EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex.

Abstract	Eph receptors are implicated in regulating the malignant progression of cancer. Here we find that despite overexpression of EphB3 in human non-small-cell lung cancer, as reported previously, the expression of its cognate ligands, either ephrin-B1 or ephrin-B2, is significantly downregulated, leading to reduced tyrosine phosphorylation of EphB3. Forced activation of EphB3 kinase in EphB3-overexpressing non-small-cell lung cancer cells inhibits cell migratory capability in vitro as well as metastatic seeding in vivo. Furthermore, we identify a novel EphB3-binding protein, the receptor for activated C-kinase 1, which mediates the assembly of a ternary signal complex comprising protein phosphatase 2A, Akt and itself in response to EphB3 activation, leading to reduced Akt phosphorylation and subsequent inhibition of cell migration. Our study reveals a novel tumour-suppressive signalling pathway associated with kinase-activated EphB3 in non-small-cell lung cancer, and provides a potential therapeutic strategy by activating EphB3 signalling, thus inhibiting tumour metastasis.
Authors	Guo Li, Xiao-Dan Ji, Hong Gao, Jiang-Sha Zhao, Jun-Feng Xu, Zhi-Jian Sun, Yue-Zhen Deng, Shuo Shi, Yu-Xiong Feng, Yin-Qiu Zhu, Tao Wang, Jing-Jing Li, Dong Xie
Journal	Nature communications (Nat Commun) Vol. 3 Pg. 667 (Feb 07 2012) ISSN: 2041-1723 [Electronic] England
PMID	22314363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Ligands Neoplasm Proteins Neuropeptides RACK1 protein, human RACK1 protein, mouse Receptors for Activated C Kinase Receptors, Cell Surface Tyrosine Receptor, EphB3 Proto-Oncogene Proteins c-akt GTP-Binding Proteins
Topics	Animals Carcinoma, Non-Small-Cell Lung (metabolism, pathology) Cell Movement GTP-Binding Proteins (metabolism) Gene Expression Regulation, Neoplastic HEK293 Cells Humans Ligands Lung Neoplasms (metabolism, pathology) Mice Mice, Nude Models, Biological Mutation Neoplasm Metastasis Neoplasm Proteins (metabolism) Neoplasm Transplantation Neuropeptides (metabolism) Phosphorylation Photons Proto-Oncogene Proteins c-akt (metabolism) Receptor, EphB3 (metabolism) Receptors for Activated C Kinase Receptors, Cell Surface (metabolism) Signal Transduction Tyrosine (chemistry)

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