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 Paper
  • Published:

The merlin tumor suppressor interacts with Ral guanine nucleotide dissociation stimulator and inhibits its activity

Oncogene volume 24, pages 5355–5364 (2005)Cite this article

Abstract

Neurofibromatosis type 2 (NF2) is the most commonly mutated gene in benign tumors of the human nervous system such as schwannomas and meningiomas. The NF2 gene encodes a protein called schwannomin or merlin, which is involved in regulating cell growth and proliferation through protein–protein interactions with various cellular proteins. In order to better understand the mechanism by which merlin exerts its function, yeast two-hybrid screening was performed and Ral guanine nucleotide dissociation stimulator (RalGDS), a downstream molecule of Ras, was identified as a merlin-binding protein. The direct interaction between merlin and RalGDS was confirmed both in vitro and in the NIH3T3 cells. The domain analyses revealed that the broad C-terminal region of merlin (aa 141–595) is necessary for the interaction with the C-terminal Ras-binding domain (RBD) of RalGDS. Functional studies showed that merlin inhibits the RalGDS-induced RalA activation, the colony formation and the cell migration in mammalian cells. These results suggest that merlin can function as a tumor suppressor by inhibiting the RalGDS-mediated oncogenic signals.

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

Similar content being viewed by others

References

  • Arvelo F and Poupon MF . (2001). Acta Cient Venez., 52, 304–312.

  • Cantor S, Urano T and Feig LA . (1995). Mol. Cell. Biol., 15, 4578–4584.

  • Chishti AH, Kim AC, Marfatia SM, Lutchman M, Hanspal M, Jindal H, Liu SC, Low PS, Rouleau GA, Mohandas N, Chasis JA, Conboy JG, Gascard P, Takakuwa Y, Huang SC, Benz Jr EJ, Bretscher A, Fehon RG, Gusella JF, Ramesh V, Solomon F, Marchesi VT, Tsukita S, Tsukita S, Arpin M, Louard D, Tonks NK, Anderson JM, Fanning AS, Bryant PJ, Woods DF and Hoover KB . (1998). Trends Biochem. Sci., 23, 281–282.

  • Feig LA, Urano T and Cantor S . (1996). Trends Biochem. Sci., 21, 438–441.

  • Fernandez-Valle C, Tang Y, Ricard J, Rodenas-Ruano A, Taylor A, Hackler E, Biggerstaff J and Iacvelli J . (2002). Nat. Genet., 31, 354–362.

  • Gietz D, St. Jean A, Woods RA and Schiestl RH . (1992). Nucleic Acids Res., 20, 1425.

  • Gildea JJ, Harding MA, Seraj MJ, Gulding KM and Theodorescu D . (2002). Cancer Res., 62, 982–985.

  • Goutebroze L, Brault E, Muchardt C, Camonis J and Thomas G . (2000). Mol. Cell. Biol., 20, 1699–1712.

  • Hirokawa Y, Tikoo A, Huynh J, Utermark T, Hanemann CO, Giovannini M, Xiao GH, Testa JR, Wood J and Maruta H . (2004). Cancer J., 10, 20–26.

  • Hofer F, Fields S, Schneider C and Martin GS . (1994). Proc. Natl. Acad. Sci. USA, 91, 11089–11093.

  • Ikeda M, Ishida O, Hinoi T, Kishida S and Kikuchi A . (1998). J. Biol. Chem., 273, 814–821.

  • Ikeda K, Saeki Y, Gonzalez-Agosti C, Ramesh V and Chiocca EA . (1999). J. Neurosurg., 91, 85–92.

  • Jannatipur M, Dion P, Khan S, Jindal H, Fan X, Laganiere J, Chishti AH and Rouleau GA . (2001). J. Biol. Chem., 276, 33093–33100.

  • Joffe EB and Adam A . (2001). Medicina, 61, 658–663.

  • Johnson KC, Kissil JL, Fry JL and Jacks T . (2002). Oncogene, 21, 5990–5997.

  • Joneson T and Bar-Sagi D . (1997). J. Mol. Med., 75, 539–587.

  • Kim H, Lim JY, Kim YH, Kim H, Park SH, Lee KH, Han H, Jeun SS, Lee JH and Rha HK . (2002). Mol. Cells, 14, 108–114.

  • Kim JY, Kim H, Jeun SS, Rha SJ, Kim YH, Ko YJ, Won J, Lee KH, Rha HK and Wang YP . (2002). Biochem. Biophys. Res. Commun., 296, 1295–1302.

  • Koga H, Araki N, Takeshia H, Nishi T, Hirota T, Kimura Y, Nakao M and Saya H . (1998). Oncogene, 17, 801–810.

  • Kressel M and Schmucker B . (2002). Hum. Mol. Genet., 11, 2269–2278.

  • Lee IK, Kim KS, Kim H, Lee JY, Ryu CH, Chun HJ, Lee KU, Lim Y, Kim YH, Huh PW, Lee KH, Han SI, Jun TY and Rha HK . (2004). Biochem. Biophys. Res. Commun., 325, 774–783.

  • Lee JY, Kim H, Ryu CH, Kim JY, Choi BH, Lim Y, Huh PW, Kim YH, Lee KH, Jun TY, Rha HK, Kang JK and Choi CR . (2004). J. Biol. Chem., 279, 30265–30273.

  • Lee T, Feig L and Montell DJ . (1996). Development, 122, 409–418.

  • Lim JY, Kim H, Kim YH, Kim SW, Huh PW, Lee KH, Jeun SS, Rha H and Kand Kang JK . (2003). Biochem. Biophys. Res. Commun., 302, 238–245.

  • Louis DN, Ramesh V and Gusella JF . (1995). Brain Pathol., 5, 163–172.

  • Lu Z, Hornia A, Joseph T, Sukezane T, Frankel P, Zhong M, Bychenok S, Xu L, Feig LA and Foster DA . (2000). Mol. Cell. Biol., 20, 462–467.

  • Matthews JN . (2002). Dev. Biol., 107, 87–94.

  • McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT and Jacks T . (1998). Genes Dev., 12, 1121–1133.

  • McCormick F and Wittinghofer A . (1996). Curr. Opin. Biotechnol., 7, 449–456.

  • Melchiori A, Carlone S, Allavena G, Aresu O, Parodi S, Aaronson SA and Albini A . (1990). Anticancer Res., 10, 37–44.

  • Morrison H, Sherman LS, Legg J, Banine F, Isacke C, Haipek CA, Gutmann DH, Ponta H and Herrlich P . (2001). Genes Dev., 15, 968–980.

  • Murthy A, Gonzalez-Agosti C, Cordero E, Pinney D, Candia C, Solomon F, Gusella J and Ramesh V . (1998). J. Biol. Chem., 273, 1273–1276.

  • Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, Hoang-Xuan K, Demczuk S, Desmaze C and Plougastel B . (1993). Nature, 363, 515–521.

  • Rusanescu G, Gotoh T, Tian X and Feig LA . (2001). Mol. Cell. Biol., 21, 2650–2658.

  • Sainio M, Zhao F, Heiska L, Turunen O, den Bakker M, Zwarthoff E, Lutchman M, Rouleau GA, Jaaskelainen J, Vaheri A and Carpen O . (1997). J. Cell Sci., 110, 2249–2260.

  • Schmucker B, Tang Y and Kressel M . (1999). Hum. Mol. Genet., 8, 1561–1570.

  • Scoles DR, Chen M and Pulst SM . (2002). Biochem. Biophys. Res. Commun., 290, 366–374.

  • Scoles DR, Huynh DP, Chen MS, Burke SP, Gutmann DH and Pulst SM . (2000). Hum. Mol. Genet., 9, 1567–1574.

  • Scoles DR, Huynh DP, Mrcos PA, Coulsell ER, Robinson NG, Tamanoi F and Pulst SM . (1998). Nat. Genet., 18, 354–359.

  • Shermn L, Xu HM, Geist RT, Saporito-Irwin S, Howells N, Ponta H, Herrlich P and Gutmann DH . (1997). Oncogene, 15, 2505–2509.

  • Sun CX, Robb VA and Gutmann DH . (2002). J. Cell Sci., 115, 3991–4000.

  • Suzuki J, Yamazaki Y, Li G, Kaziro Y and Koide H . (2000). Mol. Cell. Biol., 20, 4658–4665.

  • Takaya A, Ohba Y, Kurokawa K and Matsuda M . (2004). Mol. Biol. Cell, 15, 2549–2557.

  • Thomas G, Merel P, Sanson M, Hoang-Xuan K, Zucman J, Desmaze C, Melot T, Aurias A and Delattre O . (1994). Eur. J. Cancer, 30A, 1981–1987.

  • Tikoo A, Varga M, Ramesh V, Gusella J and Maruta H . (1994). J. Biol. Chem., 269, 23387–23390.

  • Trofatter JA, MacCollin MM, Rutter JL, Murrel JR, Duyao MP, Parry DM, Eldridge R, Kley N, Menon AG and Pulaski K . (1993). Cell, 72, 791–800.

  • Tsukita S, Yonemura S and Tsukita S . (1997). Trends Biochem. Sci., 22, 53–58.

  • Urano T, Emkey R and Feig LA . (1996). EMBO J., 15, 810–816.

  • Vojtk AB and Der CJ . (1998). J. Biol. Chem., 273, 19925–19928.

  • White MA, Vale T, Camonis JH, Schaefer E and Wigler MH . (1996). J. Biol. Chem., 71, 16439–16442.

  • Wolthuis RM, Zwartkruis F, Moen TC and Bos JL . (1998). Curr. Biol., 8, 471–474.

  • Yamaguchi A, Urano T, Goi T and Feig LA . (1997). J. Biol. Chem., 272, 31230–31234.

Download references

Acknowledgements

We wish to thank other members of the laboratory for their assistance. We also thank Dr David Gutmann and Dr Takashi Iwamoto for providing us pcDNA-NF2 and pcDNA3-RalA expression vector, respectively. This study was supported by a grant of the Korean Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea (00-PJ3-PG6-GN02-0002, 02-PJ10-PG6-GN01-0002).

Author information

Authors and Affiliations

  1. Catholic Neuroscience Center, The Catholic University of Korea, 137-701, Seoul, Korea

    Chung Hun Ryu, Kyu Hwa Lee, Joo Yong Lee, Hongtae Kim, Byung Hyune Choi, Young Hoon Kim, Tae-Youn Jun & Hyoung Kyun Rha

  2. Department of Urology, The Catholic University of Korea, 137-701, Seoul, Korea

    Chung Hun Ryu, Sae-Woong Kim & Tae-Kon Hwang

  3. Department of Pharmacology, The Catholic University of Korea, 137-701, Seoul, Korea

    Woon Kyu Lee & Kweon-Haeng Lee

  4. Department of Occupational and Environmental Medicine, The Catholic University of Korea, 137-701, Seoul, Korea

    Young Lim

  5. Department of Psychiatry, The Catholic University of Korea, 137-701, Seoul, Korea

    Tae-Youn Jun

Authors
  1. Chung Hun Ryu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sae-Woong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyu Hwa Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joo Yong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hongtae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Woon Kyu Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Byung Hyune Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Young Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Young Hoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kweon-Haeng Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tae-Kon Hwang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tae-Youn Jun
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hyoung Kyun Rha
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tae-Youn Jun.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ryu, C., Kim, SW., Lee, K. et al. The merlin tumor suppressor interacts with Ral guanine nucleotide dissociation stimulator and inhibits its activity. Oncogene 24, 5355–5364 (2005). https://doi.org/10.1038/sj.onc.1208633

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208633

Keywords

This article is cited by

Search

Advanced search

Quick links