF2 may function through TSC1-TSC2 protein complex. Similar to TSC proteins, merlin negatively regulates mTORC1 and positively regulates mTORC2 However, contrary to activation of mTORC1, the attenuated mTORC2 signaling profiles exhibited by normal arachnoid and Schwann cells in response to acute merlin loss are not consistently reflected in NF2-deficient meningiomas and schwannomas, suggesting that additional genetic events may have been acquired in tumors after initial merlin loss. Our results show that mTOR kinase inhibitor such as Torin1 is more effective in blocking signaling and inhibiting proliferation of benign (WHO grdae1) and atypical (WHO grade 2) meningioma cells. A manuscript describing these results is now in press and expected to be published soon. We have shown that implantation of benign meningioma cells form tumors and may serve as valuable preclinical model for NF2.