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.

Genomics of Squamous Cell Lung Cancer

“…Overexpression of EPHB3 has been reported in NSCLC and is associated with the promotion of a metastatic phenotype in these tumors. The ability of EPHB3 to drive metastasis is believed to be independent of its kinase activity [64,65]. EPHB3 was amplified in 37% of SQCC samples evaluated by the TCGA [8,41].…”

The Rac1 hypervariable region in targeting and signaling

“…Moreover, several studies have confirmed a role for PP2A in the control of cell migration. 123,124 Finally, proteomic analyses have identified SET in complex with a host of cellular proteins including the Rac/Cdc42 GEF βPIX and the Rac/Cdc42 effector PAK1, 125 actin and dynamin-2 119 and a β1-integrin-filamin complex. 126 A recent study by Switzer et al 127 showed that a SET-binding peptide (COG112) does not only block the Rac1-SET interaction, but also reduces EGF-induced Rac1 activation and serum-induced cell migration and invasion.…”

Forced downregulation of RACK1 inhibits glioma development by suppressing Src/Akt signaling activity

“…As a result, its dysregulation may contribute to tumorigenesis. In fact, RACK1 has been demonstrated to be involved in various types of malignant tumors including hepatocellular carcinoma, lung cancer, colon cancer, prostate cancer, cervical carcinoma, oral squamous cell carcinoma and neuroblastoma (13)(14)(15)(16)(17)(18)(19). However, whether RACK1 plays a role in malignant glioma as well as the mechanism involved remains largely unknown.…”