Since NF1 and PTEN are well-established negative regulators of RAS and PI3K signaling [7, 22], respectively, we postulated that the nf1/pten-mutant melanomas would exhibit activation of effector pathways downstream of RAS and PI3K. Indeed, we detected high levels of phosphorylated ERK (pERK), phosphorylated AKT (pAKT), and phosphorylated S6 ribosomal protein (pS6, an mTOR downstream effector) by immunohistochemistry (IHC) in the nf1/pten-mutant melanomas (Fig. 1f), indicating hyperactivation of both RAS and PI3K pathways. The gene discussed is AKT1; the disease is melanoma.