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 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.

Cited on mTOR drugs in development: TOR-101

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.

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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 type	5 - Mechanistic / In Vitro
Model system	Multiple human/mouse cell lines
Journal	Molecular Cell
Year	2006
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/j.molcel.2006.03.029 · PMID 16603397

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Rapamycin (prolonged treatment)
Target	mTORC2 / Akt
Model	Multiple human/mouse cell lines
Effect	Prolonged rapamycin inhibits mTORC2 assembly and Akt/PKB in some cells – mTORC2 is not always rapamycin-insensitive

In the Atlas

Links in the pathway map

Supports Rapamycin inhibits mTORC2

Open questions that cite this study

Cited as supporting evidence for the open question Brain-penetrant mTOR inhibition clears aggregates in models, but human dosing has not been shown to reach the brain — and mTORC2 is needed for memory in mice.

Answers that reference this study

Discussed in the plain-language answer Does rapamycin extend lifespan in humans?.
Discussed in the plain-language answer What are rapamycin's side effects?.

Learn the biology

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