TSC2 gene

The TSC2 gene (TSC2 stands for: TSC Complex Subunit 2) is a protein-coding gene located on chromosome 16p13.3.

This gene is a tumor suppressor gene that codes for the growth-inhibiting protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex, which plays a role in controlling cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling, which is an important regulator of anabolic cell growth.

Mutations in this gene have been associated with

• Tuberous sclerosis
• lymphangioleiomyomatosis
• and focal cortical dysplasia, type II

have been associated.

Related pathways include translation, insulin regulation of translation and MTOR signaling. Gene Ontology (GO) annotations for this gene include protein homodimerization activity and binding. An important paralog of this gene is RALGAPA1.

The encoded portrin forms the catalytic component of the TSC-TBC complex. This is a multiprotein complex that acts as a negative regulator of the mTORC1 complex, 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).

Within the TSC-TBC complex, TSC2 acts 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.

Mutations in TSC genes lead to tuberous sclerosis. 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).

In the absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing 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 the inhibition of mTORC1 (Menon S et al. 2014).

The encoded protein 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 and RAB5.

1. Inoki K et al. (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol. 2002 Sep;4(9):648-57
2. Menon S et al. (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771-785
3. Yang H et al. (2021) Structural insights into TSC complex assembly and GAP activity on Rheb. Nat Commun 12:339.