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.

  • Letter
  • Published:

Memo mediates ErbB2-driven cell motility

Nature Cell Biology volume 6, pages 515–522 (2004)Cite this article

Abstract

Clinical studies have revealed that cancer patients whose tumours have increased ErbB2 expression tend to have more aggressive, metastatic disease, which is associated with parameters predicting a poor outcome1,2. The molecular basis underlying ErbB2-dependent cell motility and metastases formation, however, still remains poorly understood. In this study, we show that activation of a set of signalling molecules, including MAPK, phosphatidylinositol-3-OH kinase (PI(3)K) and Src, is required for Neu/ErbB2-dependent lamellipodia formation and for motility of breast carcinoma cells. Stimulation of these molecules, however, failed to induce efficient cell migration in the absence of Neu/ErbB2 phosphorylation at Tyr 1201 or Tyr 1227. We describe a novel molecule, Memo (mediator of ErbB2-driven cell motility), that interacts with a phospho-Tyr 1227-containing peptide, most probably through the Shc adaptor protein. After Neu/ErbB2 activation, Memo-defective cells form actin fibres and grow lamellipodia, but fail to extend microtubules towards the cell cortex. Our data suggest that Memo controls cell migration by relaying extracellular chemotactic signals to the microtubule cytoskeleton.

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: Tyr 1201 (YC) and Tyr 1227 (YD) are required for HRG-induced cell migration.
Figure 2: Activition of MAPK, PI(3)K and p38-MAPK is not sufficient for Neu/ErbB2-driven cell migration.
Figure 3: Memo interacts with ErbB2 Tyr 1227 through the Shc adaptor molecule.
Figure 4: Memo is required for ErbB2-driven cell motility, but not for lamellipodia formation.
Figure 5: Memo is required for ErbB2-dependent microtubule outgrowth.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Holbro, T. & Hynes, N.E. ErbB Receptors: directing key signaling networks throughout life. Annu. Rev. Pharmacol. Toxicol. 44, 195–217 (2004).

    Article  CAS  Google Scholar 

  2. Slamon, D.J. et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235, 177–182 (1987).

    Article  CAS  Google Scholar 

  3. Segatto, O., Lonardo, F., Pierce, J.H., Bottaro, D.P. & Di Fiore, P.P. The role of autophosphorylation in modulation of erbB-2 transforming function. New Biol. 2, 187–195 (1990).

    CAS  PubMed  Google Scholar 

  4. Hazan, R. et al. Identification of autophosphorylation sites of HER2/neu. Cell Growth Differ. 1, 3–7 (1990).

    CAS  PubMed  Google Scholar 

  5. Dankort, D.L., Wang, Z., Blackmore, V., Moran, M.F. & Muller, W.J. Distinct tyrosine autophosphorylation sites negatively and positively modulate neu-mediated transformation. Mol. Cell Biol. 17, 5410–5425 (1997).

    Article  CAS  Google Scholar 

  6. Segatto, O. et al. Shc products are substrates of erbB-2 kinase. Oncogene 8, 2105–2112 (1993).

    CAS  PubMed  Google Scholar 

  7. Hellyer, N.J., Kim, M.S. & Koland, J.G. Heregulin-dependent activation of phosphoinositide 3-kinase and Akt via the ErbB2/ErbB3 co-receptor. J. Biol. Chem. 276, 42153–42161 (2001).

    Article  CAS  Google Scholar 

  8. Yarden, Y. & Sliwkowski, M.X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).

    Article  CAS  Google Scholar 

  9. Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 103, 211–225 (2000).

    Article  CAS  Google Scholar 

  10. Klemke, R.L. et al. Regulation of cell motility by mitogen-activated protein kinase. J. Cell Biol. 137, 481–492 (1997).

    Article  CAS  Google Scholar 

  11. Zrihan-Licht, S. et al. RAFTK/Pyk2 tyrosine kinase mediates the association of p190 RhoGAP with RasGAP and is involved in breast cancer cell invasion. Oncogene 19, 1318–1328 (2000).

    Article  CAS  Google Scholar 

  12. Vadlamudi, R., Adam, L., Talukder, A., Mendelsohn, J. & Kumar, R. Serine phosphorylation of paxillin by heregulin-beta1: role of p38 mitogen activated protein kinase. Oncogene 18, 7253–7264 (1999).

    Article  CAS  Google Scholar 

  13. Keely, P.J., Westwick, J.K., Whitehead, I.P., Der, C.J. & Parise, L.V. Cdc42 and Rac1 induce integrin-mediated cell motility and invasiveness through PI(3)K. Nature 390, 632–636 (1997).

    Article  CAS  Google Scholar 

  14. Beerli, R.R., Wels, W. & Hynes, N.E. Intracellular expression of single chain antibodies reverts ErbB-2 transformation. J. Biol. Chem. 269, 23931–23936 (1994).

    CAS  PubMed  Google Scholar 

  15. Graus-Porta, D., Beerli, R.R. & Hynes, N.E. Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling. Mol. Cell. Biol. 15, 1182–1191 (1995).

    Article  CAS  Google Scholar 

  16. Spencer, K.S., Graus-Porta, D., Leng, J., Hynes, N.E. & Klemke, R.L. ErbB2 is necessary for induction of carcinoma cell invasion by ErbB family receptor tyrosine kinases. J. Cell Biol. 148, 385–397 (2000).

    Article  CAS  Google Scholar 

  17. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  CAS  Google Scholar 

  18. Dankort, D. et al. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol. Cell. Biol. 21, 1540–1551 (2001).

    Article  CAS  Google Scholar 

  19. Lai, C.H., Chou, C.Y., Ch'ang, L.Y., Liu, C.S. & Lin, W. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 10, 703–713 (2000).

    Article  CAS  Google Scholar 

  20. Traxler, P. et al. Tyrosine kinase inhibitors: from rational design to clinical trials. Med. Res. Rev. 21, 499–512 (2001).

    Article  CAS  Google Scholar 

  21. Waterman-Storer, C.M. & Salmon, E. Positive feedback interactions between microtubule and actin dynamics during cell motility. Curr. Opin. Cell Biol. 11, 61–67 (1999).

    Article  CAS  Google Scholar 

  22. Enomoto, T. Microtubule disruption induces the formation of actin stress fibers and focal adhesions in cultured cells: possible involvement of the rho signal cascade. Cell Struct. Funct. 21, 317–326 (1996).

    Article  CAS  Google Scholar 

  23. Krendel, M., Zenke, F.T. & Bokoch, G.M. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nature Cell Biol. 4, 294–301 (2002).

    Article  CAS  Google Scholar 

  24. Dankort, D., Jeyabalan, N., Jones, N., Dumont, D.J. & Muller, W.J. Multiple ErbB-2/Neu phosphorylation sites mediate transformation through distinct effector proteins. J. Biol. Chem. 276, 38921–38928 (2001).

    Article  CAS  Google Scholar 

  25. Ricci, A. et al. Analysis of protein–protein interactions involved in the activation of the Shc/Grb-2 pathway by the ErbB-2 kinase. Oncogene 11, 1519–1529 (1995).

    CAS  PubMed  Google Scholar 

  26. Howard, J. & Hyman, A.A. Dynamics and mechanics of the microtubule plus end. Nature 422, 753–758 (2003).

    Article  CAS  Google Scholar 

  27. Sander, E.E. et al. Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell–cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J. Cell Biol. 143 1385–1398 (1998).

    Article  CAS  Google Scholar 

  28. Cho, S.Y. & Klemke, R.L. Extracellular-regulated kinase activation and CAS/Crk coupling regulate cell migration and suppress apoptosis during invasion of the extracellular matrix. J. Cell Biol. 149, 223–236 (2000).

    Article  CAS  Google Scholar 

  29. Kisielow, M., Kleiner, S., Nagasawa, M., Faisal, A. & Nagamine, Y. Isoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA. Biochem. J. 363, 1–5 (2002).

    Article  CAS  Google Scholar 

  30. Cappellen, D. et al. Transcriptional program of mouse osteoclast differentiation governed by the macrophage colony-stimulating factor and the ligand for the receptor activator of NFκB. J. Biol. Chem. 277, 21971–21982 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank F. Maurer and S. Lienhard for technical assistance, D. Cappellen for help with quantitative PCR and discussions, S. Kleiner for help with siRNA experiments, A. Brahmbhatt and R. Klemke for help with lamellipodia purification, W. Krek, G. Thomas and R. Chiquet for critical reading of the manuscript. This work was supported by the Novartis Research Foundation and grants from the Swiss Cancer League to A.B. and R.M.

Author information

Authors and Affiliations

  1. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, CH-4058, Switzerland

    Romina Marone, Daniel Hess, Nancy E. Hynes & Ali Badache

  2. University of California San Francisco Comprehensive Cancer Center, San Francisco, 94143-0128, CA, USA

    David Dankort

  3. Molecular oncology group, McGill University Health Center, Montreal, H3A 1A1, Quebec, Canada

    William J. Muller

Authors
  1. Romina Marone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Dankort
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. William J. Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nancy E. Hynes
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ali Badache
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy E. Hynes.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

Fig. S1, Fig. S2, Fig. S3, Fig. S4 (PDF 1900 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Marone, R., Hess, D., Dankort, D. et al. Memo mediates ErbB2-driven cell motility. Nat Cell Biol 6, 515–522 (2004). https://doi.org/10.1038/ncb1134

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1134

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing