PTEN and neoplasm: Deregulated PI3K signaling (e.g., loss of the negative regulator PTEN) is one of the most commonly mutated tumor suppressors seen in cancer, particularly malignancies of the central nervous system and endometrium [30]; constitutive Raf signaling (e.g., Raf600E mutation) drives approximately 60% of melanoma [31]; elevated Ral expression is seen in colon, bladder and prostate cancers [32]; and RalGDS activation of Ral has been implicated in Ras-driven skin cancer [33].