The PI3K-Akt signaling pathway is a central intracellular signaling cascade activated by Neurotrophic Factors, Insulin, and Cytokines that regulates cell survival, growth, metabolism, proliferation, and immune. It is critical for Insulin action, glucose metabolism, protein synthesis, and inflammatory responses.
graph TD
subgraph "Receptor Activation"
A["[Insulin](/en/concepts/insulin.md) / [IGF-1](/en/concepts/igf-1.md) /<br/>[Neurotrophic Factors](/en/concepts/neurotrophic-factors.md) /<br/>[Cytokines](/en/concepts/cytokines.md)"] --> B["Receptor tyrosine<br/>kinases / GPCRs"]
end
subgraph "PI3K β PIP3 β Akt Activation"
B --> C["PI3K activation"]
C --> D["PIP2 β PIP3<br/>(membrane phospholipid)"]
D --> E["PDK1 recruited<br/>to membrane"]
D --> F["Akt (PKB) recruited<br/>to membrane"]
E -->|"Thr308<br/>phosphorylation"| G["Akt partially<br/>active"]
G -->|"Ser473 phosphorylation<br/>(by [mTOR](/en/pathways/mtor.md)C2)"| H["Akt FULLY<br/>active"]
end
subgraph "Downstream Targets"
H --> I["[mTOR](/en/pathways/mtor.md)<br/>β [protein synthesis](/en/concepts/protein-synthesis.md)"]
H --> J["FOXO inhibited<br/>β β [autophagy](/en/concepts/autophagy.md) / apoptosis"]
H --> K["GSK3Ξ² inhibited<br/>β [glycogen synthesis](/en/glycogen-synthesis) β"]
H --> L["BAD inhibited<br/>β [cell survival](/en/cell-survival) β"]
H --> M["[GLUT4](/en/concepts/glut4.md) translocation<br/>β glucose uptake β"]
end
subgraph "Negative Regulation"
N["[PTEN](/en/pten)<br/>(tumour suppressor)"] -->|"PIP3 β PIP2<br/>(dephosphorylation)"| D
end
style A fill:#f8d7da,stroke:#dc3545
style C fill:#fff3cd,stroke:#ffc107
style H fill:#fff3cd,stroke:#ffc107
style D fill:#cce5ff,stroke:#004085
style E fill:#cce5ff,stroke:#004085
style I fill:#d4edda,stroke:#28a745
style J fill:#d4edda,stroke:#28a745
style K fill:#d4edda,stroke:#28a745
style L fill:#d4edda,stroke:#28a745
style M fill:#d4edda,stroke:#28a745
style N fill:#f8d7da,stroke:#dc3545
graph TD
subgraph "Normal Insulin Signaling"
A["[Insulin](/en/concepts/insulin.md)"] --> B["PI3K-Akt<br/>active"]
B --> C["Glucose uptake β<br/>Glycogen synthesis β<br/>Protein synthesis β"]
end
subgraph "Insulin Resistance"
D["Chronic<br/>hyperinsulinaemia"] --> E["PI3K-Akt<br/>IMPAIRED"]
E --> F["β Glucose uptake<br/>β Glycogen synthesis<br/>β [type 2 diabetes](/en/type-2-diabetes)"]
end
subgraph "Cancer Hijacking"
G["PTEN loss-of-function<br/>or PI3K mutations"] --> H["PI3K-Akt<br/>HYPERACTIVE"]
H --> I["[mTOR](/en/pathways/mtor.md) β β Uncontrolled<br/>proliferation & growth<br/>β [cancer](/en/cancer)"]
end
subgraph "Therapeutic Targets"
J["[metformin](/en/metformin)<br/>(affects [mTOR](/en/pathways/mtor.md)<br/>downstream)"]
K["PI3K inhibitors<br/>(cancer therapy)"]
end
style A fill:#f8d7da,stroke:#dc3545
style D fill:#f8d7da,stroke:#dc3545
style G fill:#f8d7da,stroke:#dc3545
style B fill:#fff3cd,stroke:#ffc107
style E fill:#fff3cd,stroke:#ffc107
style H fill:#fff3cd,stroke:#ffc107
style C fill:#d4edda,stroke:#28a745
style F fill:#d4edda,stroke:#28a745
style I fill:#d4edda,stroke:#28a745
style J fill:#cce5ff,stroke:#004085
style K fill:#cce5ff,stroke:#004085
Receptor Tyrosine kinases (Insulin, IGF-1 receptor, growth factor receptors) or G-protein coupled receptors activate phosphoinositide 3-kinase (PI3K), which phosphorylates membrane phospholipid PIP2 to PIP3. PIP3 recruits PDK1 and Akt (also called PKB) to the membrane, where Akt is phosphorylated at two sites (Thr308 and Ser473) for full activation. Activated Akt phosphorylates numerous downstream targets: mTOR (promoting protein synthesis), FOXO transcription factors (inhibiting them to reduce autophagy/apoptosis), GSK3Ξ² (enhancing glycogen synthesis), and BAD (promoting survival). In leukocytes, PI3K-Akt regulates cytokine production, cell migration, and activation. The pathway is negatively regulated by PTEN phosphatase. Chronic activation contributes to Insulin and Cancer; insufficient activation impairs growth and metabolism.
PI3K-Akt is the primary pathway mediating Insulin's metabolic effectsβInsulin involves impaired PI3K-Akt signaling despite high Insulin. This pathway is dysregulated in metabolic syndrome, Type 2 Diabetes, and Cancer. In infections like P. acnes (linked to Frozen shoulder), bacteria may hijack PI3K-Akt signaling to evade immune responses. Understanding PI3K-Akt helps explain how Neurotrophic Factors, Insulin, and inflammatory signals converge on metabolism, survival, and immune. Many therapeutic targets (PI3K inhibitors for Cancer, Metformin affecting mTOR downstream) involve this pathway.
- Activated by Insulin, IGF-1, Neurotrophic Factors, and some Cytokines
- PI3K converts PIP2 to PIP3 at plasma membrane
- Akt (PKB) phosphorylated at Thr308 and Ser473 for full activity
- Downstream targets: mTOR, FOXO, GSK3Ξ², BAD, many others
- Promotes cell survival, growth, metabolism, proliferation
- Negatively regulated by PTEN tumor suppressor
- Impaired in Insulin and Type 2 Diabetes
- Hyperactivated in many cancers
- Regulates Glucose uptake via GLUT4 translocation
- Controls protein synthesis via mTOR activation