IRS-1 / IRS-2
Insulin receptor substrate proteins - the adaptors that carry the signal from the insulin/IGF-1 receptor to PI3K. S6K1 phosphorylates and represses them, which is one of the pathway's major negative feedback loops: sustained mTORC1 activity deafens the cell to insulin, and blocking mTOR restores insulin signalling and raises Akt activity.
The adaptor that connects the insulin receptor to PI3K. The adaptor proteins that carry the signal from the insulin/IGF-1 receptor onward to PI3K. mTORC1's partner S6K1 tags them for shutdown, which is one of the pathway's main feedback brakes: too much mTORC1 activity 'deafens' the cell to insulin, and blocking mTOR restores that sensitivity and raises Akt activity.
Serine phosphorylation by S6K1 (and others) triggers IRS-1 degradation – the molecular basis of the best-characterised mTORC1 feedback loop. Note the direction: the loop degrades IRS-1 when mTORC1 is ACTIVE, so it is a mechanism of insulin resistance under nutrient excess. Inhibiting mTORC1 releases it and raises Akt signalling instead.
TL;DR. IRS-1 / IRS-2 appears in 5 curated studies in Oliver's mTOR Atlas: 1 in animal models; 4 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| IRS-1 / IRS-2 activates PI3K mechanism: recruitment · this link in full · on the map table | IRS proteins carry the signal from the insulin receptor to PI3K; without them, the receptor is still there but the wire connecting it is cut. Holds under: Cell studies (TSC1/TSC2-null mouse cells and human cells) plus a review. An adaptor relationship shown in cultured cells; differences between IRS-1 and IRS-2 by tissue are not resolved by these sources. plausible in people, not shown directly · settled in the literature | M | HAR2004, CAN2002 |
| S6K1 inhibits IRS-1 / IRS-2 mechanism: degradation · this link in full · on the map table | 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. 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. plausible in people, not shown directly · settled in the literature | A | HAR2004, SHA2004, UMX2004, ORE2006 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 1 |
| M | Molecular — cells, biochemistry, structure | 4 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 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. |
| 2026 | M | Inferring feedback regulation from static snapshots of a single signal GIN2026 Introduces AoF (Assay of Feedback), a perturbation-free single-cell imaging method that reconstructs how a signal CHANGES OVER TIME from fixed-cell snapshots, using DNA content and Geminin to order cells along the cell cycle. Applied to Akt phosphorylation, it uncovers a negative feedback loop that is active only in a narrow window at the G1/S transition; biochemistry points to mTORC1/S6K1-dependent inhibitory phosphorylation of IRS1 as the likely source, though the authors state this edge is not uniquely established. Directly relevant to the question of whether mTOR pathway activity is better described as a time-varying pattern than a fixed level. |
| 2006 | M | mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt ORE2006 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. |
| 2004 | M | The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins HAR2004 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 deficiencies SHA2004 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. |
Related entities
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