EphB6 promotes anoikis by modulating EphA2 signaling

Cell Signal. 2014 Dec;26(12):2879-84. doi: 10.1016/j.cellsig.2014.08.031. Epub 2014 Sep 17.


Anoikis is a specific type of apoptosis induced by detachment of epithelial cells from extracellular matrix, and acquiring resistance to anoikis is an important step that enables cancer cells to metastasize. EphA2, which is overexpressed in a variety of human cancers, is phosphorylated by Akt on serine 897 and mediates ligand ephrin-independent promotion of anoikis resistance through the RhoG activator Ephexin4. EphB6 is frequently silenced in invasive and metastatic cancers; however, its role in cancer progression is poorly understood. Here we show that EphB6 interacts with EphA2 and suppresses EphA2-mediated promotion of anoikis resistance in MCF7 breast cancer cells. On the other hand, knockdown of EphB6 promotes anoikis resistance. We further show that expression of EphB6 decreases serine 897 phosphorylation of EphA2 and suppresses EphA2-Ephexin4 interaction and the RhoG activation. These findings implicate EphB6 as a negative regulator of EphA2 oncogenic signaling.

Keywords: Anoikis; EphA2; EphB6; Ephexin4; Heterotypic interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anoikis*
  • Gene Knockdown Techniques
  • Guanine Nucleotide Exchange Factors / metabolism
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Ligands
  • MCF-7 Cells
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Structure, Tertiary
  • Receptor, EphA2 / chemistry
  • Receptor, EphA2 / metabolism*
  • Receptor, EphB6 / chemistry
  • Receptor, EphB6 / metabolism*
  • Signal Transduction*
  • rho GTP-Binding Proteins / metabolism


  • ARHGEF16 protein, human
  • Guanine Nucleotide Exchange Factors
  • Ligands
  • Receptor, EphB6
  • RHOG protein, human
  • Phosphoserine
  • Receptor, EphA2
  • rho GTP-Binding Proteins