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:

Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas

Oncogene volume 28, pages 854–865 (2009)Cite this article

Abstract

The NF2 gene product, merlin/schwannomin, is a cytoskeleton organizer with unique growth-inhibiting activity in specific cell types. A narrow spectrum of tumors is associated with NF2 deficiency, mainly schwannomas and meningiomas, suggesting cell-specific mechanisms of growth control. We have investigated merlin function in mouse Schwann cells (SCs). We found that merlin regulates contact inhibition of proliferation by limiting the delivery of several growth factor receptors at the plasma membrane of primary SCs. Notably, upon cell-to-cell contact, merlin downregulates the membrane levels of ErbB2 and ErbB3, thus inhibiting the activity of the downstream mitogenic signaling pathways protein kinase B and mitogen-activated protein kinase. Consequently, loss of merlin activity is associated with elevated levels of ErbB receptors in primary SCs. We also observed accumulation of growth factor receptors such as ErbB2 and 3, insulin-like growth factor 1 receptor and platelet-derived growth factor receptor in peripheral nerves of Nf2-mutant mice and in human NF2 schwannomas, suggesting that this mechanism could play an important role in tumorigenesis.

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

Similar content being viewed by others

References

  • Bache KG, Slagsvold T, Stenmark H . (2004). Defective downregulation of receptor tyrosine kinases in cancer. EMBO J 23: 2707–2712.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bretscher A, Edwards K, Fehon RG . (2002). ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol 3: 586–599.

    Article  CAS  PubMed  Google Scholar 

  • Bringold F, Serrano M . (2000). Tumor suppressors and oncogenes in cellular senescence. Exp Gerontol 35: 317–329.

    Article  CAS  PubMed  Google Scholar 

  • Buzard GS, Enomoto T, Anderson LM, Perantoni AO, Devor DE, Rice JM . (1999). Activation of neu by missense point mutation in the transmembrane domain in schwannomas induced in C3H/HeNCr mice by transplacental exposure to N-nitrosoethylurea. J Cancer Res Clin Oncol 125: 653–659.

    Article  CAS  PubMed  Google Scholar 

  • Cheng HL, Steinway M, Delaney CL, Franke TF, Feldman EL . (2000). IGF-I promotes Schwann cell motility and survival via activation of Akt. Mol Cell Endocrinol 170: 211–215.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deretic D, Traverso V, Parkins N, Jackson F, Rodriguez de Turco EB, Ransom N . (2004). Phosphoinositides, ezrin/moesin, and rac1 regulate fusion of rhodopsin transport carriers in retinal photoreceptors. Mol Biol Cell 15: 359–370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Fraenzer JT, Pan H, Minimo Jr L, Smith GM, Knauer D, Hung G . (2003). Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. Int J Oncol 23: 1493–1500.

    CAS  PubMed  Google Scholar 

  • Giovannini M, Robanus-Maandag E, Niwa-Kawakita M, van der Valk M, Woodruff JM, Goutebroze L et al. (1999). Schwann cell hyperplasia and tumors in transgenic mice expressing a naturally occurring mutant NF2 protein. Genes Dev 13: 978–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giovannini M, Robanus-Maandag E, van der Valk M, Niwa-Kawakita M, Abramowski V, Goutebroze L et al. (2000). Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev 14: 1617–1630.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen MR, Linthicum Jr FH . (2004). Expression of neuregulin and activation of erbB receptors in vestibular schwannomas: possible autocrine loop stimulation. Otol Neurotol 25: 155–159.

    Article  PubMed  Google Scholar 

  • Hardy M, Reddy UR, Pleasure D . (1992). Platelet-derived growth factor and regulation of Schwann cell proliferation in vivo. J Neurosci Res 31: 254–262.

    Article  CAS  PubMed  Google Scholar 

  • Hirokawa Y, Tikoo A, Huynh J, Utermark T, Hanemann CO, Giovannini M et al (2004). A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J 10: 20–26.

    Article  CAS  PubMed  Google Scholar 

  • Hirschberg K, Miller CM, Ellenberg J, Presley JF, Siggia ED, Phair RD et al (1998). Kinetic analysis of secretory protein traffic and characterization of golgi to plasma membrane transport intermediates in living cells. J Cell Biol 143: 1485–1503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hyun TS, Ross TS . (2004). HIP1: trafficking roles and regulation of tumorigenesis. Trends Mol Med 10: 194–199.

    Article  CAS  PubMed  Google Scholar 

  • Itahana K, Campisi J, Dimri GP . (2004). Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5: 1–10.

    Article  CAS  PubMed  Google Scholar 

  • Jones KA, Jiang X, Yamamoto Y, Yeung RS . (2004). Tuberin is a component of lipid rafts and mediates caveolin-1 localization: role of TSC2 in post-Golgi transport. Exp Cell Res 295: 512–524.

    Article  CAS  PubMed  Google Scholar 

  • Jozwiak J . (2006). Hamartin and tuberin: working together for tumour suppression. Int J Cancer 118: 1–5.

    Article  CAS  PubMed  Google Scholar 

  • Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T . (2003). Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21-activated kinase, Pak1. Mol Cell 12: 841–849.

    Article  CAS  PubMed  Google Scholar 

  • Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI . (2003). NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev 17: 1090–1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lim JY, Kim H, Kim YH, Kim SW, Huh PW, Lee KH et al. (2003). Merlin suppresses the SRE-dependent transcription by inhibiting the activation of Ras-ERK pathway. Biochem Biophys Res Commun 302: 238–245.

    Article  CAS  PubMed  Google Scholar 

  • Lobsiger CS, Schweitzer B, Taylor V, Suter U . (2000). Platelet-derived growth factor-BB supports the survival of cultured rat Schwann cell precursors in synergy with neurotrophin-3. Glia 30: 290–300.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Manent J, Oguievetskaia K, Bayer J, Ratner N, Giovannini M . (2003). Magnetic cell sorting for enriching Schwann cells from adult mouse peripheral nerves. J Neurosci Methods 123: 167–173.

    Article  PubMed  Google Scholar 

  • Mary S, Charrasse S, Meriane M, Comunale F, Travo P, Blangy A et al. (2002). Biogenesis of N-cadherin-dependent cell–cell contacts in living fibroblasts is a microtubule-dependent kinesin-driven mechanism. Mol Biol Cell 13: 285–301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McClatchey AI, Giovannini M . (2005). Membrane organization and tumorigenesis—the NF2 tumor suppressor, Merlin. Genes Dev 19: 2265–2277.

    Article  CAS  PubMed  Google Scholar 

  • Miyake K, McNeil PL, Suzuki K, Tsunoda R, Sugai N . (2001). An actin barrier to resealing. J Cell Sci 114: 3487–3494.

    CAS  PubMed  Google Scholar 

  • Morrison H, Sperka T, Manent J, Giovannini M, Ponta H, Herrlich P . (2007). Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res 67: 520–527.

    Article  CAS  PubMed  Google Scholar 

  • Muallem S, Kwiatkowska K, Xu X, Yin HL . (1995). Actin filament disassembly is a sufficient final trigger for exocytosis in nonexcitable cells. J Cell Biol 128: 589–598.

    Article  CAS  PubMed  Google Scholar 

  • Nikitin A, Ballering LA, Lyons J, Rajewsky MF . (1991). Early mutation of the neu (erbB-2) gene during ethylnitrosourea-induced oncogenesis in the rat Schwann cell lineage. Proc Natl Acad Sci USA 88: 9939–9943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perrais M, Chen X, Perez-Moreno M, Gumbiner BM . (2007). E-cadherin homophilic ligation inhibits cell growth and epidermal growth factor receptor signaling independently of other cell interactions. Mol Biol Cell 18: 2013–2025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Polo S, Pece S, Di Fiore PP . (2004). Endocytosis and cancer. Curr Opin Cell Biol 16: 156–161.

    Article  CAS  PubMed  Google Scholar 

  • Pujuguet P, Del Maestro L, Gautreau A, Louvard D, Arpin M . (2003). Ezrin regulates E-cadherin-dependent adherens junction assembly through Rac1 activation. Mol Biol Cell 14: 2181–2191.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qian X, Karpova T, Sheppard AM, McNally J, Lowy DR . (2004). E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases. EMBO J 23: 1739–1748.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rao DS, Hyun TS, Kumar PD, Mizukami IF, Rubin MA, Lucas PC et al. (2002). Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J Clin Invest 110: 351–360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sherman L, Sleeman JP, Hennigan RF, Herrlich P, Ratner N . (1999). Overexpression of activated neu/erbB2 initiates immortalization and malignant transformation of immature Schwann cells in vitro. Oncogene 18: 6692–6699.

    Article  CAS  PubMed  Google Scholar 

  • Siskova Z, Baron W, de Vries H, Hoekstra D . (2006). Fibronectin impedes ‘myelin’ sheet-directed flow in oligodendrocytes: a role for a beta 1 integrin-mediated PKC signaling pathway in vesicular trafficking. Mol Cell Neurosci 33: 150–159.

    Article  CAS  PubMed  Google Scholar 

  • Stanasila L, Abuin L, Diviani D, Cotecchia S . (2006). Ezrin directly interacts with the alpha1b-adrenergic receptor and plays a role in receptor recycling. J Biol Chem 281: 4354–4363.

    Article  CAS  PubMed  Google Scholar 

  • Stonecypher MS, Chaudhury AR, Byer SJ, Carroll SL . (2006). Neuregulin growth factors and their ErbB receptors form a potential signaling network for schwannoma tumorigenesis. J Neuropathol Exp Neurol 65: 162–175.

    Article  CAS  PubMed  Google Scholar 

  • Syroid DE, Zorick TS, Arbet-Engels C, Kilpatrick TJ, Eckhart W, Lemke G . (1999). A role for insulin-like growth factor-I in the regulation of Schwann cell survival. J Neurosci 19: 2059–2068.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tamma G, Klussmann E, Oehlke J, Krause E, Rosenthal W, Svelto M et al. (2005). Actin remodeling requires ERM function to facilitate AQP2 apical targeting. J Cell Sci 118: 3623–3630.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J Lippincott-Schwartz for the kind gift of the VSV-GFP construct, Z-Y Han for assistance with mouse genotyping, all members of the U674 lab for helpful discussions and support, L Goutebroze B Goud and O Hanemann for helpful suggestions, A McClatchey for many stimulating discussions, M Pla (Departement d’Experimentation Animale—Institut Universitaire d’Hematologie) and the Centre de Distribution, Typage et Archivage animal for mouse housing. DL personally thanks F Mechta-Grigoriou for helpful advice and discussions and continuous support and Odette Mariani for careful reading of the manuscript. This work was supported by Grants from the US Department of Defense (W81XWH-05-1-0265), Association Neurofibromatoses et Recklinghausen, Canceropôle Ile-de France, Institut National du Cancer, ANR and INSERM.

Author information

Authors and Affiliations

  1. INSERM, U674, Paris, France

    D Lallemand, J Manent, A Watilliaux, M Siena, F Chareyre, A Lampin, M Niwa-Kawakita, M Kalamarides & M Giovannini

  2. Université Paris 7, Denis Diderot, Institut Universitaire d′Hématologie, Paris, France

    D Lallemand, J Manent, A Watilliaux, M Siena, F Chareyre, A Lampin, M Niwa-Kawakita, M Kalamarides & M Giovannini

  3. APHP, Hôpital Beaujon, Service d’Anatomie et de Cytologie Pathologique, Clichy, France

    A Couvelard

  4. APHP, Hôpital Beaujon, Service de Neurochirurgie, Clichy, France

    M Kalamarides

Authors
  1. D Lallemand
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Manent
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Couvelard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Watilliaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Siena
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F Chareyre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Lampin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Niwa-Kawakita
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Kalamarides
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Giovannini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Giovannini.

Additional information

Conflict of interest

None declared.

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lallemand, D., Manent, J., Couvelard, A. et al. Merlin regulates transmembrane receptor accumulation and signaling at the plasma membrane in primary mouse Schwann cells and in human schwannomas. Oncogene 28, 854–865 (2009). https://doi.org/10.1038/onc.2008.427

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.427

Keywords

This article is cited by

Search

Advanced search

Quick links