Reactome | Inhibition of TSC complex formation by AKT (PKB)

Inhibition of TSC complex formation by AKT (PKB)

Stable Identifier

R-HSA-165181

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Inhibition of TSC complex formation by AKT (PKB)

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Tuberous sclerosis complex (TSC) is a multi-system genetic disorder caused by loss of function mutations in one of the two tumor suppressors, TSC1 and TSC2, that form the protein complex known as the TSC complex, TSC1-TSC2, TSC1:TSC2 or hamartin-tuberin complex (reviewed in Huang and Manning 2008; Huang and Manning 2009). The TSC complex regulates mTORC1 activity by acting as a GTPase activating protein (GAP) for the small GTPase RHEB (reviewed in Huang and Manning 2008). The TSC complex converts GTP-bound RHEB, which activates mTORC1, to an inactive GDP-bound form, thus inhibiting mTORC1 activation (reviewed in Huang and Manning 2008). Phosphorylation of TSC2 on multiple sites by AKT (PKB) relieves the inhibitory effect of the TSC complex on RHEB (Inoki et al. 2002, reviewed in Huang and Manning 2009). AKT-mediated phosphorylation affects TSC2 function in at least two ways: first, phosphorylation decreases the activity of TSC2; second, phosphorylation destabilizes the TSC2 protein (Inoki et al. 2002). This destabilization is achieved by disrupting complex formation between TSC1 and TSC2 and inducing ubiquitination of the free TSC2 (Inoki et al. 2002). Phosphorylation of complexed TSC2 by AKT may result in the dissociation of the TSC1:TSC2 complex (Proud 2002). On the other hand, the TSC complex attenuates a regulatory negative feedback loop in which mTORC1-activated S6K1 (RPS6KB1) inhibits insulin-mediated activation of PI3K/AKT signaling and can promote tumorigenesis in some cancer types (reviewed in Hartung et al. 2025).

Literature References

PubMed ID	Title	Journal	Year
18466115	The TSC1-TSC2 complex: a molecular switchboard controlling cell growth Huang, J, Manning, BD	Biochem J	2008
19143635	A complex interplay between Akt, TSC2 and the two mTOR complexes Huang, J, Manning, BD	Biochem Soc Trans	2009
12423332	Regulation of mammalian translation factors by nutrients Proud, CG	Eur. J. Biochem.	2002
39488444	The dual role of the TSC complex in cancer Hartung, J, Müller, C, Calkhoven, CF	Trends Mol Med	2025
12172553	TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling Inoki, K, Li, Y, Zhu, T, Wu, J, Guan, KL	Nat Cell Biol	2002
15314020	Upstream and downstream of mTOR Hay, N, Sonenberg, N	Genes Dev	2004