Pathway link MTORC2-AKT
mTORC2 Akt/PKB
mTORC2 activates Akt/PKB.
mTORC2 adds the final activating tag to Akt – the same step that long-term use of the drug rapamycin eventually disrupts. In mice, that disruption is a major reason long-term rapamycin raises blood sugar.
The conditions it holds under
Mammalian cell studies, cancer cells and one mouse and rat liver study (ARI2015). Ser473 phosphorylation is shown in cells. The glucose consequence of losing it comes from mouse work (LAM2012) and has not been measured in people.
S473 contribution to Akt output is substrate-dependent: some Akt substrates are strongly mTORC2-dependent, others barely.
- Time it takes
- seconds
- Step
- direct (one molecule acts on the other)
- Measured in
- mammalian cells
- 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 |
|---|---|---|
| 2006 | M | SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificityJAC2006 SIN1 maintains rictor-mTOR integrity and confers mTORC2 Akt-Ser473 kinase activity and substrate specificity. |
| 2006 | M | mSin1 is necessary for Akt/PKB phosphorylation, and its isoforms define three distinct mTORC2sFRI2006 mSin1 is required for mTORC2 assembly and Akt Ser473 phosphorylation; isoforms define distinct complexes. |
| 2006 | M | Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activityYAN2006 Identified Sin1 as an essential TORC2 component required for Akt phosphorylation. |
| 2015 | M | PtdIns(3,4,5)P3-Dependent Activation of the mTORC2 Kinase ComplexLIU2015 PIP3 relieves SIN1 PH-domain autoinhibition to activate the mTORC2 kinase complex. |
| 2011 | M | mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signalingROD2011 mTOR kinase inhibition triggers feedback-dependent biphasic AKT reactivation, informing resistance. |
| 2015 | M | Lysosomal mTORC2/PHLPP1/Akt regulate chaperone-mediated autophagyARI2015 Extends the mTOR-autophagy relationship to a third form of autophagy that the Atlas otherwise does not cover, and reverses two of its usual terms. Here it is mTORC2, not mTORC1, that sits on the lysosomal membrane, and it inhibits chaperone-mediated autophagy through Akt, while the phosphatase PHLPP1 counteracts it; the balance controls assembly and disassembly of the translocation complex that pulls single proteins into the lysosome. Boundary: mechanism in cells and rodent liver; the claim that restoring this axis helps in ageing or disease is proposed, not tested here. |
| 2011 | M | Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphateGAN2011 PIP3 directly stimulates mTORC2 kinase activity, linking PI3K to mTORC2. |
| 2008 | M | The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase CFAC2008 Cells lacking the mTORC2 components mTOR, SIN1 or rictor lost phosphorylation of Akt and of conventional protein kinase C at the turn motif, a site near the end of the kinase domain. This phosphorylation did not depend on growth factors, and the authors reported the same function in yeast. Turn-motif phosphorylation helped newly made Akt and PKC fold correctly and stay stable; without it, Akt was held by the chaperone Hsp90 and protected from ubiquitin-mediated breakdown. mTORC2 controlled the Akt turn-motif and hydrophobic-motif (Ser473) sites independently in vivo and phosphorylated both directly in vitro. Boundary: Cell culture, yeast and in vitro kinase assays, with mouse tissue for the in vivo site analysis. Shows a protein-maturation role of mTORC2, not an organismal phenotype. Drafted from the abstract only. |
| 2012 | A | Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1cHAG2012 The authors deleted rictor, an essential mTORC2 component, only in mouse liver. In fed knockout mice the liver lost Akt Ser473 phosphorylation and had lower glucokinase and SREBP1c activity, so it kept making glucose (gluconeogenesis) while glycolysis and fat synthesis fell, as if it could not sense that the animal had eaten. The mice became hyperglycaemic and hyperinsulinaemic with low blood lipids. In mTORC2-deficient hepatocytes, constitutively active Akt2 restored both glucose flux and lipogenesis, while extra glucokinase restored glucose flux but not lipogenesis, placing Akt as the main route from hepatic mTORC2 to these outputs. Boundary: Mouse liver with lifelong genetic loss of mTORC2, plus cultured mouse hepatocytes. Not a drug study and not tested in people. Drafted from the abstract only. |
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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