Although EphA2 interacts with and cooperates with ErbB2 (also named HER2) to activate Ras-MAPK signaling and promote tumorigenesis in HER2-positive breast cancers [45], in HER2-negative breast cancer cells and tumors, the increased EphA2 on the cell surface resulting from RNF5 depletion could be triggered by ligands through cell-cell contact to decrease EphA2-S897 phosphorylation while increasing EphA2-Y772 phosphorylation (Fig. 3C). Here, RNF5 is linked to breast cancer.