title: Attenuation of eph receptor kinase activation in cancer cells by coexpressed ephrin ligands.
abstract: The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting "in trans" with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral "cis" associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans.
authors.affiliation: Sanford-Burnham Medical Research Institute, San Diego, California, United States of America ; Department Pharmacology, University of Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Falivelli
authors.affiliation: Sanford-Burnham Medical Research Institute, San Diego, California, United States of America.
authors.forename: Erika Mathes
authors.initials: EM
authors.lastname: Lisabeth
authors.affiliation: Sanford-Burnham Medical Research Institute, San Diego, California, United States of America.
authors.forename: Elena
authors.initials: E
authors.lastname: Rubio de la Torre
authors.affiliation: Sanford-Burnham Medical Research Institute, San Diego, California, United States of America.
authors.forename: Gizeh
authors.initials: G
authors.lastname: Perez-Tenorio
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.affiliation: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Salvucci
authors.affiliation: Sanford-Burnham Medical Research Institute, San Diego, California, United States of America ; Department of Pathology, University of California San Diego, San Diego, California, United States of America.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Pasquale
mesh_terms: D045744:Cell Line, Tumor; D036342:Ephrins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D011485:Protein Binding; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism; D036121:Receptor, EphA3 / Q000235:genetics / Q000378:metabolism; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D036081:Receptors, Eph Family / Q000235:genetics / Q000378:metabolism*
chemical_list: D036342:Ephrins; D036104:Receptor, EphA2; D036121:Receptor, EphA3; D036224:Receptor, EphB4; D036081:Receptors, Eph Family