Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Oncogenic role of Merlin/NF2 in glioblastoma

Oncogene volume 34, pages 2621–2630 (2015)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Fassl A, Tagscherer KE, Richter J, Berriel Diaz M, Alcantara Llaguno SR, Campos B et al. Notch1 signaling promotes survival of glioblastoma cells via EGFR-mediated induction of anti-apoptotic Mcl-1. Oncogene 2002; 31: 4698–4708.

    Article  Google Scholar 

  2. Takebe N, Nguyen D, Yang SX . Targeting Notch signaling pathway in cancer: Clinical development advances and challenges. Pharmacol Ther. 2013; 141: 140–149.

    Article  Google Scholar 

  3. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 1993; 363: 515–521.

    Article  CAS  Google Scholar 

  4. Trofatter JA, MacCollin MM, Rutter JL, Murrell JR, Duyao MP, Parry DM et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 1993; 72: 791–800.

    Article  CAS  Google Scholar 

  5. Eldridge R . Central neurofibromatosis with bilateral acoustic neuroma. Adv Neurol 1981; 9: 57–65.

    Google Scholar 

  6. Bianchi AB, Hara T, Ramesh V, Gao J, Klein-Szanto AJ, Morin F et al. Mutations in transcript isoforms of the neurofibromatosis 2 gene in multiple human tumour types. Nat Genet 1994; 6: 185–192.

    Article  CAS  Google Scholar 

  7. Lau YK, Murray LB, Houshmandi SS, Xu Y, Gutmann DH, Yu Q . Merlin is a potent inhibitor of glioma growth. Cancer Res 2008; 68: 5733–5742.

    Article  CAS  Google Scholar 

  8. Houshmandi SS, Emnett RJ, Giovannini M, Gutmann DH . The neurofibromatosis 2 protein, merlin, regulates glial cell growth in an ErbB2- and Src-dependent manner. Mol Cel Biol 2009; 29: 1472–1486.

    Article  CAS  Google Scholar 

  9. Stamenkovic I, Yu Q . Merlin, a ‘magic’ linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Curr Protein Pept Sci 2010; 11: 471–484.

    Article  CAS  Google Scholar 

  10. Pecina-Slaus N . Merlin, the NF2 gene product. Pathol Oncol Res 2013; 19: 365–373.

    Article  CAS  Google Scholar 

  11. Sherman LS, Gutmann DH . Merlin: hanging tumor suppression on the Rac. Trends Cell Biol 2001; 11: 442–444.

    Article  CAS  Google Scholar 

  12. Li W, You L, Cooper J, Schiavon G, Pepe-Caprio A, Zhou L et al. Merlin/NF2 suppresses tumorigenesis by inhibiting the E3 ubiquitin ligase CRL4(DCAF1) in the nucleus. Cell 2010; 140: 477–490.

    Article  CAS  Google Scholar 

  13. Surace EI, Haipek CA, Gutmann DH . Effect of merlin phosphorylation on neurofibromatosis 2 (NF2) gene function. Oncogene 2004; 23: 580–587.

    Article  CAS  Google Scholar 

  14. Fernandez-Valle C, Tang Y, Ricard J, Rodenas-Ruano A, Taylor A, Hackler E et al. Paxillin binds schwannomin and regulates its density-dependent localization and effect on cell morphology. Nat Genet 2002; 31: 354–362.

    Article  CAS  Google Scholar 

  15. Alfthan K, Heiska L, Gronholm M, Renkema GH, Carpen O . Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21-activated kinase and promotes merlin-ezrin heterodimerization. J Biol Chem 2004; 279: 18559–18566.

    Article  CAS  Google Scholar 

  16. Tang X, Jang SW, Wang X, Liu Z, Bahr SM, Sun SY et al. Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat Cell Biol 2007; 9: 1199–1207.

    Article  CAS  Google Scholar 

  17. Laulajainen M, Muranen T, Carpen O, Gronholm M . Protein kinase A-mediated phosphorylation of the NF2 tumor suppressor protein merlin at serine 10 affects the actin cytoskeleton. Oncogene 2008; 27: 3233–3243.

    Article  CAS  Google Scholar 

  18. Gutmann DH, Haipek CA, Hoang Lu K . Neurofibromatosis 2 tumor suppressor protein, merlin, forms two functionally important intramolecular associations. J Neurosci Res 1999; 58: 706–716.

    Article  CAS  Google Scholar 

  19. Sherman L, Xu HM, Geist RT, Saporito-Irwin S, Howells N, Ponta H et al. Interdomain binding mediates tumor growth suppression by the NF2 gene product. Oncogene 1997; 15: 2505–2509.

    Article  CAS  Google Scholar 

  20. Okada T, You L, Giancotti FG . Shedding light on Merlin's wizardry. Trends Cell Biol 2007; 17: 222–229.

    Article  CAS  Google Scholar 

  21. Gronholm M, Muranen T, Toby GG, Utermark T, Hanemann CO, Golemis EA et al. A functional association between merlin and HEI10, a cell cycle regulator. Oncogene 2006; 25: 4389–4398.

    Article  CAS  Google Scholar 

  22. Thaxton C, Lopera J, Bott M, Baldwin ME, Kalidas P, Fernandez-Valle C . Phosphorylation of the NF2 tumor suppressor in Schwann cells is mediated by Cdc42-Pak and requires paxillin binding. Mol Cell Neurosci 2007; 34: 231–242.

    Article  CAS  Google Scholar 

  23. Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA et al. The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. Genes Dev 2001; 15: 968–980.

    Article  CAS  Google Scholar 

  24. Okada M, Wang Y, Jang SW, Tang X, Neri LM, Ye K . Akt phosphorylation of merlin enhances its binding to phosphatidylinositols and inhibits the tumor-suppressive activities of merlin. Cancer Res 2009; 69: 4043–4051.

    Article  CAS  Google Scholar 

  25. Kang CS, Zhang ZY, Jia ZF, Wang GX, Qiu MZ, Zhou HX et al. Suppression of EGFR expression by antisense or small interference RNA inhibits U251 glioma cell growth in vitro and in vivo. Cancer Gene Ther 2006; 13: 530–538.

    Article  CAS  Google Scholar 

  26. Muranen T, Gronholm M, Renkema GH, Carpen O . Cell cycle-dependent nucleocytoplasmic shuttling of the neurofibromatosis 2 tumour suppressor merlin. Oncogene 2005; 24: 1150–1158.

    Article  CAS  Google Scholar 

  27. Curto M, Cole BK, Lallemand D, Liu CH, McClatchey AI . Contact-dependent inhibition of EGFR signaling by Nf2/Merlin. J Cell Biol 2007; 177: 893–903.

    Article  CAS  Google Scholar 

  28. Noda N, Honma S, Ohmiya Y . Hes1 is required for contact inhibition of cell proliferation in 3T3-L1 preadipocytes. Genes Cells 2011; 16: 704–713.

    Article  CAS  Google Scholar 

  29. Mazzone M, Selfors LM, Albeck J, Overholtzer M, Sale S, Carroll DL et al. Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci USA 2010; 107: 5012–5017.

    Article  CAS  Google Scholar 

  30. Gonzales AJ, Fry DW . G1 cell cycle arrest due to the inhibition of erbB family receptor tyrosine kinases does not require the retinoblastoma protein. Exp Cell Res 2005; 303: 56–67.

    CAS  PubMed  Google Scholar 

  31. Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature 2011; 480: 118–122.

    Article  CAS  Google Scholar 

  32. Jacoby LB, MacCollin M, Barone R, Ramesh V, Gusella JF . Frequency and distribution of NF2 mutations in schwannomas. Genes Chromosomes Cancer 1996; 17: 45–55.

    Article  CAS  Google Scholar 

  33. Morrow KA, Das S, Metge BJ, Ye K, Mulekar MS, Tucker JA et al. Loss of tumor suppressor Merlin in advanced breast cancer is due to post-translational regulation. J Biol Chem 2011; 286: 40376–40385.

    Article  CAS  Google Scholar 

  34. Lino MM, Merlo A, Boulay JL . Notch signaling in glioblastoma: a developmental drug target? BMC Med 2010; 8: 72.

    Article  Google Scholar 

  35. Xiao GH, Gallagher R, Shetler J, Skele K, Altomare DA, Pestell RG et al. The NF2 tumor suppressor gene product, merlin, inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression. Mol Cell Biol 2005; 25: 2384–2394.

    Article  CAS  Google Scholar 

  36. Schulze KM, Hanemann CO, Muller HW, Hanenberg H . Transduction of wild-type merlin into human schwannoma cells decreases schwannoma cell growth and induces apoptosis. Hum Mol Genet 2002; 11: 69–76.

    Article  CAS  Google Scholar 

  37. Maitra S, Kulikauskas RM, Gavilan H, Fehon RG . The tumor suppressors Merlin and Expanded function cooperatively to modulate receptor endocytosis and signaling. Curr Biol 2006; 16: 702–709.

    Article  CAS  Google Scholar 

  38. Visser-Grieve S, Hao Y, Yang X . Human homolog of Drosophila expanded, hEx, functions as a putative tumor suppressor in human cancer cell lines independently of the Hippo pathway. Oncogene 2011; 31: 1189–1195.

    Article  Google Scholar 

  39. Schneider CA, Rasband WS, Eliceiri KW . NIH Image to ImageJ: 25 years of image analysis. Nat Methods 2012; 9: 671–675.

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

  1. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    P A Guerrero, W Yin, L Camacho & D Marchetti

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    D Marchetti

Authors
  1. P A Guerrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L Camacho
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Marchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D Marchetti.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2014.185

This article is cited by

Search

Advanced search

Quick links