Endothelin receptors (ETRs) is one of G protein coupled receptors, and consist of ET type A receptor (ET_AR) and ET type B receptor (ET_BR). The overexpression of endothelin (ET)-1 or ETRs is related to malignancy of human cancer, although ET-1 was originally identified as an endothelium-derived vasocontractile peptide. In cancer cells, ET-1 activates various signaling pathways, including mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase C through ETRs, although the mechanisms by which ET-1 activates these signaling pathways remain uncertain. Previously, we found that ETRs interacted with annexin A2, which is overexpressed in various cancers, and annexin A2 silencing suppressed activation of ERK upon ET-1 stimulation in human umbilical vein cell line, EA.hy926 cells. Here we examine roles of annexin A2 in ET-1 signaling pathway of melanoma cells. ET-1 stimulation induces ATK activation in melanoma cells. On the other hand, annexin A2 silencing suppressed activation of AKT upon ET-1 stimulation. These results suggested that interaction of ETRs and annexin A2 play important roles in ET-1 signaling pathway of melanoma cells.