AKT3 (AKT Serine/Threonine Kinase 3)
<div class="infobox infobox-gene">
| Property | Value | [@lindhurst2011]
|----------|-------| [@kwon2001]
| Gene Symbol | AKT3 |
| Full Name | AKT Serine/Threonine Kinase 3 |
| Chromosomal Location | 1q43-q44 |
| NCBI Gene ID | 10000 |
| OMIM ID | 611495 |
| Ensembl ID | ENSG00000163660 |
| UniProt ID | O95886 |
| Encoded Protein | RAC-gamma serine/threonine-protein kinase |
| Associated Diseases | Megalencephaly-capillary malformation syndrome, Proteus syndrome, HIV-associated neurocognitive disorder |
</div>
Overview
Mermaid diagram (expand to render)
AKT3 is a human gene whose product aKT3** encodes the RAC-gamma serine/threonine-protein kinase, one of three AKT isoforms (AKT1, AKT2, AKT3). AKT3 is the predominant AKT isoform in the brain and plays crucial roles in neuronal survival, growth, and function. Variants in AKT3 have been implicated in Megalencephaly-Capillary Malformation Syndrome (MCAP), Proteus Syndrome, Neurodegenerative Disease Associations. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
Function
AKT3 encodes the RAC-gamma serine/threonine-protein kinase, one of three AKT isoforms (AKT1, AKT2, AKT3). AKT3 is the predominant AKT isoform in the brain and plays crucial roles in neuronal survival, growth, and function.
Key normal physiological functions include:
- Neuronal survival - Phosphorylates pro-apoptotic proteins (BAD, FOXO)
- Brain development - Regulates brain size through [mTOR](/mechanisms/mtor-signaling-pathway) signaling
- Myelination - Essential for oligodendrocyte differentiation and myelination
- Synaptic plasticity - Modulates AMPA receptor trafficking
- Metabolism - Regulates glucose uptake in [neurons](/entities/neurons)
- Angiogenesis - Controls [blood-brain barrier](/entities/blood-brain-barrier) formation
- Cell growth - mTORC1 activation drives protein synthesis
Disease Associations
AKT3 mutations cause overgrowth syndrome:
- Inheritance - Autosomal dominant (de novo)
- Clinical features - Progressive megalencephaly, cutaneous capillary malformations
- Neurological - Developmental delay, seizures, Chiari malformation
- Other - Polydactyly, connective tissue abnormalities
Pathogenic mechanism: Constitutive activation (gain-of-function) causes increased AKT signaling
Proteus Syndrome
Overgrowth syndrome caused by AKT1 activation:
- Somatic mosaicism - Postzygotic mutation
- Asymmetric overgrowth - Body parts disproportionately enlarged
- Cerebellar cysts - Characteristic finding
- Connective tissue nevi - Epidermal nevi
Neurodegenerative Disease Associations
- Alzheimer's disease - AKT signaling dysregulated; related to insulin signaling
- Parkinson's disease - AKT-mediated neuroprotection affected
- HIV-associated neurocognitive disorder - AKT pathway altered
- Brain ischemia - AKT3 important for neuronal survival after injury
Expression
AKT3 is highly brain-specific:
- Brain - Highest expression in cerebral [cortex](/brain-regions/cortex), cerebellum
- Heart - Lower expression
- Other tissues - Minimal expression
Cellular localization:
- Neurons (cytoplasm and dendrites)
- Glial cells (oligodendrocytes, astrocytes)
- Vascular endothelium
AKT Signaling in Neurodegeneration
Alzheimer's Disease
AKT3 plays a complex role in Alzheimer's disease pathogenesis:
Insulin Signaling Connection: AKT is a central node in insulin/IGF-1 signaling, which is impaired in AD brains. Insulin resistance contributes to synaptic dysfunction and cognitive decline.
Tau Phosphorylation: AKT phosphorylates GSK-3β at Ser9, inhibiting its activity. Since GSK-3β is a major tau kinase, AKT dysregulation affects tau pathology.
Amyloid Metabolism: AKT signaling influences amyloid precursor protein (APP) processing through BACE1 regulation. PI3K/AKT pathway alterations affect Aβ production.
Synaptic Plasticity: AKT3 modulates mTORC1 signaling, which is crucial for synaptic plasticity and memory. mTOR dysregulation is implicated in AD cognitive deficits.
Neuronal Survival: AKT3 phosphorylates and inhibits pro-apoptotic proteins like BAD and FOXO transcription factors. Neurotrophic factor signaling through AKT promotes neuron survival.
Parkinson's Disease
Neuroprotection: AKT3 mediates neurotrophic factor signaling (BDNF, GDNF) that protects dopaminergic neurons. Parkin and PINK1 mutations affect AKT signaling.
Mitochondrial Function: AKT regulates mitochondrial dynamics, biogenesis, and quality control. Mitochondrial dysfunction is central to PD pathogenesis.
Alpha-Synuclein: AKT can phosphorylate alpha-synuclein at Ser129, potentially affecting its aggregation. The PI3K/AKT pathway is implicated in synucleinopathy.
Autophagy: AKT signaling negatively regulates autophagy through mTORC1. Impaired autophagy contributes to protein aggregate accumulation in PD.
Dopaminergic Neuron Survival: AKT3 is highly expressed in substantia nigra dopaminergic neurons. Its neuroprotective signaling is critical for these vulnerable neurons.
Amyotrophic Lateral Sclerosis (ALS)
- AKT signaling is altered in ALS motor neurons
- Mutations in ALS genes (FUS, TDP-43) affect AKT pathway
- Motor neuron survival depends on AKT-mediated neurotrophic support
Signaling Pathways
PI3K/AKT/mTOR Pathway
Growth Factors → PI3K → PIP3 → PDK1 → AKT → mTORC1 → Protein Synthesis
↓
Cell Survival
(BAD, FOXO)
AKT3 integrates multiple signals:
- Upstream: PI3K, PDK1, PTEN (negative regulator)
- Downstream: mTORC1, GSK-3β, FOXO, BAD, TSC2
Cross-talk with Neurodegeneration Pathways
Notch Signaling: AKT intersects with Notch in neural progenitor cells
Wnt Signaling: AKT can modulate β-catenin degradation
NF-κB Pathway: AKT activates IKK, affecting inflammatory responses
Therapeutic Implications
Targeting AKT in Neurodegeneration
AKT Activators: Growth factors (BDNF, IGF-1) that activate AKT are being explored
AKT Inhibitors: Overactivation may be problematic in some contexts
Challenges
- Brain delivery of therapeutic agents
- isoform-specific targeting (AKT1 vs AKT3)
- Balancing survival signaling with cell cycle re-entry risks
Interaction Network
AKT3 interacts with:
- Kinases: PDK1, SGK1, PKC
- Phosphatases: PTEN, PP2A
- Adaptors: GRB2, IRS1
- Effectors: mTOR, GSK-3β, FOXO
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [Ensembl: ENSG00000163660](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000163660)
- [NCBI Gene: AKT3](https://www.ncbi.nlm.nih.gov/gene/?term=AKT3)
- [GeneCards: AKT3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=AKT3)
- [OMIM: AKT3](https://omim.org/search?search=AKT3)
- [Allen Brain Atlas: AKT3](https://human.brain-map.org/microarray/search/show?search_term=AKT3)
References
[Riviere et al., AKT3 mutations cause MCAP (2012) (2012)](https://doi.org/10.1038/nature11030)
[Lindhurst et al., AKT1 activation in Proteus syndrome (2011) (2011)](https://doi.org/10.1056/NEJMoa1103017)
[Kwon et al., AKT in neuronal survival (2001) (2001)](https://doi.org/10.1016/S0896-6273(01)Pathway Diagram
The following diagram shows the key molecular relationships involving AKT3 Gene discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)