Abstract
Glioblastoma is the most common and aggressive primary brain tumor in adults, with a poor prognosis because of its resistance to radiotherapy and chemotherapy. Merlin/NF2 (moesin-ezrin-radixin-like protein/neurofibromatosis type 2) is a tumor suppressor found to be mutated in most nervous system tumors; however, it is not mutated in glioblastomas. Merlin associates with several transmembrane receptors and intracellular proteins serving as an anchoring molecule. Additionally, it acts as a key component of cell motility. By selecting sub-populations of U251 glioblastoma cells, we observed that high expression of phosphorylated Merlin at serine 518 (S518-Merlin), NOTCH1 and epidermal growth factor receptor (EGFR) correlated with increased cell proliferation and tumorigenesis. These cells were defective in cell-contact inhibition with changes in Merlin phosphorylation directly affecting NOTCH1 and EGFR expression, as well as downstream targets HES1 (hairy and enhancer of split-1) and CCND1 (cyclin D1). Of note, we identified a function for S518-Merlin, which is distinct from what has been reported when the expression of Merlin is diminished in relation to EGFR and NOTCH1 expression, providing first-time evidence that demonstrates that the phosphorylation of S518-Merlin in glioblastoma promotes oncogenic properties that are not only the result of inactivation of the tumor suppressor role of Merlin but also an independent process implicating a Merlin-driven regulation of NOTCH1 and EGFR.
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Acknowledgements
We are grateful to Drs F Giancotti and D Trono for providing vectors and reagents. We thank Jason Ngo, Andres Espinoza and Flavio Palalon for technical assistance. We also thank BCM Integrated Microscopy Core Facility at BCM supported by Shared Resources CPRIJ grant. The Characterized Cell Line Core at MDACC is supported by NCI Grant CA016672. This work was supported by NIH RO1 CA160335 (to DM).
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Guerrero, P., Yin, W., Camacho, L. et al. Oncogenic role of Merlin/NF2 in glioblastoma. Oncogene 34, 2621–2630 (2015). https://doi.org/10.1038/onc.2014.185
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DOI: https://doi.org/10.1038/onc.2014.185
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