Pathway link S6K1-IRS1
S6K1 IRS-1 / IRS-2
S6K1 inhibits IRS-1 / IRS-2.
This is one of the pathway's main self-limiting "off switches": strong, sustained S6K1 activity shuts down IRS-1, cutting the insulin signal off. That is how too much food can blunt the insulin signal. It also runs the other way: block mTOR and IRS-1 survives, so Akt can paradoxically become MORE active – which is why the insulin resistance seen on these drugs is blamed, on evidence from mice, on a different mechanism (loss of mTORC2), not on this loop.
The conditions it holds under
Established in cells and mouse genetics. The size of this arm's contribution to rapalog dysglycaemia in humans, relative to mTORC2 loss, has not been apportioned.
- Time it takes
- hours
- Step
- direct (one molecule acts on the other)
- Measured in
- mammalian cells
- Where in the cell
- cytosol
- Reaches people?
- plausible in people, not shown directly
- How settled
- settled in the literature
Studies behind it
| Year | Evidence | Study |
|---|---|---|
| 2004 | M | The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteinsHAR2004 One of two 2004 papers that placed mTORC1's main negative feedback loop downstream of TSC-Rheb-S6K1 (rapamycin-sensitive IRS-1 degradation had been reported earlier, Haruta 2000). When mTORC1/S6K1 activity is left switched on, S6K1 phosphorylates IRS-1 and represses its expression, so the insulin receptor can no longer signal to PI3K. This is the textbook explanation for why blocking mTORC1 paradoxically raises Akt activity, and it contributes to insulin resistance when mTORC1 is chronically overactive (for example with TSC loss or nutrient excess). The insulin resistance seen with chronic rapamycin is instead attributed mainly to mTORC2 disruption (LAM2012). |
| 2004 | M | Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficienciesSHA2004 The companion paper to Harrington 2004, published two months later. In cultured mammalian cells, constitutive Rheb/mTOR/S6K activity depletes IRS1 and IRS2, producing cellular insulin resistance and impaired survival signalling. Together the two papers establish the S6K1 -> IRS negative feedback arm. |
| 2004 | A | Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivityUMX2004 S6K1 deletion protects mice from age- and diet-induced obesity and enhances insulin sensitivity. |
| 2006 | M | mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates AktORE2006 mTORC1 inhibition relieves feedback and activates upstream RTK-PI3K-Akt signalling. The Akt activation was demonstrated both in cancer cell lines and in patient tumours treated with RAD001 (everolimus), so this record carries a human pharmacodynamic component, not only in-vitro data. |
Points the other way
No study in the Atlas contradicts this link. That means none in this curated set, not none in the literature.
Who has checked this
- Checked by
- No researcher outside the project has checked this link yet.
- Curator sign-off
- Not signed off yet. This link was drafted with AI help and has not been reviewed link by link; treat it as a proposal until it is.
- Curated by
- Oliver Barton, with AI help for drafting; see how links are checked.
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