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).
Tuberin
DefinitionThis section has been translated automatically.
General informationThis section has been translated automatically.
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.
LiteratureThis section has been translated automatically.
- Cao J et al. (2017) Tuberous sclerosis complex inactivation disrupts melanogenesis via mTORC1 activation. J Clin Invest 127:349-364.
Curatolo P et al (2008) Tuberous sclerosis. Lancet 372:657-668.
Jimbow K (1997) Tuberous sclerosis and guttate leukodermas. Semin Cutan Med Surg 16:30-35.
- Lai Y et al. (2024) A Novel TSC2 c.2489T>C Missense Variant Associated With Tuberous Sclerosis Complex: Case Report. Neurol Genet 10:e200127.
- Møller LB et al. (2017) Development of hypomelanotic macules is associated with constitutive activated mTORC1 in tuberous sclerosis complex. Mol Genet Metab 120:384-391.
- Woodford MR et al. (2017) Tumor suppressor Tsc1 is a new Hsp90 co-chaperone that facilitates folding of kinase and non-kinase clients. EMBO J 36:3650-3665.