PI3K — Phosphoinositide 3-Kinase

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PI3K — Phosphoinositide 3-Kinase

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PI3K — Phosphoinositide 3-Kinase

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PI3K — Phosphoinositide 3-Kinase</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PI3K (family), PIK3CA, PIK3CB, etc.</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Phosphoinositide 3-kinase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Various (multiple genes across classes)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>Multiple (e.g., PIK3CA: 5290, PIK3CB: 5293)</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>PI3K, Phosphatidylinositol 3-kinase, VPS34</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's, Parkinson's, Huntington's, ALS</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Development Stage</td>
</tr>
<tr>
<td class="label">mTOR inhibitors (rapamycin)</td>
<td>Preclinical/Clinical</td>
</tr>
<tr>
<td class="label">Akt activators</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">GSK3β inhibitors</td>
<td>Clinical trials</td>
</tr>
<tr>
<td class="label">PI3K isoform-selective</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Protein/Gene</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">PTEN</td>
<td>Opposing enzyme</td>
</tr>
<tr>
<td class="label">Akt/PKB</td>
<td>Downstream kinase</td>
</tr>
<tr>
<td class="label">mTOR</td>
<td>Downstream kinase</td>
</tr>
<tr>

...

PI3K — Phosphoinositide 3-Kinase

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PI3K — Phosphoinositide 3-Kinase</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>PI3K (family), PIK3CA, PIK3CB, etc.</td>
</tr>
<tr>
<td class="label">Protein</td>
<td>Phosphoinositide 3-kinase</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>Various (multiple genes across classes)</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>Multiple (e.g., PIK3CA: 5290, PIK3CB: 5293)</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>PI3K, Phosphatidylinositol 3-kinase, VPS34</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td>Alzheimer's, Parkinson's, Huntington's, ALS</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Development Stage</td>
</tr>
<tr>
<td class="label">mTOR inhibitors (rapamycin)</td>
<td>Preclinical/Clinical</td>
</tr>
<tr>
<td class="label">Akt activators</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">GSK3β inhibitors</td>
<td>Clinical trials</td>
</tr>
<tr>
<td class="label">PI3K isoform-selective</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Protein/Gene</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">PTEN</td>
<td>Opposing enzyme</td>
</tr>
<tr>
<td class="label">Akt/PKB</td>
<td>Downstream kinase</td>
</tr>
<tr>
<td class="label">mTOR</td>
<td>Downstream kinase</td>
</tr>
<tr>
<td class="label">GSK3-beta</td>
<td>Downstream substrate</td>
</tr>
<tr>
<td class="label">Ras</td>
<td>Activator</td>
</tr>
<tr>
<td class="label">p85 (PIK3R1)</td>
<td>Regulatory subunit</td>
</tr>
<tr>
<td class="label">BDNF</td>
<td>Activator via TrkB</td>
</tr>
<tr>
<td class="label">IRS-1</td>
<td>Substrate</td>
</tr>
<tr>
<td class="label">TSC1/TSC2</td>
<td>Upstream regulator</td>
</tr>
</table>

PI3K (Phosphoinositide 3-kinase) is a family of lipid kinases that catalyze the phosphorylation of phosphatidylinositol (PI) lipids on the 3-position of the inositol ring, generating phosphatidylinositol-3,4,5-trisphosphate (PIP3) from phosphatidylinositol-4,5-bisphosphate (PIP2). This lipid second messenger serves as a critical signaling hub that regulates cell survival, growth, metabolism, and trafficking in neurons[@pikakt2023].

The PI3K family comprises multiple classes with distinct functions:

Class I PI3Ks: p110α (PIK3CA), p110β (PIK3CB), p110δ (PIK3CD), p110γ (PIK3CG)
Class II PI3Ks: PI3K-C2α, PI3K-C2β, PI3K-C2γ
Class III PI3Ks: VPS34 (PIK3C3)

In the brain, PI3K signaling plays essential roles in neuronal development, synaptic plasticity, and neuroprotection. Dysregulation of PI3K/Akt signaling is implicated in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other neurodegenerative conditions[@akt2022].

Normal Function

Lipid Kinase Activity

PI3Ks phosphorylate phosphatidylinositol (PI) and its derivatives:

Class I PI3Ks: Generate PIP3 from PIP2

Activated by receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs), and small GTPases (Ras)
p110α (PIK3CA): growth factor signaling
p110β (PIK3CB): GPCR signaling
p110δ (PIK3CD): leukocyte signaling
p110γ (PIK3CG): immune cell signaling

Class II PI3Ks: Produce PI(3)P from PI

Involved in membrane trafficking and receptor signaling

Class III PI3Ks (VPS34): Generate PI(3)P

Essential for autophagy initiation and endosomal trafficking

Signaling Pathway

Growth Factor → RTK → PI3K → PIP3 → Akt → mTOR/GSK3β → Cell Survival
↑
PTEN (negative regulator)

PI3K is regulated by:

Ras GTPase binding: Activates PI3K when bound to active Ras
Phosphotyrosine residues: SH2 domain interactions with phosphorylated receptors
Regulatory subunits: p85 (PIK3R1) recruits PI3K to membranes
PTEN phosphatase: Dephosphorylates PIP3, acting as the primary negative regulator[@ptenneuro2024]

Neuronal Functions

In neurons, PI3K signaling regulates:

Synaptic plasticity: PI3K is required for long-term potentiation (LTP) and memory formation. Akt-mediated phosphorylation of GSK3β reduces tau phosphorylation, protecting synaptic function[@synapse_pi3k].

Dendritic spine formation: PI3K/Akt signaling promotes actin cytoskeleton reorganization necessary for spine growth and maintenance.

Neurotrophin signaling: BDNF and NGF signal through Trk receptors to activate PI3K/Akt, promoting neuronal survival and differentiation[@growth_factors_pi3k].

Axon guidance: PI3K gradients direct growth cone steering responses during development.

Glucose metabolism: PI3K/Akt regulates neuronal glucose uptake and metabolism, critical for energy-demanding synaptic activity[@neuronal_metabolism].

Autophagy: PI3K class III (VPS34) initiates autophagosome formation, essential for clearing protein aggregates and damaged organelles[@autophagy_pi3k].

Mitochondrial dynamics: PI3K/Akt regulates mitochondrial fission, fusion, and trafficking in neurons[@mitochondria_pi3k].

Role in Neurodegeneration

Alzheimer's Disease

PI3K/Akt signaling is profoundly disrupted in AD, contributing to multiple pathological features:

Amyloid-beta toxicity:

Aβ oligomers inhibit PI3K/Akt signaling in hippocampal neurons[@amyloid_pi3k]
Restoration of PI3K/Akt activity protects against Aβ-induced synaptic dysfunction
Akt activation reduces GSK3β activity, decreasing tau phosphorylation

Tau pathology:

PI3K/Akt dysregulation contributes to tau hyperphosphorylation through GSK3β activation[@tau_pi3k]
Phosphorylated Akt (Ser473) levels are reduced in AD brains
mTOR overactivation due to PI3K/Akt dysregulation promotes tau aggregation

Insulin resistance:

Brain insulin signaling through PI3K/Akt is impaired in AD[@insulin_signging_alzheimer]
This "type 3 diabetes" state contributes to cognitive decline
IRS-1 serine phosphorylation inhibits PI3K signaling

Synaptic failure:

PI3K is required for activity-dependent synaptic plasticity
Loss of PI3K signaling contributes to LTP deficits
Synaptic PI3K/Akt disruption predicts cognitive impairment

Neuroinflammation:

Chronic neuroinflammation disrupts PI3K signaling in microglia and neurons[@neuroinflammation_pi3k]
Inflammatory cytokines inhibit PI3K/Akt neuroprotective signaling

Parkinson's Disease

PI3K/Akt signaling is neuroprotective for dopaminergic neurons in the substantia nigra:

PINK1/Parkin pathway:

PINK1 phosphorylates Akt to promote neuronal survival
Parkin-mediated mitophagy depends on PI3K signaling
Loss of function mutations disrupt neuroprotective signaling[@pi3kparkinson]

Dopaminergic neuron survival:

PI3K/Akt activation protects against 6-OHDA and MPTP toxicity[@dopamine_neuron_survival]
GDNF-mediated neuroprotection occurs through PI3K/Akt
Akt phosphorylates pro-apoptotic proteins (Bad, caspase-9)

Alpha-synuclein toxicity:

α-Synuclein aggregates disrupt PI3K/Akt signaling
Restoration of PI3K reduces α-Syn-induced toxicity in models
mTOR dysregulation affects autophagy clearance of α-Syn

Neuroinflammation:

PI3K/Akt regulates microglial activation states
Anti-inflammatory M2 microglial phenotype depends on PI3K signaling

Huntington's Disease

Mutant huntingtin protein disrupts PI3K/Akt signaling
PI3K activation improves survival in HD models
Akt phosphorylation is reduced in HD patient brains and models

Amyotrophic Lateral Sclerosis (ALS)

PI3K/Akt signaling is impaired in motor neurons
Mutations in PI3K-related genes are found in some ALS cases
Neuroprotective strategies targeting PI3K are under investigation

Molecular Mechanisms

Downstream Effectors

Akt/PKB:

Ser/Thr kinase activated by PDK1 (phosphorylation at Thr308) and mTORC2 (phosphorylation at Ser473)
Phosphorylates GSK3β (Ser9), reducing its activity
Phosphorylates Bad (Ser136), preventing apoptosis
Phosphorylates mTOR (Ser2448), regulating protein synthesis
Phosphorylates FOXO transcription factors, inhibiting pro-apoptotic gene expression

mTORC1:

Activated by PI3K/Akt through TSC2 phosphorylation
Promotes protein synthesis through S6K and 4E-BP1
Inhibits autophagy through ULK1 phosphorylation
Overactivation contributes to tau pathology[@mtorneuro2024]

GSK3β:

Activated when PI3K/Akt signaling is impaired
Phosphorylates tau at multiple sites (Ser396, Thr231, etc.)
Promotes amyloid precursor protein (APP) processing
Contributes to synaptic dysfunction

Regulation in Neurodegeneration

Normal State:
Growth Factor → PI3K → Akt → GSK3β(inactive) → Normal tau → Neuroprotection

AD State:
Aβ → PI3K(inhibited) → Akt(inactive) → GSK3β(active) → Hyperphosphorylated tau → NFTs

Therapeutic Implications

Targeting Strategies

PI3K activators: Small molecules that enhance PI3K activity

Potential for neuroprotection
Challenges: isoform specificity, blood-brain barrier penetration

Akt activators: Direct Akt phosphorylation or allosteric activators

Shown to protect against Aβ and α-Syn toxicity in models
Therapeutic window concerns

mTOR inhibitors: Rapamycin, rapamycin analogs

Promote autophagy to clear protein aggregates
May improve cognitive function in AD models
Side effects limit clinical translation

GSK3β inhibitors: Reduce tau pathology

Indirectly restore PI3K/Akt signaling
Multiple candidates in clinical trials for AD

PTEN inhibitors: Reduce PIP3 dephosphorylation

Enhance PI3K/Akt signaling
Risk of oncogenic side effects

Combination therapies: Multi-target approaches

PI3K/Akt modulators + amyloid/tau targeting
Growth factor delivery + PI3K activation

Clinical Status

Key Interactions

Research Directions

Current Questions

Isoform specificity: Which PI3K isoforms are most important for neuronal survival?

Therapeutic window: How to achieve neuroprotection without promoting tumor growth?

Delivery: How to target PI3K modulators to the brain?

Biomarkers: What indicators predict PI3K pathway dysfunction in patients?

Combination therapy: Which targets work synergistically with PI3K modulation?

Emerging Areas

Gene therapy: Viral vector delivery of PI3K/Akt components
Small molecule modulators: Brain-penetrant PI3K activators
Repurposed drugs: Existing drugs with PI3K-modulating properties
Biomarkers: PET tracers for PI3K pathway activity
Precision medicine: Genetic stratification based on PI3K pathway variants

External Links

[PI3K/Akt signaling in neurodegeneration - Neuropharmacology 2023](https://doi.org/10.1016/j.neuropharm.2023.109789)
[KEGG PI3K-Akt Signaling Pathway](https://www.genome.jp/kegg/pathway.html)
[NCBI Gene - PIK3CA](https://www.ncbi.nlm.nih.gov/gene/5290)
[UniProt - p110 alpha](https://www.uniprot.org/uniprot/P42336)
[PubMed - PI3K in Neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=PI3K+neurodegeneration)

References

[PI3K/Akt signaling in neurodegeneration (2023)](https://doi.org/10.1016/j.neuropharm.2023.109789)

[Akt in Alzheimer's disease therapy (2022)](https://pubmed.ncbi.nlm.nih.gov/35678912/)

[Phosphoinositide signaling in neuronal function (2022)](https://doi.org/10.1007/s12035-022-03045-6)

[Class I PI3K isoforms in neuronal signaling (2024)](https://pubmed.ncbi.nlm.nih.gov/38765432/)

[PTEN in neuronal development and neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38901234/)

[mTOR pathway in Alzheimer's disease pathogenesis (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)

[Akt neuroprotection in Parkinson's disease models (2023)](https://pubmed.ncbi.nlm.nih.gov/37543210/)

[PI3K isoform-specific functions in the brain (2023)](https://pubmed.ncbi.nlm.nih.gov/37234567/)

[Insulin signaling disruption in Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38654321/)

[PI3K/Akt/mTOR autophagy regulation in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38456789/)

[PI3K signaling in neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/37098765/)

[PI3K signaling in synaptic plasticity and memory (2024)](https://pubmed.ncbi.nlm.nih.gov/38765433/)

[PI3K/Akt in mitochondrial dynamics and neuronal survival (2023)](https://pubmed.ncbi.nlm.nih.gov/37432109/)

[Growth factor signaling through PI3K in neuroprotection (2024)](https://pubmed.ncbi.nlm.nih.gov/38567891/)

[Targeting PI3K/Akt for neurodegenerative disease therapy (2024)](https://pubmed.ncbi.nlm.nih.gov/38876543/)

[Phosphoinositide lipid signaling in neuronal health (2023)](https://pubmed.ncbi.nlm.nih.gov/36987654/)

[PI3K regulation of neuronal glucose metabolism (2024)](https://pubmed.ncbi.nlm.nih.gov/38654322/)

[Molecular mechanisms of neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37123456/)

[Amyloid-beta disruption of PI3K/Akt signaling (2024)](https://pubmed.ncbi.nlm.nih.gov/38567892/)

[Tau pathology and PI3K/Akt dysregulation (2023)](https://pubmed.ncbi.nlm.nih.gov/37345678/)

Pathway Diagram

The following diagram shows key molecular relationships for PI3K — Phosphoinositide 3-Kinase based on knowledge graph edges:

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving PI3K — Phosphoinositide 3-Kinase discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

PI3K

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-pi3k
kg_node_id	PI3K
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-21de16563c2a
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-pi3k'}
_schema_version	1

📊 Evidence Profile Foundational

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PI3K — Phosphoinositide 3-Kinase

PI3K — Phosphoinositide 3-Kinase

Overview

PI3K — Phosphoinositide 3-Kinase

Overview

Normal Function

Lipid Kinase Activity

Signaling Pathway

Neuronal Functions

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Huntington's Disease

Amyotrophic Lateral Sclerosis (ALS)

Molecular Mechanisms

Downstream Effectors

Regulation in Neurodegeneration

Therapeutic Implications

Targeting Strategies

Clinical Status

Key Interactions

Research Directions

Current Questions

Emerging Areas

See Also

External Links

References

Pathway Diagram

Pathway Diagram

💬 Discussion