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:

Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis

Oncogene volume 18, pages 3399–3406 (1999)Cite this article

Abstract

HGF/NK2, a naturally occurring truncated HGF isoform, antagonizes the mitogenic and morphogenic activities of full length HGF, but stimulates cell scatter, or the motogenic response to HGF. We studied postreceptor signaling by these HGF isoforms in the human breast epithelial cell line 184B5, and in murine myeloid progenitor 32D cells transfected with c-Met, the human HGF receptor (32D/c-Met). HGF stimulated DNA synthesis in 184B5 and 32D/c-Met cells, while HGF/NK2 was mitogenically inactive, despite the ability of HGF/NK2 to stimulate c-Met autophosphorylation, mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) in both cell systems. In 184B5 cells, HGF stimulated sustained MAPK activation, while activation by HGF/NK2 declined rapidly. In contrast, both isoforms activated MAPK with rapidly attenuated kinetics in 32D/c-Met cells. In both cell systems the increased motility observed in response to either HGF or HGF/NK2 treatment was more potently blocked by the PI3 kinase inhibitor wortmannin, than by PD98059, an inhibitor of MAPK kinase (MEK1). These data suggest that (1) alternative HGF isoforms signaling through c-Met generate both common and distinct biological responses, (2) the extent and duration of ligand-stimulated c-Met and MAPK activities are dependent on the cellular context and are not predictive of mitogenic signaling, and (3) in at least some HGF target cells, the activation of both MAPK and PI3K signaling pathways is insufficient for mitogenesis elicited through c-Met.

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

Similar content being viewed by others

References

  • Aaronson SA, Falco JP, Taylor WG, Cech AC, Marchese C, Finch PW, Rubin J, Weissman BE and Di Fiore PP. . 1989 Ann. N.Y. Acad. Sci. 567: 122–129.

  • Bladt F, Riethmacher D, Isenmann S, Aguzzi A and Birchmeier C. . 1995 Nature 376: 768–771.

  • Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM and Vogt PK. . 1997 Science 276: 1848–1850.

  • Cioce V, Csaky KG, Chan AM-L, Bottaro DP, Taylor WG, Jensen R, Aaronson SA and Rubin JS. . 1996 J. Biol. Chem. 271: 13110–13115.

  • Cowley S, Paterson H, Kemp P and Marshall CJ. . 1994 Cell 77: 841–852.

  • Falco JP, Taylor WG, Di Fiore PP, Weissman BE and Aaronson SA. . 1988 Oncogene 2: 573–578.

  • Fournier TM, Kamikura D, Teng K and Park M. . 1996 J. Biol. Chem. 271: 22211–22217.

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

  • Hunter T. . 1997 Cell 88: 333–346.

  • Huwiler A, Stabel S, Fabbro D and Pfeilschifter J. . 1995 Biochem. J. 305: 777–784.

  • Ishihara H, Sasaoka T, Ishiki M, Takata Y, Imamura T, Usui I, Langlois WJ, Sawa T and Kobayashi M. . 1997 J. Biol. Chem. 272: 9581–9586.

  • Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalez-Garcia A, Leonardo E, Wennström S, von Kobbe C, Toran JL, R-Borlado L, Calvo V, Sergio GC, Albar JP, Gaspar ML, Diez E, Marcos MAR, Downward J, Martinez-A C, Mérida I and Carrera AC. . 1998 EMBO J. 17: 743–753.

  • Kennedy SG, Wagner AJ, Conzen SD, Jordán J, Bellacosa A, Tsichlis PN and Hay N. . 1997 Genes & Dev. 11: 701–713.

  • Kubota Y, Angelotti T, Niederfellner G, Herbst R and Ullrich A. . 1998 Cell Growth Differ. 9: 247–256.

  • Mansour SJ, Matten WT, Hermann AS, Candia JM, Rong S, Fukasawa K, Vande Woude GF and Ahn NG. . 1994 Science 265: 966–970.

  • Montesano R, Soriano JV, Malinda KM, Ponce LM, Kleinman HK, Bafico A, Bottaro DP and Aaronson SA. . 1998 Cell Growth Diff. 9: 355–365.

  • Matsumoto K and Nakamura T. . 1997 Biochem. Biophys. Res. Comm. 239: 639–644.

  • Naka D, Ishii T, Shimomura T, Hishida T and Hara H. . 1993 Exp. Cell Res. 209: 317–324.

  • Nguyen L, Holgado-Madruga M, Maroun C, Fixman ED, Kamikura D, Fournier T, Charest A, Tremblay ML, Wong AJ and Park M. . 1997 J. Biol. Chem. 272: 20811–20819.

  • Okuda K, Sanghera JS, Pelech SL, Kanakura Y, Hallek M, Griffin JD and Druker BJ. . 1992 Blood 79: 2880–2887.

  • Pierce JP, Ruggiero M, Fleming TP, Di Fiore PP, Greenberger JS, Varticovski L, Schlessinger J, Rovera G and Aaronson SA. . (1988) Science 239: 628–631.

  • Ponzetto C, Bardelli A, Zhen A, Maina F, dalla Zonca P, Giodano S, Graziani A, Panayotou G and Comoglio PM. . 1994 Cell 77: 261–271.

  • Ponzetto C, Zhu Z, Audero E, Maina F, Bardelli A, Basile ML, Giodano S, Narsimhan R and Comoglio P. . 1996 J. Biol. Chem. 271: 14119–14123.

  • Rahimi N, Tremblay E and Elliott B. . 1996 J. Biol. Chem. 271: 24850–24855.

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

  • Rodrigues GA, Park M and Schlessinger J. . 1997 EMBO J. 16: 2634–2645.

  • Royal I, Fournier TM and Park M. . 1997 J. Cell. Phys. 173: 196–201.

  • Royal I and Park M. . (1995). J. Biol. Chem 270: 27780–27787.

  • Rubin JS, Bottaro DP and Aaronson SA. . 1993 Biochim. Biophys. Acta 1155: 357–371.

  • Sakata H, Stahl SJ, Taylor WG, Rosenberg JM, Sakaguchi K, Wingfield PT and Rubin JS. . 1997 J. Biol. Chem. 272: 9457–9463.

  • Schmidt C, Bladt F, Goedecke S, Brinkmann B, Zschiesche W, Sharpe M, Gherardi E and Birchmeier C. . 1995 Nature 373: 699–702.

  • Schwall RH, Chang LY, Kahn DW, Hillan KJ, Bauer KD and Zioncheck TF. . 1996 J. Cell Biol. 133: 709–718.

  • Scrimgeor GaG, Blakesley VA, Stannard BS and LeRoith D. . 1997 Endocrinology 138: 2552–2558.

  • Shoelson SE, White MF and Kahn CR. . (1988) J. Biol. Chem. 263: 4852–4860.

  • Stahl SJ, Wingfield PT, Kaufman JD, Pannell LK, Cioce V, Sakata H, Taylor WG, Rubin JS and Bottaro DP. . 1997 Biochem. J. 326: 763–772.

  • Taipale J and Keski-oja J. . 1997 FASEB J. 11: 51–59.

  • Uehara Y, Minowa O, Mori C, Shiota K, Kuno J, Noda T and Kitamura N. . 1995 Nature 373: 702–705.

  • Ueno H, Honda H, Nakamoto T, Yamagata T, Sasaki K, Miyagawa K, Mitani K, Yazaki Y and Hirai H. . 1997 Oncogene 14: 3067–3072.

  • Uren A, Yu J-C, Gholami NS, Pierce JH and Heidaran MA. . 1994 Biochem. Biophys. Res. Comm. 204: 628–634.

  • Varticovski L, Findik-Harrison D, Keeler ML and Susa M. . 1994 Biophys. Biochim. Acta 1226: 1–11.

  • Verlhac M-H, Kubiak JZ, Clarke HJ and Maro B. . 1994 Development 120: 1017–1025.

  • Wang L-M, Keegan AD, Paul WE, Heidaran MA, Gutkind JS and Pierce JH. . 1992 EMBO J. 11: 4899–4908.

  • Weidner KM, Di Cesare S, Sachs M, Brinkmann V, Behrens J and Birchmeier W. . 1996 Nature 384: 173–176.

  • Zhu H, Naujokas MA, Fixman ED, Torossian K and Park M. . 1994 J. Biol. Chem. 269: 29943–29948.

  • Zioncheck TF, Richardson L, Liu J, Chang L, King KL, Bennett GL, Fugedi P, Chamow SM, Schwall RH and Stack RJ. . 1995 J. Biol. Chem. 270: 16871–16878.

Download references

Acknowledgements

We thank Drs Jeff Rubin, William Taylor, Yuichiro Suzuki and Silvio Gutkind for helpful discussions, and Nelson Ellmore for technical assistance.

Author information

Authors and Affiliations

  1. Division of Basic Sciences, Laboratory of Cellular and Molecular Biology, National Cancer Institute, Building 37, Room 1E24, 37 Convent Drive MSC 4255, Bethesda, 20892-4255, Maryland, USA

    Regina M Day, Diane Breckenridge, Paola Castagnino & Donald P Bottaro

  2. Laboratory of Biochemical Genetics, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Vittoria Cioce

Authors
  1. Regina M Day
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vittoria Cioce
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diane Breckenridge
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paola Castagnino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donald P Bottaro
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Day, R., Cioce, V., Breckenridge, D. et al. Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis. Oncogene 18, 3399–3406 (1999). https://doi.org/10.1038/sj.onc.1202683

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1202683

Keywords

This article is cited by

Search

Advanced search

Quick links