EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex.
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.
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of Chinese Academy of Sciences, Shanghai 200031, China.
Guo
G
Li
Xiao-Dan
XD
Ji
Hong
H
Gao
Jiang-Sha
JS
Zhao
Jun-Feng
JF
Xu
Zhi-Jian
ZJ
Sun
Yue-Zhen
YZ
Deng
Shuo
S
Shi
Yu-Xiong
YX
Feng
Yin-Qiu
YQ
Zhu
Tao
T
Wang
Jing-Jing
JJ
Li
Dong
D
Xie
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009154:Mutation; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D017785:Photons; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D036223:Receptor, EphB3 / Q000378:metabolism*; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000737:chemistry
D008024:Ligands; D009363:Neoplasm Proteins; D009479:Neuropeptides; C419368:RACK1 protein, human; C090294:RACK1 protein, mouse; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D014443:Tyrosine; D036223:Receptor, EphB3; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins