title: Antibodies binding the ADAM10 substrate recognition domain inhibit Eph function.
abstract: The ADAM10 transmembrane metalloprotease cleaves a variety of cell surface proteins that are important in disease, including ligands for receptor tyrosine kinases of the erbB and Eph families. ADAM10-mediated cleavage of ephrins, the ligands for Eph receptors, is suggested to control Eph/ephrin-mediated cell-cell adhesion and segregation, important during normal developmental processes, and implicated in tumour neo-angiogenesis and metastasis. We previously identified a substrate-binding pocket in the ADAM10 C domain that binds the EphA/ephrin-A complex thereby regulating ephrin cleavage. We have now generated monoclonal antibodies specifically recognising this region of ADAM10, which inhibit ephrin cleavage and Eph/ephrin-mediated cell function, including ephrin-induced Eph receptor internalisation, phosphorylation and Eph-mediated cell segregation. Our studies confirm the important role of ADAM10 in cell-cell interactions mediated by both A- and B-type Eph receptors, and suggest antibodies against the ADAM10 substrate-recognition pocket as promising therapeutic agents, acting by inhibiting cleavage of ephrins and potentially other ADAM10 substrates.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia.
authors.forename: Lakmali
authors.initials: L
authors.lastname: Atapattu
authors.forename: Nayanendu
authors.initials: N
authors.lastname: Saha
authors.forename: Carmen
authors.initials: C
authors.lastname: Llerena
authors.forename: Mary E
authors.initials: ME
authors.lastname: Vail
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.forename: Dimitar B
authors.initials: DB
authors.lastname: Nikolov
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
authors.forename: Peter W
authors.initials: PW
authors.lastname: Janes
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001666:Binding Sites, Antibody; D002417:Cattle; D002448:Cell Adhesion; D036342:Ephrins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D011485:Protein Binding; D036081:Receptors, Eph Family / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000911:Antibodies, Monoclonal; D036342:Ephrins; D036081:Receptors, Eph Family; D051722:ADAM Proteins