Overexpression of endothelin (ET)-1 and endothelin receptors (ETRs) are associated with human cancer malignancy. In cancer cells, ET-1 activates various signaling pathways, including mitogen-activated protein kinase pathway, phosphatidylinositol 3-kinase pathway, and protein kinase C pathway, through ETRs, although the mechanisms by which ET-1 activates these signaling pathways remain unclear. We previously reported that ETRs interacted with annexin A2, which is overexpressed in various cancers, and annexin A2 silencing suppressed ERK activation upon ET-1 stimulation in human umbilical vein cell line, EA.hy926 cells. Here we examined roles of annexin A2 in ET-1 signaling pathway of melanoma cells. In melanoma cells, ET-1 stimulation activated ATK, and phosphorylated serin residues of annexin A2. Annexin A2 silencing suppressed activation of AKT upon ET-1 stimulation. In addition, we found that serine residues mutant of annexin A2 suppressed activation of AKT. Our results suggested that phosphorylation of annexin A2 plays important roles in AKT activation of melanoma cells upon ET-1 stimulation.