Tuberin

Tuberin forms the catalytic component of the TSC-TBC complex and is encoded by the TSC2 gene. TSC1 and TSC2 encode hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target-of-rapamycin pathway, which controls cell growth and proliferation (Curatolo P et al. 2008). The hamartin-tuberin complex is a multiprotein complex that acts as a negative regulator of the mTORC1 complex. This is an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis. This promotes cellular biomass formation and growth (Inoki K et al. 2002; Yang H et al. 2021). It has been shown that a 2:2:1 stoichiometry of TSC1, TSC2 and TBC1D7 is present in the human TSC complex. The two GAP domains of TSC2 are symmetrically embedded in the core module, which consists of the dimerization domain of TSC2 and the central coiled coil of TSC1 (Yang H et al. 2021).

Within the TSC-TBC complex, TSC2 functions as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. It inhibits the RHEB-mediated activation of mTORC1.

In the absence of nutrients, the TSC-TBC complex inhibits mTORC1 and thereby prevents the phosphorylation of ribosomal protein S6 kinase and EIF4EBP1 (4E-BP1) by mTORC1 signaling. The TSC-TBC complex is inactivated in response to nutrients, thereby removing inhibition of mTORC1 (Menon S et al. 2014).

Tuberin is involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling. Also stimulates the intrinsic GTPase activity of Ras-related proteins RAP1A (RAP1A = Ras-Related Protein-1A/ RAP1A counteracts the mitogenic function of Ras because it can interact with Ras GAPs and RAF in a competitive manner) and RAB5.

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