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:

Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway

Oncogene volume 21, pages 2309–2319 (2002)Cite this article

A Corrigendum to this article was published on 09 July 2002

Abstract

Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering and morphogenesis of epithelial cells through the activation of the MET tyrosine kinase receptor. Although the activated MET receptor recruits a number of signaling proteins, little is known of the downstream signaling pathways activated by HGF/SF. In this study, we wished to examine the signaling pathway leading to activation of the ETS1 transcription factor. Using in vitro and in vivo kinase assays, we found that HGF/SF activates the ERK1 MAP kinase, leading to the phosphorylation of the threonine 38 residue of ETS1 within a putative MAP kinase phosphorylation site (PLLT38P). This threonine residue was neither phosphorylated by JNK1, nor by p38 MAP kinases and was required for the induction of transcriptional activity of ETS1 by HGF/SF. Using kinase and transcription assays, we further demonstrated that phosphorylation and activation of ETS1 occurs downstream of a RAS-RAF-MEK-ERK pathway. The functional involvement of this pathway in HGF/SF action was demonstrated using U0126, a pharmacological inhibitor of MEK, which blocked phosphorylation and activation of ETS1, RAS-dependent transcriptional responses, cell scattering and morphogenesis. These data demonstrated that ETS1 is a downstream target of HGF/SF acting through a RAS-RAF-MEK-ERK pathway and provides a signaling pathway leading to the regulation of gene expression by HGF/SF.

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 5
Figure 3
Figure 4
Figure 6

Similar content being viewed by others

References

  • Baker DA, Mille-Baker B, Wainwright SM, Ish-Horowicz D, Dibb NJ . 2001 Nature 411: 330–334

  • Behrens J, Mareel MM, Van Roy F, Birchmeier W . 1989 J. Cell Biol. 108: 2435–2447

  • Brunner D, Dücker K, Oellers NEH, Scholz H, Klämbt C . 1994 Nature 370: 386–389

  • Chang C, Gralla JD . 1993 Mol. Cell. Biol. 13: 7469–7475

  • Chen JH . 1990 Oncogene Res. 5: 277–285

  • Defossez PA, Baert JL, Monnot M, de Launoit Y . 1997 Nucleic Acids Res. 25: 4455–4463

  • Delannoy-Courdent A, Mattot V, Fafeur V, Fauquette W, Pollet I, Calmels T, Vercamer C, Boilly B, Vandenbunder B, Desbiens X . 1998 J. Cell Sci. 111: 1521–1534

  • Fafeur V, Tulasne D, Queva C, Vercamer C, Dimster V, Mattot V, Stehelin D, Desbiens X, Vandenbunder B . 1997 Cell Growth Differ. 8: 655–665

  • Fowles LF, Martin ML, Nelsen L, Stacey KJ, Redd D, Clark YM, Nagamine Y, McMahon M, Hume DA, Ostrowski MC . 1998 Mol. Cell. Biol. 18: 5148–5156

  • Furge KA, Zhang YW, Vande Woude GF . 2000 Oncogene 19: 5582–5589

  • Gambarotta G, Boccaccio C, Giordano S, Ando M, Stella MC, Comoglio PM . 1996 Oncogene 13: 1911–1917

  • Graves B, Pertersen JM . 1998 Advances in Cancer Research, Vol. 75. Vande Woude GF and Klein G. (eds) Academic press pp 1–56

    Book  Google Scholar 

  • Hartmann G, Weidner KM, Schwarz H, Birchmeier W . 1994 J. Biol. Chem. 269: 21936–21939

  • Howe LR, Leevers SJ, Gomez N, Nakielny S, Cohen P, Marshall CJ . 1992 Cell 71: 335–342

  • Khwaja A, Lehmann K, Marte BM, Downward J . 1998 J. Biol. Chem. 273: 18793–18801

  • Kim KR, Yoshizaki T, Miyamori H, Hasegawa K, Horikawa T, Furukawa M, Harada S, Seiki M, Sato H . 2000 Oncogene 19: 1764–1771

  • Kodaki T, Woscholski R, Hallberg B, Rodriguez-Viciana P, Downward J, Parker PJ . 1994 Curr. Biol. 4: 798–806

  • Kodama A, Takaishi K, Nakano K, Nishioka H, Takai Y . 1999 Oncogene 18: 3996–4006

  • Laudet V, Hanni C, Stehelin D, Duterque-Coquillaud M . 1999 Oncogene 18: 1351–1359

  • Marais R, Light Y, Paterson HF, Marshall CJ . 1995 EMBO J. 14: 3136–3145

  • Minden A, Lin A, McMahon M, Lange-Carter C, Dérijard B, Davis RJ, Johnson GL, Karin M . 1994 Science 266: 1719–1723

  • Nakamura T, Nawa K, Ichihara A . 1984 Biochem. Biophys. Res. Commun. 122: 1450–1459

  • Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK, Birchmeier W, Comoglio PM . 1991 EMBO J. 10: 2867–2878

  • O'Neill EM, Rebay I, Tjian R, Rubin GM . 1994 Cell 78: 137–147

  • Paumelle R, Tulasne D, Leroy C, Coll J, Vandenbunder B, Fafeur V . 2000 Mol. Biol Cell 11: 3751–3763

  • Pepper MS, Matsumoto K, Nakamura T, Orci L, Montesano R . 1992 J. Biol. Chem. 267: 20493–20496

  • Potempa S, Ridley AJ . 1998 Mol. Biol. Cell 9: 2185–2200

  • Rabault B, Roussel MF, Quang CT, Ghysdael J . 1996 Oncogene 13: 877–881

  • Ridley AJ, Comoglio PM, Hall A . 1995 Mol. Cell. Biol. 15: 1110–1122

  • Slupsky CM, Gentile LN, Donaldson LW, Mackereth CD, Seidel JJ, Graves BJ, McIntosh LP . 1998 Proc. Natl. Acad. Sci. USA 95: 12129–12134

  • Smith DB, Johnson KS . 1988 Gene 67: 31–40

  • Smith JL, Schaffner AE, Hofmeister JK, Hartman M, Wei G, Forsthoefel D, Hume DA, Ostrowski MC . 2000 Mol. Cell. Biol. 20: 8026–8034

  • Stacey KJ, Fowles LF, Colman MS, Ostrowski MC, Hume DA . 1995 Mol. Cell. Biol. 15: 3430–3441

  • Terauchi R, Kitamura N . 2000 Exp. Cell Res. 256: 411–422

  • Treisman R . 1996 Curr. Opin. Genet. Dev. 4: 96–101

  • Tulasne D, Paumelle R, Weidner KM, Vandenbunder B, Fafeur V . 1999 Mol. Biol. Cell 10: 551–565

  • Wasylyk B, Hagman J, Gutierrez-Hartmann A . 1998 Trends Biochem. Sci. 23: 213–216

  • Weidner KM, Sachs M, Birchmeier W . 1993 J. Cell Biol. 121: 145–154

  • Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ . 1995 Science 269: 403–407

  • Xiao GH, Jeffers M, Bellacosa A, Mitsuuchi Y, Vande Woude GF, Testa JR . 2001 Proc. Natl. Acad. Sci. USA 98: 247–252

  • Yang B-S, Hauser CA, Henkel G, Colman MS, Van Beveren C, Stacey KJ, Hume DA, Maki RA, Ostrowski MC . 1996 Mol. Cell. Biol. 16: 538–547

  • Yang SH, Whitmarsh AJ, Davis RJ, Sharrocks AD . 1998 EMBO J. 17: 1740–1749

  • Yordy JS, Muise-Helmericks RC . 2000 Oncogene 19: 6503–6513

  • Zondag GC, Evers EE, ten Klooster JP, Janssen L, van der Kammen RA, Collard JG . 2000 J. Cell Biol. 149: 775–782

Download references

Acknowledgements

The authors are grateful to Stéphane Ansieau, Agnès Bègue, Benoit Dérijard, Sydonia Rayter, Philippe Lenorman, Philippe Chavrier and Michael Ostrowski for providing reagents used in these studies. This work was supported by the Institut Pasteur de Lille and the CNRS and by grants from the Ligue Nationale contre le Cancer, Ligue Régionale-Comité Nord contre le Cancer and the Association pour la recherche contre le Cancer.

Author information

Author notes

  1. Syline Reveneau

    Present address: Cancer Immunotherapy Laboratory, EPHE-INSERM U517, BP 87900, Dijon, 21079, France

Authors and Affiliations

  1. CNRS FRE 2353, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P.447, Lille, 59021, France

    Rejane Paumelle, David Tulashe, Zoulika Kherrouche, Serge Plaza, Catherine Leroy, Syline Reveneau, Bernard Vandenbunder & Veronique Fafeur

Authors
  1. Rejane Paumelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David Tulashe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zoulika Kherrouche
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Serge Plaza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Catherine Leroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Syline Reveneau
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernard Vandenbunder
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Veronique Fafeur
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Veronique Fafeur.

Additional information

During the publication process of this manuscript, the role of the pointed domain of ETS1 as an ERK docking site has been elucidated (Seidel and Graves, 2002, Genes Dev., 16, 127–1327). These data complement our present demonstration that the threonine 38 residue of ETS1 is a phosphoacceptor site for ERK.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paumelle, R., Tulashe, D., Kherrouche, Z. et al. Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene 21, 2309–2319 (2002). https://doi.org/10.1038/sj.onc.1205297

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205297

Keywords

This article is cited by

Search

Advanced search

Quick links