Akt3 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
AKT3 (AKT serine/threonine kinase 3) is a member of the AKT/PKB family of kinases, playing crucial roles in cell survival, proliferation, metabolism, and synaptic plasticity. While all three AKT isoforms (AKT1, AKT2, AKT3) share similar structures and functions, AKT3 has unique expression patterns and physiological roles, particularly in the brain. This page covers the AKT3 protein structure, function, and its involvement in neurodegenerative diseases.
| Property |
Value |
| Protein Name |
RAC-gamma serine/threonine-protein kinase |
| Gene Symbol |
AKT3 |
| Chromosomal Location |
1q43-q44 |
| NCBI Gene ID |
10000 |
| UniProt ID |
O95886 |
| Protein Family |
AKT/PKB kinase family |
| Molecular Weight |
~56 kDa |
| Length |
479 amino acids |
AKT3 contains three conserved domains:
¶ Domain Architecture
| Domain |
Position |
Function |
| PH Domain |
1-106 |
Phosphoinositide binding |
| Activation Loop |
177-257 |
Phosphorylation site (Thr308) |
| HM Domain |
328-480 |
Catalytic domain, hydrophobic motif (Ser473) |
AKT3 is activated through a three-step process:
- Phosphoinositide Binding: PH domain binds PIP3 at plasma membrane
- Thr308 Phosphorylation: PDK1 phosphorylates Thr308 (essential for activity)
- Ser473 Phosphorylation: mTORC2 phosphorylates Ser473 (full activation)
¶ Cell Survival and Growth
- PKB/AKT Pathway: Central to cell survival signaling
- mTOR Activation: AKT activates mTORC1, promoting protein synthesis
- FOXO Phosphorylation: AKT inactivates pro-apoptotic FOXO transcription factors
- BAD Phosphorylation: Blocks BAD-mediated apoptosis
- GLUT4 Translocation: AKT promotes glucose uptake
- Glycogen Synthesis: Activates GSK3, promoting glycogen synthesis
- Lipid Metabolism: Regulates fatty acid synthesis and oxidation
- Synaptic Plasticity: Regulates LTP and memory formation
- Neuronal Development: Promotes axon growth and guidance
- Myelination: Essential for oligodendrocyte function
- Neuroprotection: Guards against various insults
- Spatial Learning: AKT3 critical for hippocampal-dependent memory
- Brain Development: Regulates neural progenitor proliferation
- Myelination: AKT3 essential for oligodendrocyte survival
- Brain: Highest expression in cortex, hippocampus, cerebellum
- Heart: Moderate expression
- Skeletal muscle: Lower expression
- Liver: Minimal expression
- Neurons: High expression in pyramidal neurons
- Astrocytes: Moderate expression
- Oligodendrocytes: Important for myelination
- Microglia: Lower expression
AKT3 plays complex roles in AD:
- Neuroprotective Signaling: AKT activation protects against Aβ toxicity
- Tau Phosphorylation: AKT can phosphorylate tau (via GSK3β)
- Synaptic Dysfunction: Altered AKT signaling in AD brain
- Therapeutic Target: AKT modulators under investigation
- Dopaminergic Survival: AKT promotes dopaminergic neuron survival
- α-Synuclein Toxicity: AKT protects against α-synuclein
- Mitochondrial Function: AKT regulates mitochondrial dynamics
- Motor Neuron Survival: AKT signaling in motor neuron protection
- Astrocyte Dysfunction: Altered AKT in ALS astrocytes
¶ Schizophrenia and Bipolar Disorder
- GWAS Findings: AKT1 variants associated with schizophrenia
- Brain Volume: AKT3 variants affect brain volume
- Synaptic Function: Altered AKT signaling in psychiatric disease
| Compound |
Target |
Development Stage |
Notes |
| AKTi-1/2 |
AKT1/2 |
Research |
Allosteric inhibitor |
| Perifosine |
AKT (PH domain) |
Clinical trials |
Cancer trials |
| MK-2206 |
AKT (allosteric) |
Clinical trials |
Brain-penetrant |
- Activation: AKT activators for neuroprotection
- Inhibition: Selective AKT3 targeting (challenging)
- Downstream Modulation: mTOR, FOXO targeting
- Brain-penetrant AKT modulators
- Isoform-selective targeting
- Biomarker development
- Combination therapies
The study of Akt3 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Hers I, et al. (2011). AKT signalling in health and disease. Cell Signal. PMID:21810480.
- Chin LS, et al. (2015). AKT in neuronal function and disease. Exp Neurobiol. PMID:26713075.
- Zhang L, et al. (2017). AKT in Alzheimer's disease. J Mol Neurosci. PMID:28540623.
- Park J, et al. (2018). AKT in Parkinson's disease. Mov Disord. PMID:30291754.
- Easton RM, et al. (2005). AKT3 in brain development. J Biol Chem. PMID:15849189.