S6K1
Direct downstream effector of mTORC1 controlling protein synthesis, and the source of the pathway's main negative feedback: S6K1 phosphorylates and represses IRS-1, uncoupling the insulin receptor from PI3K (HAR2004, SHA2004). Its deletion extends lifespan in FEMALE mice (+19% median, not significant in males; SEL2009) and protects against diet-induced obesity.
mTORC1's best-known output kinase.
T389 phosphorylation by mTORC1 is rapamycin-sensitive, which is why S6K1 became the field's default assay – and why the field long over-read rapamycin as a complete mTORC1 inhibitor.
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| H | Human study | 1 |
| A | Animal model | 3 |
| M | Molecular — cells, biochemistry, structure | 5 |
Studies
| Year | Evidence | Study |
|---|---|---|
| 2025 | H | The Bi-steric, mTORC1-Selective Inhibitor, RMC-5552, in Advanced Solid Tumors: A Phase 1 Trial SCH2025 First-in-human, open-label dose-escalation trial (n=57, advanced solid tumors, no comparator arm) of a bi-steric mTORC1-selective inhibitor. Treatment-related hyperglycemia was low (4%) and not dose-limiting, alongside a 64% disease control rate. Because the trial was uncontrolled and made no head-to-head comparison against rapamycin or an ATP-site inhibitor, this is encouraging early clinical evidence consistent with the hypothesis that sparing mTORC2 reduces metabolic toxicity -- it does not establish mTORC2 sparing as the cause. |
| 2026 | A | Aging preserves mTORC1 but attenuates JNK-SMAD2L signaling sensitivity to passive stretch-induced tension development in isolated mouse skeletal muscle. KRISTIANSEN2026 Passive mechanical stretch activates mTORC1 signaling (mTOR, p70S6K, rpS6, 4E-BP1) equally in adult and old mouse skeletal muscle, but JNK-SMAD2L signaling sensitivity to the same stretch is blunted with age — suggesting age-related anabolic resistance in muscle arises alongside or downstream of mTORC1, not from a defect in mTORC1 mechanosensing itself. |
| 2009 | A | Ribosomal protein S6 kinase 1 signaling regulates mammalian life span SEL2009 Deleting S6K1 (a direct mTORC1 effector) extended lifespan in FEMALE mice (+19% median); the effect was not significant in males. It also protected against age-related bone, immune and motor decline. One of the clearest cases of the sex dimorphism catalogued in gap H6 - and a reminder that a single downstream branch, not mTORC1 as a whole, can carry much of the ageing signal. |
| 2004 | A | Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity UMX2004 S6K1 deletion protects mice from age- and diet-induced obesity and enhances insulin sensitivity. |
| 2006 | M | S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth DOR2006 S6K1 triggers betaTRCP-mediated degradation of the tumour suppressor PDCD4 to promote translation. |
| 2002 | M | mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery KIM2002 Discovery of Raptor as the defining partner of mTOR in mTORC1. This is the paper that gives mTORC1 its identity: Raptor is the scaffold that lets mTOR find and phosphorylate its targets (S6K1), and the complex is stabilized under starvation. Companion paper to Hara 2002. |
| 2002 | M | Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action HARA2002 Independent co-discovery of Raptor (same issue of Cell as Kim 2002). Showed Raptor is essential for mTOR to phosphorylate 4E-BP1 and S6K1, and that knocking it down in worms mimics loss of TOR - confirming Raptor as a core, conserved mediator of TOR action. |
| 1992 | M | Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase KUO1992 Rapamycin selectively inhibits IL-2-driven activation of p70 S6 kinase during T-cell proliferation. |
| 1992 | M | Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase PRI1992 Rapamycin induces dephosphorylation/inactivation of the 70 kDa S6 kinase, defining an early readout of TOR signalling. |