title: EphB6 promotes anoikis by modulating EphA2 signaling.
abstract: Anoikis is a specific type of apoptosis induced by detachment of epithelial cells from extracellular matrix, and acquiring resistance to anoikis is an important step that enables cancer cells to metastasize. EphA2, which is overexpressed in a variety of human cancers, is phosphorylated by Akt on serine 897 and mediates ligand ephrin-independent promotion of anoikis resistance through the RhoG activator Ephexin4. EphB6 is frequently silenced in invasive and metastatic cancers; however, its role in cancer progression is poorly understood. Here we show that EphB6 interacts with EphA2 and suppresses EphA2-mediated promotion of anoikis resistance in MCF7 breast cancer cells. On the other hand, knockdown of EphB6 promotes anoikis resistance. We further show that expression of EphB6 decreases serine 897 phosphorylation of EphA2 and suppresses EphA2-Ephexin4 interaction and the RhoG activation. These findings implicate EphB6 as a negative regulator of EphA2 oncogenic signaling.
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Akada
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Harada
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Negishi
authors.affiliation: Laboratory of Molecular Neurobiology, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hirokato@pharm.kyoto-u.ac.jp.
authors.forename: Hironori
authors.initials: H
authors.lastname: Katoh
mesh_terms: D023102:Anoikis; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017434:Protein Structure, Tertiary; D036104:Receptor, EphA2 / Q000737:chemistry / Q000378:metabolism*; D036261:Receptor, EphB6 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C556035:ARHGEF16 protein, human; D020662:Guanine Nucleotide Exchange Factors; D008024:Ligands; D036261:Receptor, EphB6; C075397:RHOG protein, human; D010768:Phosphoserine; D036104:Receptor, EphA2; D020741:rho GTP-Binding Proteins
keywords: Anoikis; EphA2; EphB6; Ephexin4; Heterotypic interaction