Ephexin4-mediated promotion of cell migration and anoikis resistance is regulated by serine 897 phosphorylation of EphA2

EphA2 is activated through phosphorylation on serine 897 (S897) by Akt to promote cancer cell motility and invasion, independently of stimulation by ephrin, its ligand. Here we show that S897 phosphorylation of EphA2 strengthens the interaction between EphA2 and Ephexin4, a guanine nucleotide exchange factor for the small GTPase RhoG. S897A mutation of EphA2 abolished the EphA2/Ephexin4-mediated RhoG activation, promotion of cell migration, and resistance to anoikis. Our results suggest that S897-phosphorylated EphA2 recruits Ephexin4 to promote cell migration and anoikis resistance, providing a molecular link between S897 phosphorylation of EphA2 and tumor progression. ▸ S897 phosphorylation of EphA2 strengthens the interaction between EphA2 and Ephexin4. ▸ S897A mutation of EphA2 suppresses EphA2-mediated RhoG activation. ▸ S897A mutation blocks EphA2/Ephexin4-mediated cell migration and anoikis resistance.