Fig. 2

Simplified Upstream and Downstream Signaling Pathways in TSC. Growth factors (not shown) bind to transmembrane receptors and lead to PI-3 Kinase activity causing an increase in PIP3 production leading to activation of AKT. AKT and/or ERK can then directly inhibit tuberin by phosphorylation. However, phosphorylation of tuberin by AMPK at other amino acid residues is activating. Hamartin binding seems to be required for stabilization and function of tuberin. Tuberin contains a C terminal GAP (GTPase activating protein) domain that inhibits the G protein Rheb, an important activator of mTORC1. Intermediary steps are not completely understood but may involve binding of FKBP38 [70] and/or enzymatic activity of PLD1 [71]. Loss of hamartin or tuberin function by mutation or inhibitory phosphorylation then allows constitutive activity of mTORC1 with subsequent increases of levels of phosphorylated ribosomal S6-kinase and phosphorylated ribosomal S6. How these alterations lead to the specific pathological changes in TSC is not well understood. Rapamycin (Rapa) and similar drugs potently inhibit mTOR activity within mTORC1. ATP indicates sites of phosphorylation by kinases. Figure modified from [72]