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 the pathway's principal negative feedback loop: 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.
Serine phosphorylation by S6K1 (and others) triggers IRS-1 degradation — the molecular basis of the best-characterised mTORC1 feedback loop and of rapalog-associated insulin resistance.
| Tier | What it means | Studies |
|---|---|---|
| C | Animal in vivo | 1 |
| D | Mechanistic / in vitro / review | 2 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or mechanistic work.
| Study | Year | Tier | Finding |
|---|---|---|---|
| UMX2004 | 2004 | C | S6K1 deletion protects mice from age- and diet-induced obesity and enhances insulin sensitivity. |
| HAR2004 | 2004 | D | One half of the discovery of mTORC1's main negative feedback loop. When mTORC1/S6K1 activity is left switched on, S6K1 phosphorylates IRS-1 and represses its expression, so the insulin receptor can no |
| SHA2004 | 2004 | D | 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 i |