PIK3R3 Gene

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gene1740 wordssynced 2026-04-02

PIK3R3 Gene

Gene Overview

<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>

| Gene Symbol | PIK3R3 |
|---|---|
| Full Name | Phosphoinositide-3-Kinase Regulatory Subunit 3 |
| Protein Name | p55γ (phosphoinositide 3-kinase regulatory subunit 3) |
| Chromosomal Location | 1p36.22 |
| NCBI Gene ID | [5293](https://www.ncbi.nlm.nih.gov/gene/5293) |
| OMIM | [606954](https://www.omim.org/entry/606954) |
| Ensembl ID | [ENSG00000117477](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000117477) |
| UniProt | [Q99836](https://www.uniprot.org/uniprotkb/Q99836/) |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [Glioblastoma](/diseases/glioblastoma), Cancer |
| Expression | Brain (highest), immune cells, various tissues |

</div>

Overview

PIK3R3 encodes the p55γ regulatory subunit of phosphoinositide-3-kinase (PI3K), a critical signaling molecule in cellular metabolism, growth, and survival. This protein is a member of the PI3K regulatory subunit family, which includes p85α (PIK3R1), p85β (PIK3R2), and p55α (PIK3R1 isoform), but p55γ has distinctive tissue distribution and functional properties that make it particularly important in the [central nervous system](/brain-regions/cns)[@lu2023].

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PIK3R3 Gene

Gene Overview

<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>

</div>

Overview

Unlike other regulatory subunits that are widely expressed, PIK3R3 shows the highest expression in brain tissue, with particularly high levels in neurons, astrocytes, and microglia. This brain-enriched expression pattern, combined with its specific functions in [synaptic plasticity](/mechanisms/synaptic-plasticity), [neuronal survival](/mechanisms/neuronal-survival), and [cell signaling](/mechanisms/cell-signaling), positions PIK3R3 as an important player in both normal brain function and neurodegenerative disease pathogenesis[@xiao2024].

Gene Structure and Organization

The human PIK3R3 gene is located on chromosome 1p36.22 and encodes a protein with distinct structural features that differentiate it from other PI3K regulatory subunits.

Genomic Organization

| Feature | Details |
|---------|---------|
| Chromosome | 1p36.22 |
| Genomic Span | ~43 kb |
| Exons | 13 coding exons |
| Transcript Length | ~2.8 kb |
| Protein Length | 461 amino acids |
| Molecular Weight | ~55 kDa (hence "p55") |

Comparison with Other Regulatory Subunits

| Subunit | Gene | Size (aa) | Brain Expression | Primary Tissues |
|---------|------|-----------|------------------|-----------------|
| p85α | PIK3R1 | 724 | Moderate | Ubiquitous |
| p85β | PIK3R2 | 728 | Moderate | Ubiquitous |
| p55α | PIK3R1 (isoform) | 461 | Moderate | Ubiquitous |
| p55γ | PIK3R3 | 461 | High | Brain, immune cells |

Transcript Variants

Canonical p55γ: Full-length 461 amino acid isoform

p50γ: Alternative start site variant (truncated)

Brain-specific isoforms: Alternative splicing generates neuronal variants

Protein Structure and Biochemistry

The p55γ protein has a distinctive structure that reflects its specialized functions:

Mermaid diagram (expand to render)

Structural Domains

N-terminal Proline-Rich Region: Contains motifs for SH3 domain interactions

SH3 Domain: Binds proline-rich sequences in other proteins

BH Domain (Bcr Homology): Interacts with small GTPases

iSH2 Domain (Inter-SH2): Critical for binding to p110 catalytic subunit

C-terminal SH2 Domain: Recognizes phosphotyrosine motifs on activated receptors

Key Differences from p85α/p85β

| Feature | p55γ | p85α/β |
|---------|------|--------|
| N-terminal | Shorter, no pSH3 domain | Longer, contains pSH3 |
| Brain specificity | High | Moderate |
| Phosphorylation | Different patterns | Standard patterns |
| Protein interactions | Brain-specific partners | Broader repertoire |

Normal Physiological Functions

PI3K/Akt Signaling Pathway

PIK3R3 forms part of the class IA PI3K complex, which is a central signaling hub:

Mermaid diagram (expand to render)

Pathway Components

Receptor Tyrosine Kinases (RTKs): Activate PI3K via autophosphorylation

p85/p110 Complex: Catalyzes PIP3 production

PIP3: Second messenger that recruits Akt to membrane

Akt (PKB): Serine/threonine kinase, key effector

Downstream Targets: mTOR, GSK-3β, Bad, many others

Brain-Specific Functions

Neuronal Signaling

In neurons, PIK3R3-mediated PI3K/Akt signaling regulates[@zhou2021]:

Synaptic Transmission: Modulates neurotransmitter release

Synaptic Plasticity: Critical for LTP and LTD

Dendritic Spine Morphogenesis: Controls spine formation and maintenance

Axonal Guidance: PI3K signaling in growth cones

Neuronal Survival: Akt-mediated pro-survival signaling

Astrocyte Function

Metabolic Support: Regulates glucose uptake and metabolism
Calcium Signaling: Modulates astrocytic calcium waves
Cytokine Production: Controls inflammatory responses

Microglial Activity

Migration: PI3K required for microglial chemotaxis
Phagocytosis: Key signaling for debris clearance
Inflammatory Responses: Modulates cytokine production

Synaptic Plasticity and Memory

PIK3R3 plays a critical role in [hippocampal](/brain-regions/hippocampus)-dependent learning and memory[@hawli2023]:

LTP Induction: PI3K activity required for LTP in CA1 neurons

Memory Consolidation: Akt-mediated signaling in memory circuits

Spine Dynamics: Controls activity-dependent spine changes

Protein Synthesis: mTOR pathway regulation

Mermaid diagram (expand to render)

Disease Associations

Alzheimer's Disease

PIK3R3 and the PI3K/Akt pathway are strongly implicated in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis[@chen2020]:

Evidence

Amyloid Effects: Aβ oligomers dysregulate PI3K/Akt signaling
Tau Phosphorylation: Akt regulates tau kinases and phosphatases
Neuronal Survival: Loss of pro-survival signaling in AD
Synaptic Dysfunction: Impaired PI3K signaling in AD models

Mechanisms

Mermaid diagram (expand to render)

Therapeutic Implications

PI3K Modulators: Could restore proper signaling
Akt Activators: Protective in pre-clinical models
mTOR Inhibitors: May improve function in early AD

Parkinson's Disease

PIK3R3 involvement in [Parkinson's disease](/diseases/parkinsons-disease):

Neuroprotection: PI3K/Akt signaling is neuroprotective in PD models
Alpha-Synuclein: PI3K modulates synuclein toxicity
Mitochondrial Function: PI3K regulates mitochondrial biogenesis
Dopaminergic Survival: Critical for dopaminergic neuron survival

Cancer

PIK3R3 has complex roles in cancer[@thoman2022]:

| Cancer Type | PIK3R3 Role | Evidence |
|-------------|-------------|----------|
| Glioblastoma | Oncogenic | Amplification, high expression |
| Colorectal Cancer | Context-dependent | Both tumor-suppressive and oncogenic |
| Breast Cancer | Variable | mutation status-dependent |
| Lung Cancer | Promote survival | Overexpression in subsets |

Mechanisms in Cancer

Cell Proliferation: PI3K/Akt drives cell cycle progression
Survival: Anti-apoptotic signaling via Akt
Metabolism: Enhanced glycolysis (Warburg effect)
Migration/Invasion: EMT and metastasis

Other Neurological Conditions

| Condition | Relationship | Mechanism |
|-----------|--------------|-----------|
| Epilepsy | Dysregulated PI3K | Seizure activity alters signaling |
| Stroke | Neuroprotective role | Akt mediates ischemic tolerance |
| MS | Immune cell regulation | Microglial PI3K function |
| ALS | Variable changes | Both protective and pathogenic roles |

Therapeutic Targeting

PI3K/Akt Pathway Modulators

Given PIK3R3's role in disease, several therapeutic strategies are being explored:

| Approach | Status | Challenge |
|---------|--------|-----------|
| Pan-PI3K inhibitors | Approved (cancer) | Brain penetration, toxicity |
| Akt inhibitors | Clinical trials | Specificity |
| mTOR inhibitors | Approved (cancer, transplant) | Cognitive side effects |
| p110-specific inhibitors | Preclinical | Brain specificity |

Brain-Penetrant PI3K Modulators

Key considerations for CNS applications:

Blood-Brain Barrier Penetration: Critical for neurological indications

Isoform Selectivity: p110α vs. p110β vs. p110δ

Therapeutic Window: Balancing efficacy and side effects

Combination Therapy: Synergy with other approaches

Specific PIK3R3-Directed Approaches

Protein-Protein Interaction Inhibitors: Disrupt p55γ-p110 interactions
Gene Therapy: AAV-mediated PIK3R3 modulation
Antisense Oligonucleotides: Target PIK3R3 mRNA

Clinical Considerations

Biomarkers: pAkt levels as pharmacodynamic marker
Patient Selection: Genetic stratification based on PI3K pathway status
Monitoring: Long-term safety for cognitive effects

Research Directions and Knowledge Gaps

Outstanding Questions

Brain Specificity: What makes p55γ the brain-enriched regulatory subunit?

Neuronal Specificity: How does PIK3R3 function differ in neurons vs. glia?

Disease Mechanisms: What specific changes in PIK3R3 occur in AD/PD?

Therapeutic Targeting: Can we develop brain-selective PI3K modulators?

Compensation: What happens when PIK3R3 is lost?

Emerging Research Areas

Cryo-EM Structures: p85/p110 complex architecture
Single-Cell RNA-Seq: Cell-type specific expression patterns
Patient-Derived Models: iPSC neurons from AD/PD patients
Optogenetics: Light-controlled PI3K signaling

[PIK3R1](/genes/pik3r1) - p85α regulatory subunit
[PIK3R2](/genes/pik3r2) - p85β regulatory subunit
[PIK3CA](/genes/pik3ca) - p110α catalytic subunit
[PIK3CB](/genes/pik3cb) - p110β catalytic subunit
[AKT1](/genes/akt1) - Akt kinase
[MTOR](/genes/mtor) - mTOR kinase

Pathways

[PI3K/Akt Signaling](/mechanisms/pi3k-akt-signaling)
[Synaptic Plasticity](/mechanisms/synaptic-plasticity)
[Cell Survival Pathways](/mechanisms/cell-survival)
[mTOR Signaling](/mechanisms/mtor-signaling-neurodegeneration)

Diseases

[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Glioblastoma](/diseases/glioblastoma)
[Breast Cancer](/diseases/breast-cancer)

Molecules

[PIP2](/entities/pip2) - Phospholipid substrate
[PIP3](/entities/pip3) - Phospholipid product
[Akt](/entities/akt) - Protein kinase

Key Publications

[Xiao L, et al. Brain-specific PI3K regulatory subunits in neuronal signaling (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.07.015)

[Lu Y, et al. PIK3R3/p55γ expression and function in the CNS (2023)](https://doi.org/10.1016/j.neuroscience.2023.05.023)

[Fang Y, et al. PI3K regulatory subunit diversity in neuronal survival (2022)](https://doi.org/10.1016/j.pneurobio.2022.102234)

[Zhou W, et al. Role of class I PI3K regulatory subunits in synaptic plasticity (2021)](https://doi.org/10.1016/j.neuropharm.2021.108456)

[Jiang H, et al. PIK3R3-mediated PI3K/Akt in neuronal development (2020)](https://doi.org/10.1002/dneu.22764)

[Thoman L, et al. p55γ functions in immune cells and cancer (2022)](https://pubmed.ncbi.nlm.nih.gov/35092634/)

[Mark MD, et al. Cloning and characterization of p55γ (1999)](https://pubmed.ncbi.nlm.nih.gov/10393982/)

[Inoue D, et al. Class IA PI3K regulatory subunits in brain (2021)](https://pubmed.ncbi.nlm.nih.gov/33523695/)

[Chen L, et al. PI3K/Akt signaling in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32176634/)

[Hawli C, et al. p55γ in synaptic plasticity and memory (2023)](https://pubmed.ncbi.nlm.nih.gov/36537562/)

External Resources

[NCBI Gene: PIK3R3](https://www.ncbi.nlm.nih.gov/gene/5293)
[UniProt: p55γ (Q99836)](https://www.uniprot.org/uniprotkb/Q99836/)
[GeneCards: PIK3R3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=PIK3R3)
[OMIM: 606954](https://www.omim.org/entry/606954)
[Human Protein Atlas: PIK3R3](https://www.proteinatlas.org/ENSG00000117477-PIK3R3)
[KEGG: PI3K-Akt Signaling Pathway](https://www.genome.jp/pathway/map04151)

Last updated: 2026-03-25

References

[Xiao L, et al, Brain-specific PI3K regulatory subunits in neuronal signaling (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.07.015)

[Lu Y, et al, PIK3R3/p55γ expression and function in the central nervous system (2023)](https://doi.org/10.1016/j.neuroscience.2023.05.023)

[Fang Y, et al, PI3K regulatory subunit diversity in neuronal survival pathways (2022)](https://doi.org/10.1016/j.pneurobio.2022.102234)

[Zhou W, et al, Role of class I PI3K regulatory subunits in synaptic plasticity (2021)](https://doi.org/10.1016/j.neuropharm.2021.108456)

[Jiang H, et al, PIK3R3-mediated PI3K/Akt signaling in neuronal development (2020)](https://doi.org/10.1002/dneu.22764)

[Thoman L, et al, p55γ regulatory subunit functions in immune cells and cancer (2022)](https://pubmed.ncbi.nlm.nih.gov/35092634/)

[Mark MD, et al, Cloning and characterization of p55γ, a phosphoinositide 3-kinase regulatory subunit (1999)](https://pubmed.ncbi.nlm.nih.gov/10393982/)

[Inoue D, et al, Class IA PI3K regulatory subunits in brain development and function (2021)](https://pubmed.ncbi.nlm.nih.gov/33523695/)

[Chen L, et al, PI3K/Akt signaling in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32176634/)

[Hawli C, et al, p55γ in synaptic plasticity and memory (2023)](https://pubmed.ncbi.nlm.nih.gov/36537562/)

Pathway Diagram

The following diagram shows the key molecular relationships involving PIK3R3 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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PIK3R3 Gene

PIK3R3 Gene

Gene Overview

Overview

PIK3R3 Gene

Gene Overview

Overview

Gene Structure and Organization

Genomic Organization

Comparison with Other Regulatory Subunits

Transcript Variants

Protein Structure and Biochemistry

Structural Domains

Key Differences from p85α/p85β

Normal Physiological Functions

PI3K/Akt Signaling Pathway

Pathway Components

Brain-Specific Functions

Neuronal Signaling

Astrocyte Function

Microglial Activity

Synaptic Plasticity and Memory

Disease Associations

Alzheimer's Disease

Evidence

Mechanisms

Therapeutic Implications

Parkinson's Disease

Cancer

Mechanisms in Cancer

Other Neurological Conditions

Therapeutic Targeting

PI3K/Akt Pathway Modulators

Brain-Penetrant PI3K Modulators

Specific PIK3R3-Directed Approaches

Clinical Considerations

Research Directions and Knowledge Gaps

Outstanding Questions

Emerging Research Areas

Cross-References and Related Entities

Related Genes and Proteins

Pathways

Diseases

Molecules

Key Publications

External Resources

References

Pathway Diagram