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:

A reciprocal tensin-3–cten switch mediates EGF-driven mammary cell migration

Nature Cell Biology volume 9, pages 961–969 (2007)Cite this article

Abstract

Cell migration driven by the epidermal growth factor receptor (EGFR) propels morphogenesis1 and involves reorganization of the actin cytoskeleton2. Although de novo transcription precedes migration3,4, transcript identity remains largely unknown. Through their actin-binding domains, tensins link the cytoskeleton to integrin-based adhesion sites5. Here we report that EGF downregulates tensin-3 expression, and concomitantly upregulates cten, a tensin family member that lacks the actin-binding domain6. Knockdown of cten or tensin-3, respectively, impairs or enhances mammary cell migration. Furthermore, cten displaces tensin-3 from the cytoplasmic tail of integrin β1, thereby instigating actin fibre disassembly. In invasive breast cancer, cten expression correlates not only with high EGFR and HER2, but also with metastasis to lymph nodes. Moreover, treatment of inflammatory breast cancer patients with an EGFR/HER2 dual-specificity kinase inhibitor significantly downregulated cten expression. In conclusion, a transcriptional tensin-3–cten switch may contribute to the metastasis of mammary cancer.

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: EGF-induced downregulation of tensin-3, along with upregulation and reorganization of cten.
Figure 2: Mammary cell migration is inhibited following knockdown of cten and increased following tensin-3 knockdown.
Figure 3: Cten expression disrupts actin stress fibre organization, induces cell migration and displaces tensin-3 from focal adhesions.
Figure 4: Cten displaces tensin-3 from the tail of integrin β1.
Figure 5: Cten expression in mammary tumours associates with EGFR activation, and undergoes downregulation in patients treated with an EGFR-specific kinase inhibitor.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Wells, A., Kassis, J., Solava, J., Turner, T. & Lauffenburger, D. A. Growth factor-induced cell motility in tumor invasion. Acta Oncol. 41, 124–130 (2002).

    Article  CAS  Google Scholar 

  2. Ridley, A. J. et al. Cell migration: integrating signals from front to back. Science 302, 1704–1709 (2003).

    Article  CAS  Google Scholar 

  3. Bauer, J. et al. In vitro model of angiogenesis using a human endothelium-derived permanent cell line: contributions of induced gene expression, G-proteins, and integrins. J. Cell Physiol. 153, 437–449 (1992).

    Article  CAS  Google Scholar 

  4. Gordon, S. R. & Staley, C. A. Role of the cytoskeleton during injury-induced cell migration in corneal endothelium. Cell Motil. Cytoskeleton 16, 47–57 (1990).

    Article  CAS  Google Scholar 

  5. Lo, S. H. Tensin. Int. J. Biochem. Cell Biol. 36, 31–34 (2004).

    Article  CAS  Google Scholar 

  6. Lo, S. H. & Lo, T. B. Cten, a COOH-terminal tensin-like protein with prostate restricted expression, is down-regulated in prostate cancer. Cancer Res. 62, 4217–4221 (2002).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Ridley, A. J. & Hall, A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70, 389–399 (1992).

    Article  CAS  Google Scholar 

  9. Malliri, A. et al. The transcription factor AP-1 is required for EGF-induced activation of rho-like GTPases, cytoskeletal rearrangements, motility, and in vitro invasion of A431 cells. J. Cell Biol. 143, 1087–1099 (1998).

    Article  CAS  Google Scholar 

  10. Manos, E. J. et al. Dolichol-phosphate-mannose-3 (DPM3)/prostin-1 is a novel phospholipase C-gamma regulated gene negatively associated with prostate tumor invasion. Oncogene 20, 2781–2790 (2001).

    Article  CAS  Google Scholar 

  11. Amit, I. et al. A module of negative feedback regulators defines growth factor signaling. Nature Genet. 39, 503–512 (2007).

    Article  CAS  Google Scholar 

  12. Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell Biol. 5, 816–826 (2004).

    Article  CAS  Google Scholar 

  13. Irie, H. Y. et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J. Cell Biol. 171, 1023–1034 (2005).

    Article  CAS  Google Scholar 

  14. Geiger, B., Bershadsky, A., Pankov, R. & Yamada, K. M. Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nature Rev. Mol. Cell Biol. 2, 793–805 (2001).

    Article  CAS  Google Scholar 

  15. Rodrigue, C. M. et al. The cancer chemopreventive agent resveratrol induces tensin, a cell-matrix adhesion protein with signaling and antitumor activities. Oncogene 24, 3274–3284 (2005).

    Article  CAS  Google Scholar 

  16. Kook, S. et al. Caspase-dependent cleavage of tensin induces disruption of actin cytoskeleton during apoptosis. Biochem. Biophys. Res. Commun. 303, 37–45 (2003).

    Article  CAS  Google Scholar 

  17. Garcia-Alvarez, B. et al. Structural determinants of Integrin recognition by Talin. Mol. Cell 11, 49–58 (2003).

    Article  CAS  Google Scholar 

  18. Wu, M. & Merajver, S. D. Molecular biology of inflammatory breast cancer: applications to diagnosis, prognosis, and therapy. Breast Dis. 22, 25–34 (2005).

    Article  CAS  Google Scholar 

  19. Allred, D. C. et al. HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. J. Clin. Oncol. 10, 599–605 (1992).

    Article  CAS  Google Scholar 

  20. Xia, W. et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21, 6255–6263 (2002).

    Article  CAS  Google Scholar 

  21. Spector, N. L. et al. Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J. Clin. Oncol. 23, 2502–2512 (2005).

    Article  CAS  Google Scholar 

  22. Thiery, J. P. Epithelial–mesenchymal transitions in tumour progression. Nature Rev. Cancer 2, 442–454 (2002).

    Article  CAS  Google Scholar 

  23. Zamir, E. et al. Dynamics and segregation of cell–matrix adhesions in cultured fibroblasts. Nature Cell Biol. 2, 191–196 (2000).

    Article  CAS  Google Scholar 

  24. Albiges-Rizo, C., Frachet, P. & Block, M. R. Downregulation of talin alters cell adhesion and the processing of the α5β1 integrin. J. Cell Sci. 108, 3317–3329 (1995).

    CAS  PubMed  Google Scholar 

  25. Hazan, R. B., Qiao, R., Keren, R., Badano, I. & Suyama, K. Cadherin switch in tumor progression. Ann. NY Acad. Sci. 1014, 155–163 (2004).

    Article  CAS  Google Scholar 

  26. Friedl, P. & Wolf, K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nature Rev. Cancer 3, 362–374 (2003).

    Article  CAS  Google Scholar 

  27. Sasaki, H., Yukiue, H., Kobayashi, Y., Fukai, I. & Fujii, Y. Cten mRNA expression is correlated with tumor progression in thymoma. Tumour Biol. 24, 271–274 (2003).

    Article  CAS  Google Scholar 

  28. Sasaki, H. et al. Cten mRNA expression was correlated with tumor progression in lung cancers. Lung Cancer 40, 151–155 (2003).

    Article  Google Scholar 

  29. Cui, Y., Liao, Y. C. & Lo, S. H. Epidermal growth factor modulates tyrosine phosphorylation of a novel tensin family member, tensin3. Mol. Cancer Res. 2, 225–232 (2004).

    CAS  PubMed  Google Scholar 

  30. Calderwood, D. A. et al. Integrinβ cytoplasmic domain interactions with phosphotyrosine-binding domains: a structural prototype for diversity in integrin signaling. Proc. Natl Acad. Sci. USA 100, 2272–2277 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Kenneth Yamada, Shin Lin and Mark Ginsberg for plasmids; Dalia Seger and Hadassa Degani for guidance with xenografts; Miriam Eisenstein for structure prediction; and Benjamin Geiger and Alexander Bershadsky for critical comments. Our laboratory is supported by research grants from the Israel Cancer Research Fund, the German Israel Foundation, the Prostate Cancer Foundation, the European Commission and the National Cancer Institute (grants CA72981 and CA102537). Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair. T.S. was supported in part by the Ridgefield Foundation, the Israel Science Fund and the European Commission (EC FP6). S.C. is the recipient of a grant from Fundação para Ciência e Tecnologia (FCT), Lisboa, Portugal.

Author information

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Menachem Katz, Ido Amit, Ami Citri, Sara Lavi, Nir Ben-Chetrit, Gabi Tarcic, Moshit Lindzen, Roi Avraham & Yosef Yarden

  2. Department of Physics of Complex Systems, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Tal Shay

  3. IPATIMUP – Institute of Molecular Pathology and Immunology of the University of Porto, Porto, 4200-465, Portugal

    Silvia Carvalho, Fernanda Milanezi & Fernando Schmitt

  4. Targeted Molecular Diagnostics, Westmont, 60559, Illinois, USA

    Ljuba Lyass, Patricia Trusk & Sarah S. Bacus

  5. Department of Pediatric Hemato-Oncology and Functional Genomics, The Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel

    Ninette Amariglio, Jasmine Jacob-Hirsch & Gideon Rechavi

  6. Department of Orthopaedic Surgery, Center for Tissue Regeneration and Repair, University of California-Davis, Sacramento, 95817, California, USA

    Yi-Chun Liao & Su Hao Lo

  7. Boston University, Boston, 02215, Massachusetts, USA

    Asya Lyass

  8. Department of Exploratory Medical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, 27709

    Neil L. Spector

  9. Medical Faculty of Porto University, Porto, 4200-465, Portugal

    Fernando Schmitt

Authors
  1. Menachem Katz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ido Amit
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ami Citri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tal Shay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Silvia Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sara Lavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fernanda Milanezi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ljuba Lyass
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ninette Amariglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jasmine Jacob-Hirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nir Ben-Chetrit
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gabi Tarcic
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Moshit Lindzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Roi Avraham
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yi-Chun Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Patricia Trusk
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Asya Lyass
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Gideon Rechavi
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Neil L. Spector
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Su Hao Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Fernando Schmitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Sarah S. Bacus
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Yosef Yarden
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yosef Yarden.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figure S1, S2, S3, S4 and Table S1 (PDF 1308 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Katz, M., Amit, I., Citri, A. et al. A reciprocal tensin-3–cten switch mediates EGF-driven mammary cell migration. Nat Cell Biol 9, 961–969 (2007). https://doi.org/10.1038/ncb1622

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1622

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