マル　ヨシロウ   Maru Yoshiro   丸　義朗    所属   医学部 医学科    職種   教授・基幹分野長
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	ADAM12-cleaved ephrin-A1 contributes to lung metastasis.
掲載誌名	正式名：Oncogene 略　 称：Oncogene ISSNコード：(1476-5594)0950-9232(Linking)
巻・号・頁	33(17),pp.2179-90
著者・共著者	Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, Duffy S L, Coulthard M G, Boyd A, Maru Y
担当区分	最終著者,責任著者
発行年月	2014/04
概要	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.
DOI	10.1038/onc.2013.180
PMID	23686306