Abstract 3434: EphB3 mediates kinase-dependent suppression of non-small cell lung cancer metastasis

Abstract

Abstract Eph family is one of the largest subfamily of receptor tyrosine kinases. Their important but controversial roles in cancer development have drawn growing attentions in recent years. We have recently reported that EphB3 acts as a tumor promoter in human non-small-cell lung cancer (NSCLC) independent of its kinase activity (Cancer Research. 71(3):1156, 2011). In the present study, we find that despite overexpression of EphB3 in NSCLC, the expression of its cognate ligands, ephrin-B1 and ephrin-B2, is significantly down-regulated, leading to reduced tyrosine phosphorylation of EphB3. Activation of EphB3 kinase with either ligand stimulation or genomic engineering (Y608/614E) in EphB3-overexpressing NSCLC cells inhibits cell migratory capability in vitro as well as in vivo metastatic seeding. Furthermore, we have identified a novel EphB3-binding protein, the receptor for activated C-kinase 1 (RACK1), which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A (PP2A), Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. Our study reveals a novel tumor-suppressing signaling pathway associated with kinase-activated EphB3 in NSCLC, and provides a potential therapeutic strategy by activating EphB3 signaling, thus inhibiting tumor metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3434. doi:1538-7445.AM2012-3434