Hamartin-tuberin complex: Central regulator of cell-signalling

After growth-factor stimulation, the hamartin-tuberin complex is phosphorylated and its GTPase-activating protein activity is decreased, whereas in response to stimuli such as hypoxia or low energy it is phosphorylated and its GTPase-activating protein activity increased. The complex deactivates RHEB by causing GTP to be cleaved from it. Activated RHEB stimulates mTOR, which has a crucial role in the translation of proteins such as c-Myc or ornithine decarboxylase, and participates in cell-cycle control. mTOR binds to raptor and GβL to exert its effect, which is mediated by S6K1 and 4E-BP1, proteins that participate in ribosome biogenesis and translation initiation, respectively. Nutrients might boost translation through PI3KIII, which phosphorylates mTOR. TSC1 and TSC2 interact also with other proteins, such as ERα, calmodulin, p27, SMAD2, 14-3-3 proteins, and PAM.