Inhibition of TSC complex formation by AKT (PKB)

Inhibition of TSC complex formation by AKT (PKB) 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).