Master regulator of cellular growth, autophagy, and protein synthesis. mTORC1 (raptor-containing) responds to amino acids (especially leucine via Sestrin/GATOR), energy status (AMPK), and growth factors (IGF-1/insulin → PI3K → AKT → TSC1/2 → Rheb → mTORC1) — outputs include S6K1 (translation) and 4E-BP1 (cap-dependent translation initiation). mTORC2 (rictor-containing) phosphorylates AKT itself, closing a positive loop. RAPAMYCIN (and analogs sirolimus / everolimus / temsirolimus) form a complex with FKBP12 that selectively inhibits mTORC1 — the basis for their use in transplant immunosuppression + oncology (RCC, NET, TSC-associated SEGA).
Organ Systems
endocrine
immune-hematologic
musculoskeletal
Pathway Steps
igf-1 → pi3k-activation — via IGF-1R → PI3K (also activated by insulin / insulin-R). Growth-factor receptors (IGF-1R, insulin-R, RTKs) recruit class I PI3K via IRS adaptors — the input node where growth and nutrient signals converge. PI3K is among the most frequently amplified/mutated oncogenic nodes, and PTEN (which reverses its product downstream) is a major tumor suppressor, making this axis central in cancer.
pi3k-activation → akt-activation — via PI3K → PIP3 → PDK1 → AKT phosphorylation. PI3K generates PIP3, recruiting AKT and PDK1 to the membrane via their PH domains; PDK1 phosphorylates AKT at Thr308. Full activation additionally needs Ser473 from mTORC2 — so mTOR sits both upstream of AKT (as mTORC2) and downstream (as mTORC1), a feedback-rich topology.
akt-activation → mtorc1-activation — via AKT → TSC1/2 inhibition → Rheb-GTP → mTORC1 activation. AKT activates mTORC1 indirectly: it phosphorylates and inhibits the TSC1/2 complex (a GAP for Rheb), so relieved inhibition lets Rheb-GTP switch on mTORC1 at the lysosome. mTORC1 also demands amino-acid sufficiency signaled through the Rag GTPases — integrating growth factors with nutrient availability before committing to growth.
mtorc1-activation → protein-synthesis — via S6K1 + 4E-BP1 phosphorylation → cap-dependent translation. Active mTORC1 phosphorylates S6K1 and 4E-BP1 to drive cap-dependent translation and ribosome biogenesis while suppressing autophagy (via ULK1). Rapamycin, complexed with FKBP12, acutely inhibits the S6K1 arm; chronic dosing also disrupts mTORC2 (the glucose-intolerance side effect), and this growth-vs-autophagy switch underlies mTOR’s role in aging.