ADAM12-cleaved ephrin-A1 contributes to lung metastasis

K. Ieguchi, T. Tomita, T. Omori, A. Komatsu, A. Deguchi, J. Masuda, S. L. Duffy, M. G. Coulthard, A. Boyd, Y. Maru

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31 Citations (Scopus)

Abstract

Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-β1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis.

Original languageEnglish
Pages (from-to)2179-2190
Number of pages12
JournalOncogene
Volume33
Issue number17
DOIs
Publication statusPublished - Apr 24 2014
Externally publishedYes

Keywords

  • Eph
  • cell adhesion
  • permeability
  • tyrosine kinase

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Ieguchi, K., Tomita, T., Omori, T., Komatsu, A., Deguchi, A., Masuda, J., Duffy, S. L., Coulthard, M. G., Boyd, A., & Maru, Y. (2014). ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene, 33(17), 2179-2190. https://doi.org/10.1038/onc.2013.180