Interestingly, despite A2B receptor mediates Epac/PI3K/Akt signaling pathway in cardiac fibroblast, stimulation of A3 receptors also activates PI3K-dependent Akt phosphorylation, leading to the reduction of ERK1/2 phosphorylation, which in turn suppresses cell proliferation in human melanoma cells (A375 cells) (Merighi et al., 2005). Here, RAPGEF4 is linked to melanoma.