The most common mechanisms underlying the hyperresponsiveness of cancer cells to mitogenic signaling include increased expression of growth factor receptors (GFR) and their ligands (e.g., epidermal GFR (EGFR) in nonsmall cell lung cancers) and constitutively active GFR signaling pathways (e.g., mutated b-Raf driving MAP kinase cascades in melanoma or mutated PI3 kinase stimulating Akt kinase in various tumors) (Figure 1). Here, RAPGEF5 is linked to melanoma.