title: ADAM12-cleaved ephrin-A1 contributes to lung metastasis.
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.
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ieguchi
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Tomita
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Omori
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Komatsu
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Deguchi
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Masuda
authors.affiliation: Laboratoire de Morphogenèse et Signalisation Cellulaires, UMR 144, CNRS, Institut Curie, Paris, France.
authors.forename: S L
authors.initials: SL
authors.lastname: Duffy
authors.affiliation: Leukemia Foundation Research Laboratory, The Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: M G
authors.initials: MG
authors.lastname: Coulthard
authors.affiliation: Leukemia Foundation Research Laboratory, The Queensland Institute of Medical Research, Brisbane, Queensland, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Department of Pharmacology, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Maru
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072199:ADAM12 Protein; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000201:enzymology* / Q000556:secondary; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D036382:Ephrin-A1 / Q000378:metabolism*; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000556:secondary; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D059748:Proteolysis; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D036382:Ephrin-A1; D053773:Transforming Growth Factor beta1; D036104:Receptor, EphA2; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C096115:Adam12 protein, mouse