Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, Duffy S L, Coulthard M G, Boyd A, Maru Y
Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
Laboratoire de Morphogenèse et Signalisation Cellulaires, UMR 144, CNRS, Institut Curie, Paris, France.
Oncogene. 2014 Apr 24;33(17):2179-90. doi: 10.1038/onc.2013.180. Epub 2013 May 20.
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.
Eph受体酪氨酸激酶及其ephrin配体与神经元发育和新血管形成有关。ephrin-A1的过表达与肿瘤进展和不良预后有关。然而，其机制尚不清楚。在此，我们报道了Eph/ephrin系统在细胞黏附机制中的作用。质膜上聚集的促红细胞生成素产生肝细胞受体A1（EphA1）/ephrin-A1复合物未发生内吞作用，细胞彼此保持黏附。即使在没有E-钙黏蛋白的情况下，细胞间接触也以Eph酪氨酸激酶活性非依赖的方式维持。EphA1和ephrin-A1在肺内皮细胞中共定位，并调节肺血管通透性和转移。我们通过酵母双杂交筛选鉴定出ADAM12（一种去整合素和金属蛋白酶12）作为EphA1结合伴侣，并发现ADAM12在原发性肿瘤中响应转化生长因子-β1增强ephrin-A1的裂解。血清中释放的可溶性ephrin-A1以内分泌方式破坏肺中EphA1/ephrin-A1介导的细胞黏附，导致肺通透性增加，促进肿瘤细胞进入肺。用其中和抗体消耗可溶性ephrin-A1可显著抑制肺转移。
