TSC1-TSC2 complex

Abstract: The mammalian target of rapamycin (mTOR) is a protein kinase that forms two functionally distinct complexes important for nutrient and growth factor signaling. Both complexes phosphorylate a hydrophobic motif on downstream protein kinases, which contributes to the activation of these kinases. mTOR complex 1 (mTORC1) phosphorylates S6K1, while mTORC2 phosphorylates Akt. The TSC1-TSC2 complex is a critical negative regulator of mTORC1. However, how mTORC2 is regulated and whether the TSC1-TSC2 complex is involved are unknown. We find that mTORC2 isolated from a variety of cells lacking a functional TSC1-TSC2 complex is impaired in its kinase activity toward Akt. Importantly, the defect in mTORC2 activity in these cells can be separated from effects on mTORC1 signaling and known feedback mechanisms affecting insulin receptor substrate-1 and phosphatidylinositol 3-kinase. Our data also suggest that the TSC1-TSC2 complex positively regulates mTORC2 in a manner independent of its GTPase-activating protein activity toward Rheb. Finally, we find that the TSC1-TSC2 complex can physically associate with mTORC2 but not mTORC1. These data demonstrate that the TSC1-TSC2 complex inhibits mTORC1 and activates mTORC2, which through different mechanisms promotes Akt activation.

Abstract: Publisher Summary The complexity and breadth of the signaling network upstream of the TSC1 (hamartin)–TSC2 (tuberin) complex is a testament to the importance of proper regulation of mTORC1 in the tight control over cellular growth and proliferation. The TSC1–TSC2 complex negatively regulates TORC1 through its guanosine triphosphatase (GTPase)-activating protein (GAP) activity toward the small G-protein Ras homolog enriched in brain (Rheb), an essential activator of TORC1. In contrast, TORC2 in mammalian cells is positively regulated by the TSC1–TSC2 complex through both Rheb and TORC1-dependent and independent mechanisms. The regulatory relationship between the TSC1–TSC2 complex and TORC1 appears to be conserved in most eukaryotes, including species of yeast. Multisite phosphorylation of both TSC1 and TSC2 promotes or inhibits the ability of the complex to inhibit Rheb downstream of a wide variety of kinases and signaling pathways. Several of these pathways include important oncogene products and tumor suppressors that can promote inhibition of the TSC1–TSC2 complex and contribute to the aberrantly elevated levels of mTORC1 signaling detected in the majority of human cancers. Inactivating mutations in the TSC1 and TSC2 genes give rise to a multifaceted tumor syndrome known as “tuberous sclerosis complex.”