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Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor

Oncogene volume 20, pages 788–799 (2001)Cite this article

Abstract

Tight control of cell proliferation and morphogenesis is required to ensure normal tissue patterning and prevent cancer formation. Overexpression of the ErbB-2/Neu receptor tyrosine kinase is associated with increased progression in human breast cancer, yet in breast explant cultures, the ErbB-2/Neu receptor contributes to alveolar differentiation. To examine the consequence of deregulated ErbB-2/Neu activation on epithelial morphogenesis, we have expressed a constitutively activated mutant of ErbB-2/Neu in a Madin–Darby canine kidney (MDCK) epithelial cell model. Using two-dimensional cultures we demonstrate that activated ErbB-2/Neu induces breakdown of cell–cell junctions, increased cell motility and dispersal of epithelial colonies. This correlates with reorganization of the actin cytoskeleton and focal adhesions and loss of insoluble cell–cell junction complexes involving E-cadherin. Interestingly, a constitutively activated ErbB-2/Neu receptor promotes an invasive morphogenic program in MDCK cells in a three-dimensional matrix. We show that two tyrosines in the carboxy-terminal tail of ErbB-2/Neu, involved in the phosphorylation of the Shc adapter protein, are each sufficient to promote epithelial-mesenchymal like transition and enhanced cell motility in two-dimensional culture and cell invasion rather than a morphogenic response in matrix culture. This provides a model system to investigate ErbB-2/Neu induced signaling pathways required for epithelial cell dispersal and invasion versus morphogenesis.

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Abbreviations

EGF:

Epidermal Growth Factor

EMT:

Epithelial-Mesenchymal Transition

HGF:

Hepatocyte Growth Factor

MAPK:

Mitogen Activated Protein Kinase

MDCK:

Madin-Darby Canine Kidney epithelial cells

NT:

Constitutively activated ErbB-2/Neu mutant

NYPD:

Neu Tyrosine Phosphorylation-Deficient mutant

PI3K,:

Phosphatidylinositol-3′ Kinase

WTNeu:

Wild type ErbB-2/Neu receptor

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Acknowledgements

We are grateful to members of the Park lab for helpful discussions and to Mrs Minglun Wang for technical assistance. Thin layer sections were performed by Mrs Jo-Ann Bader from the Molecular Oncology Group, Royal Victoria Hospital. This research was supported by operating grants from the Canadian Breast Cancer Research Initiative (CBCRI) with funds from the Canadian Cancer Society to M Park and WJ Muller. M Park and WJ Muller are Scientists of the Medical Research Council of Canada (MRC). Financial support was provided by the Fonds de la Recherche en Santé du Québec (FRSQ) and the Royal Victoria Hospital Research Institute as studentships (to H Khoury), and scholarships from the NSERC and Cancer Research Society (to DL Dankort).

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Authors and Affiliations

  1. Department of Biochemistry, Molecular Oncology Group, McGill University Hospital Centre, Montreal, Quebec, H3A 1A1, Canada

    Hanane Khoury & Morag Park

  2. Department of Medicine, Molecular Oncology Group, McGill University Hospital Centre, Montreal, Quebec, H3A 1A1, Canada

    Svetlana Sadekova, Monica A Naujokas & Morag Park

  3. Department of Oncology, Molecular Oncology Group, McGill University Hospital Centre, Montreal, Quebec, H3A 1A1, Canada

    Morag Park

  4. Department of Biology, The Institute for Molecular Biology and Biotechnology, Medical Sciences McMaster University, Hamilton, Canada

    David L Dankort & William J Muller

  5. Department of Pathology and Molecular Medicine, The Institute for Molecular Biology and Biotechnology, Medical Sciences McMaster University, Hamilton, Canada

    William J Muller

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  1. Hanane Khoury
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  2. David L Dankort
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  4. Monica A Naujokas
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  5. William J Muller
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Khoury, H., Dankort, D., Sadekova, S. et al. Distinct tyrosine autophosphorylation sites mediate induction of epithelial mesenchymal like transition by an activated ErbB-2/Neu receptor. Oncogene 20, 788–799 (2001). https://doi.org/10.1038/sj.onc.1204166

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