Interestingly, a few years after the discovery of Epac, a study performed in HEK293 and neuroblastoma cells demonstrated that Epac activated the PLCε specifically through the Rap2 GTPase, resulting in the generation of inositol-1,4,5-trisphosphate (IP3) and the subsequent release of Ca2+ from intracellular stores [122]. This evidence concerns the gene RAPGEF4 and neuroblastoma.