RAPGEF3 has been implicated in cancer progression through various downstream signals [57], e.g. RAPGEF3 promotes cancer cell proliferation and/or suppresses apoptosis via Rap1/Akt/CREB signaling [58], Rap1/B-Raf/ERK and mTOR signaling [59] or acting synergistically with PDE4 to promote the Cyclin E1-Cnx43 axis [60]. This evidence concerns the gene CREB1 and cancer.