RHEB gene

The RHEB gene (RHEB stands for: Ras Homolog, MTORC1 Binding) is a protein coding gene located on chromosome 7q36.1. Three pseudogenes have been mapped, two on chromosome 10 and one on chromosome 22. An important paralog of this gene is RHEBL1.

The RHEB gene belongs to the superfamily of small GTPases (G-proteins or GTPases are a heterogeneous group of intracellular proteins capable of binding the guanine-based nucleotides GDP and GTP) and encodes a lipid-anchored cell membrane protein with five repeats of the RAS-related GTP-binding region. The RHEB protein is critical for the regulation of growth and cell cycle progression due to its role in the insulin/TOR/S6K signaling pathway. The protein has GTPase activity and shuttles between a GDP-bound form and a GTP-bound form, and farnesylation of the protein is required for this activity.

Clinical: Diseases associated with RHEB include:

• Tuberous sclerosis
• and
• hemimegalencephaly.

The RHEB protein functions as a small GTPase and acts as an activator of the mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic responses and macromolecule biosynthesis to promote cellular biomass formation and growth (Inoki K et al. 2002; Long X et al. 2005; Yao Y et al. 2020). In response to nutrients, growth factors or amino acids, it specifically activates the protein kinase activity of MTOR, the catalytic component of the mTORC1 complex: it causes a conformational change that allows the alignment of residues in the active site of MTOR, thereby enhancing the phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) (Yang H et al. 2017). RHEB is also required for the localization of the TSC-TBC complex to lysosomal membranes. In response to starvation, RHEB is inactivated by the TSC-TBC complex, preventing the activation of mTORC1 (Yang H et al. 2017).

TSC2 and RHEB: 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.

1. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signaling. Nat Cell Biol. 2002 Sep;4(9):648-57.
2. Long X et al. (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15:702-713.
3. Yang H et al. (2017) Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature 552:368-373.
4. Yao Y et al. (2020) Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity. Mol Cell 80:437-451.e6.