The PI3K/Akt/mTOR Pathway
The cell’s growth-and-survival switch, and how PTEN controls it
The PI3K/Akt/mTOR pathway is the cell’s main "grow, divide, and survive" switch. PI3K turns the signal on; PTEN turns it off. It is the most frequently activated signalling pathway in human cancer.
The cascade, step by step
- A growth factor (or insulin) binds a receptor at the cell surface.
- PI3K is activated and phosphorylates the membrane lipid PIP2 into PIP3.
- PIP3 recruits AKT to the membrane, where it is switched on.
- AKT activates mTORC1 and other effectors, and inhibits brakes such as GSK3β.
- The result: protein synthesis, cell growth, proliferation, and resistance to cell death.
PTEN is the off-switch
PTEN dephosphorylates PIP3 straight back to PIP2, erasing the very signal AKT depends on. This single reaction is why PTEN is the pathway’s primary brake. Lose PTEN and PIP3 accumulates, AKT stays active, and the cell receives a constant growth signal — the through-line of PTEN and cancer.
What the pathway controls
- Cell growth and size (mTORC1 drives ribosome and protein production).
- Proliferation and cell-cycle progression.
- Survival — active AKT suppresses programmed cell death.
- Metabolism and nutrient sensing.
- Autophagy, which mTOR restrains when nutrients are plentiful.
When it goes wrong
Persistent hyperactivation drives cancer — through PTEN loss, activating PIK3CA mutations, or AKT amplification — and is a common route to treatment resistance. In neurons, the opposite problem applies: the pathway is held down as they mature, which is why injured axons stop growing (see PTEN and neural regeneration).
Drugging the pathway
| Inhibitor class | Acts on | Note |
|---|---|---|
| PI3K inhibitors | PI3K isoforms | Several approved in specific cancers |
| AKT inhibitors | AKT1/2/3 | In trials and approved combinations |
| mTOR inhibitors (rapalogs) | mTORC1 | Established; mTORC1/2 inhibitors newer |
The pathway is one of the most intensively drugged networks in oncology, but redundancy and feedback loops make durable responses hard — an active area of 2023–2024 clinical research.
Studying the pathway in the lab
To interrogate the PTEN node specifically, researchers use recombinant PTEN protein for phosphatase assays, PTEN siRNA to remove the brake, and the inhibitor SF1670 to block it acutely. For research use only.
Frequently asked questions
What does the PI3K/Akt/mTOR pathway do?
It is the cell’s main growth-and-survival signalling network: PI3K produces PIP3, which activates AKT, which activates mTOR to drive protein synthesis, growth, proliferation, and survival.
How does PTEN regulate PI3K/Akt/mTOR?
PTEN dephosphorylates PIP3 back to PIP2, removing the signal AKT needs. It is the pathway’s main off-switch, so losing PTEN leaves the pathway constitutively on.
What is PIP3?
PIP3 (phosphatidylinositol-3,4,5-trisphosphate) is the membrane lipid second messenger that PI3K makes and PTEN erases. It recruits and activates AKT.
Why is this pathway important in cancer?
It is the most frequently activated pathway in human cancer — through PTEN loss, PIK3CA mutation, or AKT amplification — and a major driver of growth, survival, and treatment resistance.
Key references
- 1.Glaviano A, Foo ASC, Lam HY, et al. “PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.” Molecular Cancer. 2023. DOI ↗
- 2.Peng Y, Wang Y, Zhou C, et al. “PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway?” Frontiers in Oncology. 2022. DOI ↗
- 3.Worby CA, Dixon JE. “PTEN.” Annual Review of Biochemistry. 2014. DOI ↗
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Related research reagents
Tools for studying PTEN in the lab — research use only.
Educational content based on peer-reviewed research — not medical advice. Reagents are supplied for laboratory research use only and are not for human or veterinary use.