Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is characterized by benign tumors (hamartomas and hamartias) involving multiple organ systems, due to inactivating mutations in TSC1 or TSC2. Here, we review recent advances in our understanding of the growth and signaling functions of the TSC1 and TSC2 proteins. Led by seminal studies in Drosophila, the TSC1/TSC2 complex has been positioned in an ancestrally conserved signaling pathway that regulates cell growth. TSC1/TSC2 receives inputs from at least three major signaling pathways in the form of kinase-mediated phosphorylation events that regulate its function as a GTPase activating protein (GAP): the PI3K-Akt pathway, the ERK1/2-RSK1 pathway and the LKB1-AMPK pathway. TSC1/TSC2 functions as a GAP towards Rheb, which is a major regulator of the mammalian target of rapamycin (mTOR). In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth. As a specific inhibitor of mTOR, rapamycin has therapeutic potential for the treatment of TSC hamartomas.