Oncogenic role of Merlin/NF2 in glioblastoma

• Published in: Oncogene Vol. 34; no. 20; pp. 2621 - 2630
• Main Authors: Guerrero, P A, Yin, W, Camacho, L, Marchetti, D
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-05-2015; Nature Publishing Group
• Subjects: 13; 13/106; 13/109; 13/31; 13/44; 13/95; 42; 42/35; 42/44; 59; 631/80/83; 64; 64/60; Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - biosynthesis; Basic Helix-Loop-Helix Transcription Factors - genetics; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cell Biology; Cell Line, Tumor; Cell proliferation; Chemotherapy; Contact inhibition; Cyclin D1; Cyclin D1 - biosynthesis; Cyclin D1 - genetics; Drug resistance; Enhancer-of-split protein; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - biosynthesis; ErbB Receptors - genetics; Ezrin; Female; Gene Expression Regulation, Neoplastic - genetics; Glioblastoma; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - genetics; Human Genetics; Humans; Internal Medicine; Kinases; Medicine; Medicine & Public Health; Mice; Mice, Nude; Moesin; Mutation; Nervous system; Neurofibromatosis; Neurofibromatosis 2; Neurofibromin 2; Neurofibromin 2 - genetics; Neurofibromin 2 - metabolism; Notch1 protein; Oncology; original-article; Phosphorylation; Phosphorylation - genetics; Proteins; Radiation therapy; Radiology; Radixin; Receptor, Notch1 - biosynthesis; Receptor, Notch1 - genetics; Serine; Transcription Factor HES-1; Tumor suppressor genes; Tumorigenesis; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2014.185

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.