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:

Unique role of SNT-2/FRS2β/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways

Oncogene volume 25, pages 6457–6466 (2006)Cite this article

Abstract

The membrane-linked docking protein SNT-2/FRS2β/FRS3 becomes tyrosine phosphorylated in response to fibroblast growth factors (FGFs) and neurotrophins and serves as a platform for recruitment of multiple signaling proteins, including Grb2 and Shp2, to FGF receptors or neurotrophin receptors. We previously reported that SNT-2 is not tyrosine phosphorylated significantly in response to epidermal growth factor (EGF) but that it inhibits ERK activation via EGF stimulation by forming a complex with ERK2. In the present report, we show that expression of SNT-2 suppressed EGF-induced cell transformation and proliferation, and expression level of SNT-2 is downregulated in cancer. The activities of the major signaling molecules in EGF receptor (EGFR) signal transduction pathways, including autophosphorylation of EGFR, were attenuated in cells expressing SNT-2 but not in cells expressing SNT-2 mutants lacking the ERK2-binding domain. Furthermore, SNT-2 constitutively bound to EGFR through the phosphotyrosine binding (PTB) domain both with and without EGF stimulation. Treatment of cells with MEK inhibitor U0126 partially restored the phosphorylation levels of MEK and EGFR in cells expressing SNT-2. On the basis of these findings, we propose a novel mechanism of negative control of EGFR tyrosine kinase activity with SNT-2 by recruiting ERK2, which is the site of negative-feedback loop from ERK, ultimately leading to inhibition of EGF-induced cell transformation and proliferation.

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

  • Buday L, Downward J . (1993). Cell 73: 611–620.

  • Canagarajah BJ, Khokhlatchev A, Cobb MH, Goldsmith EJ . (1997). Cell 90: 859–869.

  • Chen C, Okayama H . (1987). Mol Cell Biol 7: 2745–2752.

  • Dhalluin C, Yan KS, Plotnikova O, Lee KW, Zeng L, Kuti M et al. (2000). Mol Cell 6: 921–929.

  • Gotoh N, Ito M, Yamamoto S, Yoshino I, Song N, Wang Y et al. (2004a). Proc Natl Acad Sci USA 101: 17144–17149 [E-pub 2004 Nov 29].

  • Gotoh N, Laks S, Nakashima M, Lax I, Schlessinger J . (2004b). FEBS Lett 564: 14–18.

  • Gotoh N, Manova K, Tanaka S, Murohashi M, Hadari Y, Lee A et al. (2005). Mol Cell Biol 25: 4105–4116.

  • Gotoh N, Muroya K, Hattori S, Nakamura S, Chida K, Shibuya M . (1995). Oncogene 11: 2525–2533.

  • Gotoh N, Tojo A, Hino M, Yazaki Y, Shibuya M . (1992). Biochem Biophys Res Commun 186: 768–774.

  • Gotoh N, Tojo A, Muroya K, Hashimoto Y, Hattori S, Nakamura S et al. (1994). Proc Natl Acad Sci USA 91: 167–171.

  • Gotoh N, Toyoda M, Shibuya M . (1997). Mol Cell Biol 17: 1824–1831.

  • Habib AA, Chun SJ, Neel BG, Vartanian T . (2003). Mol Cancer Res 1: 219–233.

  • Hadari YR, Gotoh N, Kouhara H, Lax I, Schlessinger J . (2001). Proc Natl Acad Sci USA 98: 8578–8583.

  • Hadari YR, Kouhara H, Lax I, Schlessinger J . (1998). Mol Cell Biol 18: 3966–3973.

  • Harada A, Katoh H, Negishi M . (2005). J Biol Chem 280: 18418–18424. [E-pub 2005 Feb 28].

  • Hirata A, Hosoi F, Miyagawa M, Ueda S, Naito S, Fujii T et al. (2005). Cancer Res 65: 4253–4260.

  • Ho R, Minturn JE, Hishiki T, Zhao H, Wang Q, Cnaan A et al. (2005). Cancer Res 65: 9868–9875.

  • Huang L, Gotoh N, Zhang S, Shibuya M, Yamamoto T, Tsuchida N . (2004). Biochem Biophys Res Commun 324: 1011–1017.

  • Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW . (2003). Exp Cell Res 284: 31–53.

  • Kitamura T, Koshino Y, Shibata F, Oki T, Nakajima H, Nosaka T et al. (2003). Exp Hematol 31: 1007–1014.

  • Kouhara H, Hadari YR, Spivak-Kroizman T, Schilling J, Bar-Sagi D, Lax I et al. (1997). Cell 89: 693–702.

  • Lax I, Wong A, Lamothe B, Lee A, Frost A, Hawes J et al. (2002). Mol Cell 10: 709–719.

  • Lee M, Draoui M, Zia F, Gazdar A, Oie H, Bepler G et al. (1992). J Natl Cancer Inst Monogr 13: 117–123.

  • Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P et al. (1993). Nature 363: 85–88.

  • Okutani T, Okabayashi Y, Kido Y, Sugimoto Y, Sakaguchi K, Matuoka K et al. (1994). J Biol Chem 269: 31310–31314.

  • Ong SH, Guy GR, Hadari YR, Laks S, Gotoh N, Schlessinger J et al. (2000). Mol Cell Biol 20: 979–989.

  • Ong SH, Hadari YR, Gotoh N, Guy GR, Schlessinger J, Lax I . (2001). Proc Natl Acad Sci USA 98: 6074–6079. [E-pub 2001 May 15].

  • Payne DM, Rossomando AJ, Martino P, Erickson AK, Her JH, Shabanowitz J et al. (1991). EMBO J 10: 885–892.

  • Rabin SJ, Cleghon V, Kaplan DR . (1993). Mol Cell Biol 13: 2203–2213.

  • Riedel H, Massoglia S, Schlessinger J, Ullrich A . (1988). Proc Natl Acad Sci USA 85: 1477–1481.

  • Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W et al. (1992). Nature 360: 689–692.

  • Rubenstein M, Shaw M, Mirochnik Y, Slobodskoy L, Glick R, Lichtor T et al. (1999). Methods Find Exp Clin Pharmacol 21: 391–393.

  • Schlessinger J . (2000). Cell 103: 211–225.

  • Wu Y, Chen Z, Ullrich A . (2003). Biol Chem 384: 1215–1226.

  • Xu H, Lee KW, Goldfarb M . (1998). J Biol Chem 273: 17987–17990.

  • Yarden Y, Sliwkowski MX . (2001). Nat Rev Mol Cell Biol 2: 127–137.

Download references

Acknowledgements

We are grateful to Dr Toshio Kitamura for valuable reagents for retrovirus expression system and Ms Takako Horii for technical assistance. We thank Drs Jun Yokota and Masachika Tani for valuable cell lines and discussion. This work was supported by Grants-in-Aid for Special Project Research on Stem Cells (17045008) to NG and on Cancer-Bioscience (17013025) to NG and (17014020) to MS from the Ministry of Education, Science, Sports and Culture of Japan, by The Mochida Memorial Foundation for Medical and Pharmaceutical Research to NG, by NOVARTIS Foundation (Japan) for the Promotion of Science to NG, by Grants-in-Aid for the program ‘Research for the Future’ of the Japan Society for the Promotion of Science and for the program ‘Promotion of Fundamental Research in Health Sciences’ from the Organization for Pharmaceutical Safety and Research (OPSR) to MS, and by Japan Society for the Promotion of Science (16390520) to NT. LH is a recipient of Honjo International Scholarship Foundation.

Author information

Author notes

  1. L Huang

    Present address: Chemotherapy Division of Cancer Proteomics Project, National Cancer Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

  2. N Gotoh and N Tsuchida: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Cellular Oncology and Microbiology, Graduate School, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan

    L Huang & N Tsuchida

  2. Division of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    L Huang, M Watanabe, M Shibuya & N Gotoh

  3. Division of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    M Chikamori & T Yamamoto

  4. Division of Diabetes and Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan

    Y Kido

Authors
  1. L Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Chikamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Y Kido
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Shibuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Gotoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N Tsuchida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to N Gotoh or N Tsuchida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, L., Watanabe, M., Chikamori, M. et al. Unique role of SNT-2/FRS2β/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways. Oncogene 25, 6457–6466 (2006). https://doi.org/10.1038/sj.onc.1209656

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209656

Keywords

This article is cited by

Search

Advanced search

Quick links