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ADAM12-cleaved ephrin-A1 contributes to lung metastasis

Oncogene volume 33, pages 2179–2190 (2014)Cite this article

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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.

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Acknowledgements

We thank Dr Yoichiro Iwakura at the University of Tokyo for providing EphA2-KO mice, Dr Ulla Wewer at the University of Copenhagen for providing human ADAM12 cDNA clones and Ms. Helen Jeays at the Queensland Institute of Medical Research for proofreading. This work was supported by grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, grant nos. 21117008 (to YM), 23590347 (to TT), 25122716 and 25870760 (to KI), and the Global COE program, Multidisciplinary Education and Research Center for Regenerative Medicine from Japan.

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Authors and Affiliations

  1. Department of Pharmacology, Tokyo Women’s Medical University, Tokyo, Japan

    K Ieguchi, T Tomita, T Omori, A Komatsu, A Deguchi, J Masuda & Y Maru

  2. Laboratoire de Morphogenèse et Signalisation Cellulaires, UMR 144, CNRS, Institut Curie, Paris, France

    S L Duffy

  3. Leukemia Foundation Research Laboratory, The Queensland Institute of Medical Research, Brisbane, Queensland, Australia

    M G Coulthard & A Boyd

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  1. K Ieguchi
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Correspondence to Y Maru.

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Ieguchi, K., Tomita, T., Omori, T. et al. ADAM12-cleaved ephrin-A1 contributes to lung metastasis. Oncogene 33, 2179–2190 (2014). https://doi.org/10.1038/onc.2013.180

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