TSC1/TSC2 (Tuberous Sclerosis Complex 1/2)

Classification

Category: Upstream regulator (GTPase-activating complex)

Aliases: Hamartin (TSC1), Tuberin (TSC2), TSC complex

Relationship to mTOR complexes: Upstream of mTORC1 (acts on Rheb) — see mTORC1 vs mTORC2 for the full complex-level map.

Summary

TSC1/TSC2 form a heterodimeric GTPase-activating protein (GAP) complex that converts Rheb-GTP to its inactive Rheb-GDP form, thereby suppressing mTORC1. TSC1/TSC2 is the integration point where growth-factor signaling (via AKT) and energy-status signaling (via AMPK) converge to control mTORC1.

• AKT (downstream of insulin/IGF-1-PI3K signaling) phosphorylates and INHIBITS TSC2, relieving the brake on Rheb/mTORC1
• AMPK (low-energy state) phosphorylates and ACTIVATES TSC2, reinforcing the brake on Rheb/mTORC1
• Hypoxia, via REDD1, also promotes TSC1/2 activity

• Converts Rheb-GTP (active) to Rheb-GDP (inactive), removing Rheb's activation of mTORC1

• TSC1/TSC2 is the node where growth-factor signals (AKT, activating mTORC1 by inhibiting TSC2) and energy-stress signals (AMPK, inhibiting mTORC1 by activating TSC2) are integrated before reaching Rheb.
• Loss-of-function mutations in TSC1/TSC2 cause tuberous sclerosis complex, a genetic disease with hyperactive mTORC1 signaling -- a clinical (not longevity-supplement) context distinct from this site's intervention pages.

Source tier

Tier 2 · Biological synthesis (author-cluster reviews, not primary trial data) Reference synthesis attributed in the brief to the Saxton & Sabatini; Laplante & Sabatini; and Liu & Sabatini mTOR review literature (author-cluster attribution, tier 2, brief §4). Exact article-level PMID/DOI not supplied in the sourcing brief and is not fabricated here.