Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase
What this study shows
The companion paper to BYF2005, from a different laboratory: the amino acid input to mTORC1 is separate from the insulin input and runs through class 3 PI3K (hVps34), not through class 1 PI3K. Historically important because it states that the amino acid branch is the older one and that insulin signalling was grafted onto it. Boundary: cell lines, pharmacological and knockdown evidence; the later Rag/Ragulator account describes a different route to the same target, and the two accounts are not reconciled in the work this Atlas holds.
Abstract
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During the evolution of metazoans and the rise of systemic hormonal regulation, the insulin-controlled class 1 phosphatidylinositol 3OH-kinase (PI3K) pathway was merged with the primordial amino acid-driven mammalian target of rapamycin (mTOR) pathway to control the growth and development of the organism. Insulin regulates mTOR function through a recently described canonical signaling pathway, which is initiated by the activation of class 1 PI3K. However, how the amino acid input is integrated with that of the insulin signaling pathway is unclear.
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: Human 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 | Human cell lines |
| Journal | Proceedings of the National Academy of Sciences |
| Year | 2005 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1073/pnas.0506925102 · PMID 16176982 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
People in the Atlas
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Showed as first author that amino acids activate mTOR through the lipid kinase hVps34, by a route separate from insulin signalling through TSC, in parallel with a study from Jonathan Backer's laboratory
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Purified and cloned S6K1, the kinase that became the classic readout of mTORC1 activity. His lab later showed that mice lacking S6K1 resist diet-induced obesity, and that amino acids signal to mTORC1 through the lipid kinase hVps34 (GUL2008)
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First author of the study proposing that amino acids activate mTORC1 through a rise in intracellular calcium and calmodulin binding to hVps34, and later of work linking the obesity gene FTO to amino-acid sensing by mTORC1
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Showed as first author that the lipid kinase hVps34 is regulated by nutrients and is needed for amino acids to activate S6 kinase through mTOR, in parallel with a study from George Thomas's group
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Showed that the class III PI 3-kinase hVps34, best known for its role in autophagy, is regulated by nutrients and is needed for amino acids to activate S6 kinase through mTOR, in parallel with George Thomas's group
Related studies
- M GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR
KIM2003 · 2003 · Shares: Raptor, mTOR, mTORC1
- M Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action
HARA2002 · 2002 · Shares: Raptor, mTOR, mTORC1
- M mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery
KIM2002 · 2002 · Shares: Raptor, mTOR, mTORC1
- M Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34
GUL2008 · 2008 · Shares: mTORC1, Vps34 (PIK3C3)
- M hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase
BYF2005 · 2005 · Shares: mTORC1, Vps34 (PIK3C3)
More related studies
- M Architecture of human Rag GTPase heterodimers and their complex with mTORC1
ANA2019 · 2019 · Shares: Raptor, mTORC1
- M ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase
RUS2013 · 2013 · Shares: Vps34 (PIK3C3)
- M Tor forms a dimer through an N-terminal helical solenoid with a complex topology
BAR2016 · 2016 · Shares: Raptor, mTOR
- M
- M Structural basis for mTORC1 activation on the lysosomal membrane
CUI2025 · 2025 · Shares: Raptor, mTORC1
- M Structure of the lysosomal mTORC1-TFEB-Rag-Ragulator megacomplex
CUI2023 · 2023 · Shares: Raptor, mTORC1
- M Structural basis for the docking of mTORC1 on the lysosomal surface
ROG2019 · 2019 · Shares: Raptor, mTORC1
- M Dynamics of mTORC1 activation in response to amino acids
MAN2016 · 2016 · Shares: Raptor, 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 | Amino acid stimulation; hVps34 knockdown and pharmacological PI3K inhibition |
| Target | Class 3 PI3K (hVps34) -> mTOR/raptor |
| Model | Human cell lines |
| Effect | Amino acids signal to mTOR/raptor through hVps34, a route separate from insulin and class 1 PI3K |
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