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

Nat Commun. 2012 Feb 7;3:667. doi: 10.1038/ncomms1675.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Movement
  • GTP-Binding Proteins / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • HEK293 Cells
  • Humans
  • Ligands
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / 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

Substances

  • 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