Figure 1.

Overview of mTOR-TSC regulation and upstream and downstream mediators. Mutations in either TSC1 or TSC2 genes lead to hyperactivation of the downstream mTOR pathway by suppression of Rheb-mediated mTORC1 inhibition. The TSC1-TSC2 protein complex integrates cues such as nutrients, growth factors, hormones, and mitogens to regulate the activity of mTOR. mTOR complexes 1 and 2 are mediators of important cellular functions. Some of the downstream targets of mTORC1 were already clearly identified, including S6K1 and 4E-BP1 proteins, which play a major role in the regulation of cell growth, proliferation, and metabolism. TSC1 and TSC2 proteins have additional roles besides the modulation of mTOR, since inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin. Sirolimus and everolimus are effective inhibitors of mTORC1 via FKBP12.