Pathway link RAPA-MTORC2
Rapamycin mTORC2
Rapamycin inhibits mTORC2.
Rapamycin doesn't touch mTORC2 right away, but over days it stops new mTORC2 from being built.
The conditions it holds under
Strictly time- and cell-type-dependent: absent acutely, present after prolonged exposure, and the sensitivity varies between cell lines. LAM2012 shows the same loss of mTORC2 signalling in mouse liver in vivo, so this is not a cell-culture-only phenomenon. Treating this edge as unconditional is a common error.
- Time it takes
- long exposure (days to weeks)
- Step
- indirect (through steps not drawn here)
- 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 |
|---|---|---|
| 2006 | M | Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKBSAR2006 The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but prolonged treatment can also inhibit the assembly of NEW mTORC2 in susceptible cell types, reducing mTORC2 abundance and cutting Akt signaling over time. The wording matters: this is prevention of new assembly, not the dismantling of complexes already built, and the response depends on cell context and length of exposure. This is the mechanistic root of the insulin-resistance side effect later shown in mice (see Lamming 2012) - crucial for anyone dosing rapamycin for longevity. |
| 2012 | A | Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevityLAM2012 Chronic rapamycin (about 2 mg/kg a day, close to the lifespan-extending dose) made mice glucose intolerant and insulin resistant. A clamp test placed the problem in the liver, which kept making glucose, while muscle and fat took up glucose normally. Removing mTORC1 from the liver did not cause this. Rapamycin did break up mTORC2 (it separated mTOR from Rictor) in liver, fat and muscle, and deleting Rictor in the liver alone reproduced the glucose problem. In the genetic part, female mice with one working copy each of mTOR and mLST8 had about 50% less mTORC1 signalling in the liver, normal mTORC2 signalling and normal glucose tolerance, and lived 14.4% longer on average (p = 0.046). Males did not. Boundary: mouse drug and genetics work, not people, and the lifespan gain is female-only. It supports separating the two effects, but the paper does not test a drug that blocks mTORC1 without touching mTORC2. |
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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