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A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis

Oncogene volume 24, pages 7859–7868 (2005)Cite this article

Abstract

Receptor tyrosine kinases of the Eph family are upregulated in several different types of cancer. One family member in particular, the EphA2 receptor, has been linked to breast, prostate, lung and colon cancer, as well as melanoma. However, mechanisms by which EphA2 contributes to tumor progression are far from clear. In certain tumor cell lines, EphA2 receptor is underphosphorylated, raising the question of whether ligand-induced receptor phosphorylation and its kinase activity play a role in oncogenesis. To test directly the role of EphA2 receptor phosphorylation/kinase activity in tumor progression, we generated EphA2 receptor variants that were either lacking the cytoplasmic domain or carrying a point mutation that inhibits its kinase activity. Expression of these EphA2 mutants in breast cancer cells resulted in decreased tumor volume and increased tumor apoptosis in primary tumors. In addition, the numbers of lung metastases were significantly reduced in both experimental and spontaneous metastasis models. Reduced tumor volume and metastasis are not due to defects in tumor angiogenesis, as there is no significant difference in tumor vessel density between wild-type tumors and tumors expressing EphA2-signaling-defective mutants. In contrast, tumor cells expressing the EphA2 mutants are defective in RhoA GTPase activation and cell migration. Taken together, these results suggest that receptor phosphorylation and kinase activity of the EphA2 receptor, at least in part, contribute to tumor malignancy.

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Acknowledgements

We thank Donna Hicks and Yoonha Hwang for expert administrative and technical help, and Rut Porta for early technical assistance. This work was supported by National Institutes of Health Grants CA95004, CA114301, and Department of Defense grant DAMD17-02-1-0604 to J Chen; an NCI breast cancer training Grant 2T32 CA78136 and an DOD predoctoral fellowship BC043255 to WB Fang; Department of Defense postdoctoral fellowship DAMD17-03-1-0379 to D Brantley-Sieders; and an NIH postdoctoral fellowship 5F32 HL074517 to M Parker.

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Author notes

  1. Alastair D Reith

    Present address: GlaxoSmithKline Medicines Research Center, Stevenage, Herts, UK

  2. Wei Bin Fang and Dana M Brantley-Sieders: Both these authors contributed equally

Authors and Affiliations

  1. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Wei Bin Fang & Jin Chen

  2. Department of Medicine, Division of Rhematology and Immunology, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Dana M Brantley-Sieders, Monica A Parker & Jin Chen

  3. Ludwig Institute for Cancer Research, University College London Branch, London, UK

    Alastair D Reith

  4. Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Jin Chen

  5. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, 37232, TN, USA

    Jin Chen

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Correspondence to Jin Chen.

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Fang, W., Brantley-Sieders, D., Parker, M. et al. A kinase-dependent role for EphA2 receptor in promoting tumor growth and metastasis. Oncogene 24, 7859–7868 (2005). https://doi.org/10.1038/sj.onc.1208937

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