Pathway link INS-PI3K
Insulin PI3K
Insulin activates PI3K.
Insulin lands on its own receptor on the cell surface. The message is passed inward by IRS proteins to PI3K, which builds a signalling lipid, and that is the beginning of the route to mTORC1. This is also the step that breaks when the pathway is overactive for too long.
The conditions it holds under
Insulin and IGF-1 share this receptor arm; growth hormone does not, and is kept separate for that reason. The amplitude and the time pattern of the insulin signal are not interchangeable: KUB2012 shows the AKT pathway multiplexes insulin's temporal pattern, so a single arrow understates what the cell reads. Cell and genetic work, plus human physiology for the insulin-resistance end of it.
- Time it takes
- minutes
- Step
- indirect (through steps not drawn here)
- Measured in
- human, mammalian cells, Drosophila
- Where in the cell
- plasma membrane
- 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). |
| 2003 | M | Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2GAR2003 Insulin activates Rheb-GTP, inhibited by TSC1/2, positioning Rheb as the direct upstream activator of TOR. |
| 2003 | M | Rheb promotes cell growth as a component of the insulin/TOR signalling networkSAU2003 Rheb promotes cell growth as a component of the insulin/TOR network in Drosophila. |
| 2007 | M | PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinaseSAN2007 Identified PRAS40 as the missing insulin-controlled brake INSIDE mTORC1. When insulin is absent PRAS40 clamps the complex shut; insulin makes Akt phosphorylate PRAS40, releasing the brake so Rheb can fully switch mTORC1 on. Explained how hormone signals set the exact strength of mTORC1 activity. |
| 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. |
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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