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Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB

Sarbassov DD, Ali SM, Sengupta S, Sheen JH, Hsu PP, Bagley AF, Markhard AL, Sabatini DM · 2006 · Molecular Cell · Atlas ID SAR2006

What this study shows

The molecular explanation for rapamycin's dark side. Short-term rapamycin only hits mTORC1, but LONG-term treatment also strips down mTORC2 in many cells, cutting Akt signaling. 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.

Abstract

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The drug rapamycin has important uses in oncology, cardiology, and transplantation medicine, but its clinically relevant molecular effects are not understood. When bound to FKBP12, rapamycin interacts with and inhibits the kinase activity of a multiprotein complex composed of mTOR, mLST8, and raptor (mTORC1). The distinct complex of mTOR, mLST8, and rictor (mTORC2) does not interact with FKBP12-rapamycin and is not thought to be rapamycin sensitive. mTORC2 phosphorylates and activates Akt/PKB, a key regulator of cell survival.

Read the full abstract on PubMed →

At a glance

Evidence type M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Multiple human/mouse cell lines) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type5 - Mechanistic / In Vitro
Model systemMultiple human/mouse cell lines
JournalMolecular Cell
Year2006
Peer reviewedYes
Record last updated2026-08-22
SourceDOI 10.1016/j.molcel.2006.03.029 · PMID 16603397

Extracted findings

InterventionRapamycin (prolonged treatment)
TargetmTORC2 / Akt
ModelMultiple human/mouse cell lines
EffectProlonged rapamycin inhibits mTORC2 assembly and Akt/PKB in some cells – mTORC2 is not always rapamycin-insensitive

In the Atlas

Related topics

RapamycinRictorAkt/PKBmTORC2

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Cite this paper

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Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J. H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006). Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Molecular Cell. https://doi.org/10.1016/j.molcel.2006.03.029

@article{SAR2006,
  author       = {Sarbassov, D. D. and Ali, S. M. and Sengupta, S. and Sheen, J. H. and Hsu, P. P. and Bagley, A. F. and Markhard, A. L. and Sabatini, D. M.},
  title        = {{Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB}},
  journal      = {Molecular Cell},
  year         = {2006},
  doi          = {10.1016/j.molcel.2006.03.029},
  note         = {PMID: 16603397},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record SAR2006) [Data set]. https://mtor-atlas.org/study/SAR2006/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_SAR2006,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record SAR2006},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/SAR2006/},
  doi          = {10.5281/zenodo.22059963}
}