Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, resulting in ANXA2 activation and increased ANXA2 nuclear distribution in GC cells, which may drive GC invasion and metastasis. This evidence concerns the gene EPHA2 and gastric cancer.