A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation

Dalle Pezze P, Sonntag AG, Thien A, Prentzell MT, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB, Baumeister R, Shanley DP, Thedieck K · 2012 · Science Signaling · Atlas ID DAL2012

What this study shows

A time-resolved, data-fitted model of the whole core insulin-mTOR network, including the mTORC1 negative feedback loop onto PI3K. Perturbing it in silico and in cells showed that TSC1-TSC2 is not a regulator of mTORC2, directly or through the feedback loop, and that mTORC2 activation runs through a PI3K variant insensitive to that loop. One of the few places where the feedback loops in the atlas are treated as a dynamical system rather than a diagram.

Abstract

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The kinase mammalian target of rapamycin (mTOR) exists in two multiprotein complexes (mTORC1 and mTORC2) and is a central regulator of growth and metabolism. Insulin activation of mTORC1, mediated by phosphoinositide 3-kinase (PI3K), Akt, and the inhibitory tuberous sclerosis complex 1/2 (TSC1-TSC2), initiates a negative feedback loop that ultimately inhibits PI3K. We present a data-driven dynamic insulin-mTOR network model that integrates the entire core network and used this model to investigate the less well understood mechanisms by which insulin regulates mTORC2.

Read the full abstract on PubMed →

At a glance

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Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Data-driven dynamic model of the insulin-mTOR network, tested in HeLa and other 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	Data-driven dynamic model of the insulin-mTOR network, tested in HeLa and other cell lines
Journal	Science Signaling
Year	2012
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1126/scisignal.2002469 · PMID 22457331

Where this study fits

How this study connects to the pathway map, open questions, people and other studies in the Atlas.

Pathway relations

Supports

PI3K activates mTORC2

Strongest evidence: M (Molecular — cells, biochemistry, structure) · emerging, few independent studies · Status: Proposed

plausible in people, not shown directly

Growth-factor dependence of mTORC2 assembly and activity, shown in mammalian cells. The ribosome requirement (ZIN2011) means the readout is not a clean separation of PI3K input from translational state.

People in the Atlas

Piero Dalle Pezze first author · 2 studies in the Atlas

First author of two Atlas modelling studies: the dynamic insulin–mTOR network model (TSC-independent mTORC2) and the systems study of concurrent AMPK and mTOR activation by amino acids.
Kathrin Thedieck last author · 3 studies in the Atlas

Senior author of three Atlas studies that treat mTOR signalling as a dynamic network: TSC-independent mTORC2 activation, concurrent AMPK and mTOR activation by amino acids, and G3BP tethering of TSC to lysosomes.
Annika G. Sonntag 2 studies in the Atlas

Experimental researcher in the Thedieck group who contributed cell data to the dynamic mTOR network model and the AMPK–mTOR amino acid study.
Mirja Tamara Prentzell 2 studies in the Atlas

First author of the study showing that G3BP proteins anchor the TSC complex to lysosomes, a physical brake on mTORC1; earlier co-author on the dynamic insulin–mTOR network model.
Ralf Baumeister 2 studies in the Atlas

Head of the Freiburg department that hosted the Thedieck group during the mTOR network modelling work; co-author on the dynamic mTOR model and the G3BP–TSC study.

More: 6 other authors

Daryl P. Shanley 2 studies in the Atlas

Systems biologist of ageing whose Newcastle modelling group built, with the Thedieck lab, the dynamic models of mTOR signalling in the Atlas.

No profile yet: Thien A, Gödel M, Fischer S, Neumann-Haefelin E, Huber TB

Related studies

M
Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway
MAN2002 · 2002 · Shares: TSC1/TSC2, Akt/PKB, PI3K, S6K1
M
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
INO2002 · 2002 · Shares: TSC1/TSC2, Akt/PKB, PI3K, mTORC1
M
Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate
GAN2011 · 2011 · Shares: Akt/PKB, PI3K, mTORC2
M
Activation of mTORC2 by association with the ribosome
ZIN2011 · 2011 · Shares: Akt/PKB, PI3K, mTORC2
M
A systems study reveals concurrent activation of AMPK and mTOR by amino acids
DAL2016 · 2016 · Shares: PI3K, mTORC1, mTORC2

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M
IGF2BP3-Mediated m6A Modification of OLR1 mRNA Promotes Immune Evasion in CRC via the PI3K/AKT/mTOR Pathway
CHEN2026B · 2026 · Shares: Akt/PKB, PI3K, mTORC1
A
LncRNA DLX6-AS1 promotes necroptosis through PI3K/AKT/mTOR signaling pathway in myocardial ischemia/reperfusion injury mice
SU2026 · 2026 · Shares: Akt/PKB, PI3K, mTORC1
R
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M
Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways
ROM2001 · 2001 · Shares: Akt/PKB, PI3K, mTORC1
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Impaired mTOR/SREBP1-Mediated Lipogenesis as a Mechanism of Hepatic Glycogen Accumulation in a Carnivorous Fish Model, Largemouth Bass (Micropterus salmoides)
TAO2026 · 2026 · Shares: TSC1/TSC2, Akt/PKB, S6K1
H
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SCH2025 · 2025 · Shares: mTORC1, mTORC2, S6K1
M
Inferring feedback regulation from static snapshots of a single signal
GIN2026 · 2026 · Shares: Akt/PKB, mTORC1, S6K1
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KUB2018 · 2018 · Shares: Akt/PKB, mTORC1, S6K1

All 212 studies on mTORC1

Topics

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	In silico and experimental perturbations (insulin, inhibitors, knockdowns)
Target	mTORC1; mTORC2; TSC1-TSC2; PI3K; negative feedback loop
Model	Human cell lines
Effect	mTORC2 is not regulated by TSC1-TSC2 or by the mTORC1-driven negative feedback loop

Cite this paper

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Dalle Pezze, P., Sonntag, A. G., Thien, A., Prentzell, M. T., Gödel, M., Fischer, S., Neumann-Haefelin, E., Huber, T. B., Baumeister, R., Shanley, D. P., & Thedieck, K. (2012). A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Science Signaling. https://doi.org/10.1126/scisignal.2002469

@article{DAL2012,
  author       = {Dalle Pezze, P. and Sonntag, A. G. and Thien, A. and Prentzell, M. T. and Gödel, M. and Fischer, S. and Neumann-Haefelin, E. and Huber, T. B. and Baumeister, R. and Shanley, D. P. and Thedieck, K.},
  title        = {{A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation}},
  journal      = {Science Signaling},
  year         = {2012},
  doi          = {10.1126/scisignal.2002469},
  note         = {PMID: 22457331},
}

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 DAL2012) [Data set]. https://mtor-atlas.org/study/DAL2012/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_DAL2012,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record DAL2012},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/DAL2012/},
  doi          = {10.5281/zenodo.22059963}
}

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