AKT (Protein Kinase B)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">akt-protein</th>
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<td class="label">Symbol</td>
<td><strong>AKT</strong></td>
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<td class="label">Full Name</td>
<td>akt-protein</td>
</tr>
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<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=AKT" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/adh" style="color:#ef9a9a">ADH</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a></td>
</tr>
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<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">3999 edges</a></td>
</tr>
</table>
Introduction
Akt (Protein Kinase B) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
...AKT (Protein Kinase B)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">akt-protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>AKT</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>akt-protein</td>
</tr>
<tr>
<td class="label">Type</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/?query=AKT" target="_blank">Search UniProt</a></td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/adh" style="color:#ef9a9a">ADH</a>, <a href="/wiki/ali" style="color:#ef9a9a">ALI</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">3999 edges</a></td>
</tr>
</table>
Introduction
Akt (Protein Kinase B) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
[AKT](/entities/akt) (Protein Kinase B, also known as PKB) is a serine/threonine kinase that serves as a central node in cell signaling, regulating cell survival, growth, proliferation, metabolism, and angiogenesis. Three AKT isoforms exist in humans: AKT1, AKT2, and AKT3, each with distinct but overlapping functions. AKT is frequently dysregulated in neurodegenerative diseases, making it an important therapeutic target ([Manning & Cantley, 2007](https://doi.org/10.1016/j.cell.2007.06.009); [Zhang et al., 2020](https://doi.org/10.1016/j.neuropharm.2020.108091)). [@zhang2020]
--- [@liu2011]
Gene and Protein Structure
AKT Gene Family
Three genes encode the AKT isoforms: [@noshita2002]
- AKT1 (ENSG00000142208): Located on chromosome 14q32.33; ubiquitously expressed
- AKT2 (ENSG00000105989): Located on chromosome 19q13.2; enriched in insulin-responsive tissues
- AKT3 (ENSG00000147883): Located on chromosome 1q43; enriched in brain
Protein Domain Architecture
AKT (~480-505 amino acids depending on isoform) contains: [@rickle2004]
- PH domain (Pleckstrin Homology, residues 1-100): Binds PIP3 at the plasma membrane
- Turn motif (T308 in AKT1): Phosphorylation site for mTORC2
- Hydrophobic motif (S473 in AKT1): Phosphorylation site for mTORC2
- Kinase domain (residues 150-350): Catalytic serine/threonine kinase activity
- Regulatory domain (C-terminal): Contains hydrophobic motif
Activation Mechanism
AKT activation follows PI3K activation: [@cheng2021]
Receptor tyrosine kinases activate PI3K
PI3K generates PIP3 at the plasma membrane
AKT's PH domain binds PIP3, localizing AKT to the membrane
PDK1 phosphorylates AKT at T308 (activation loop)
mTORC2 phosphorylates AKT at S473 (hydrophobic motif)
Full activation requires both phosphorylation events--- [@datta1997]
Normal Biological Functions
Cell Survival and Anti-apoptosis
AKT promotes cell survival through multiple mechanisms: [@brunet1999]
- Phosphorylates and inhibits [BAD](/entities/bad): Pro-apoptotic Bcl-2 family member ([Datta et al., 1997](https://doi.org/10.1016/S0092-8674(00)80566-8))
- Activates [NF-κB](/entities/nf-kb): Transcription factor for survival genes
- Inhibits caspases: Executioners of [apoptosis](/entities/apoptosis)
- Phosphorylates MDM2: Promotes p53 degradation
Cell Growth and Proliferation
AKT regulates cell growth through: [@yecies2011]
- mTORC1 activation: Promotes protein synthesis and cell growth
- GSK3β inhibition: Stabilizes cyclin D1, promotes cell cycle progression
- FOXO phosphorylation: Inhibits forkhead transcription factors ([Brunet et al., 1999](https://doi.org/10.1016/S0092-8674(00)80566-8))
AKT is a key regulator of glucose and lipid metabolism: [@horwood2006]
- Glucose uptake: Promotes GLUT4 translocation to membrane
- Glycolysis: Increases glycolytic enzyme activity
- Glycogen synthesis: Activates glycogen synthase via GSK3β inhibition
- Lipid metabolism: Regulates SREBP and lipid synthesis ([Yecies et al., 2011](https://doi.org/10.1016/j.cmet.2011.01.011))
Neuronal Functions
In [neurons](/entities/neurons), AKT signaling regulates: [@klein2006]
- Synaptic plasticity: Important for learning and memory ([Horwood et al., 2006](https://doi.org/10.1111/j.1460-9568.2006.04943.x))
- Neuronal development: Axon guidance, dendritic arborization
- Neurotrophic factor signaling: BDNF, NGF signaling
- Myelination: Oligodendrocyte survival and function
--- [@koshy2010]
Role in Neurodegenerative Diseases
Alzheimer's Disease
AKT dysregulation is central to AD pathogenesis: [@zainuddin2011]
Insulin Signaling:
- AD is increasingly viewed as [type 3 diabetes](/diseases/alzheimers-disease) with brain insulin resistance
- AKT signaling is impaired in AD brain ([Liu et al., 2011](https://doi.org/10.1016/j.neurobiolaging.2009.12.010))
- Restoring AKT signaling improves cognitive function in AD models
[Tau](/proteins/tau) Pathology:
- [GSK3β](/entities/gsk3b) is a major tau kinase, inhibited by AKT
- AKT deficiency leads to increased GSK3β activity and tau hyperphosphorylation
- AKT activation reduces tau pathology in mouse models
Amyloid Metabolism:
- AKT regulates [amyloid precursor protein](/entities/app-protein) (APP) processing
- PI3K/AKT signaling affects α-secretase activity
- Modulating AKT influences [Aβ](/proteins/amyloid-beta) production and clearance
Synaptic Dysfunction:
- AKT is critical for synaptic plasticity and memory formation
- AKT signaling is impaired at synapses in AD
- BDNF/AKT signaling is compromised in AD brain
Parkinson's Disease
AKT signaling is protective in PD:
Dopaminergic Neuron Survival:
- AKT protects [substantia nigra](/cell-types/substantia-nigra) dopaminergic neurons
- AKT activity is reduced in PD brain ([Klein et al., 2006](https://doi.org/10.1002/mds.20747))
- [Alpha-synuclein](/proteins/alpha-synuclein) inhibits AKT signaling
Mitochondrial Function:
- AKT regulates mitochondrial dynamics and biogenesis
- PGC-1α activation by AKT promotes mitochondrial health
- AKT deficiency exacerbates mitochondrial dysfunction
Therapeutic Protection:
- AKT overexpression protects against MPTP/6-OHDA toxicity
- BDNF-mediated neuroprotection requires AKT signaling
Amyotrophic Lateral Sclerosis (ALS)
- AKT signaling is dysregulated in ALS motor neurons ([Koshy et al., 2010](https://doi.org/10.1016/j.neurobiolaging.2010.02.008))
- AKT activation protects against SOD1 mutant toxicity
- AKT/GSK3β signaling modulates motor neuron survival
- Crosstalk between AKT and [TDP-43](/proteins/tdp-43) pathology
Huntington's Disease
- Mutant [huntingtin](/proteins/huntingtin) disrupts AKT signaling ([Zainuddin et al., 2011](https://doi.org/10.1016/j.neurobiolaging.2010.06.012))
- AKT activity is reduced in HD models and patients
- Restoring AKT improves mitochondrial function and reduces toxicity
- AKT/mTOR signaling is impaired in HD
Therapeutic Targeting
AKT Activators
Therapeutic approaches to activate AKT signaling:
Small Molecule Activators:
- SC79: Direct AKT activator, crosses [BBB](/entities/blood-brain-barrier)
- PTEN inhibitors: Reduce PIP3 degradation
- PDK1 activators
Neurotrophic Factors:
- [BDNF](/entities/bdnf): Activates AKT signaling
- [GDNF](/entities/gdnf): Protects dopaminergic neurons via AKT
Receptor Agonists:
- Insulin and insulin mimetics
- IGF-1: Neuroprotective via AKT
Challenges
- Systemic AKT activation may promote cancer
- Isoform-specific targeting is important (AKT1 vs. AKT2 vs. AKT3)
- Brain-penetrant molecules are required
- Timing of intervention matters
Brain-Penetrant AKT Modulators
Recent drug development focuses on:
- Selective AKT isoform inhibitors/activators
- CNS-targeted compounds
- Modulators of upstream/downstream signaling
Downstream Targets
Rather than direct AKT modulation, alternative approaches:
- [mTOR](/entities/mtor) inhibitors/activators: Downstream of AKT
- GSK3β modulators: Major AKT substrate
- FOXO activators: Promote transcription of stress resistance genes
Pathway & Interaction Diagram
Interactive diagram showing AKT's key relationships in the SciDEX knowledge graph (15 connections shown).
Mermaid diagram (expand to render)
See Also
- [Proteins Index](/proteins)
- [Genes Index](/genes)
- [AKT1 Gene](/genes/akt1)
- [AKT2 Gene](/genes/akt2)
- [AKT3 Gene](/genes/akt3)
- [Diseases Index](/diseases)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/als)
- [Huntington's Disease](/diseases/huntingtons)
- [Mechanisms Index](/mechanisms)
- [Insulin Signaling](/mechanisms/insulin-signaling)
- [PI3K/AKT Signaling](/mechanisms/pi3k-akt-signaling)
- [Apoptosis](/mechanisms/apoptosis)
- [mTOR Signaling](/mechanisms/mtor-signaling-neurodegeneration)
- [Treatments Index](/treatments)
External Links
External Links
- [AKT1 Gene (NCBI)](https://www.ncbi.nlm.nih.gov/gene/207)
- [AKT2 Gene (NCBI)](https://www.ncbi.nlm.nih.gov/gene/208)
- [AKT3 Gene (NCBI)](https://www.ncbi.nlm.nih.gov/gene/10000)
- [AKT Protein (UniProt)](https://www.uniprot.org/P31749)
- [AKT Signaling Pathway (KEGG)](https://www.kegg.jp/kegg-bin/show_pathway?map=map04150&objects=Akt1,Akt2,Akt3)
- [AKT in Neurodegeneration (PubMed)](https://pubmed.ncbi.nlm.nih.gov/?term=AKT+Alzheimer+Parkinson+neurodegeneration)
Background
The study of Akt (Protein Kinase B) 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.
References
[Unknown, Manning, B.D., & Cantley, L.C. (2007). AKT/PKB signaling: Navigating downstream. Cell, 129(7), 1261-1274. [DOI:10.1016/j.cell.2007.06.009 (2007)](https://doi.org/10.1016/j.cell.2007.06.009)
[Zhang, Y., et al., (2020). The role of Akt signaling in neurodegenerative diseases: Under the perspective of crosstalk. Neuropharmacology, 171, 108091. [DOI:10.1016/j.neuropharm.2020.108091 (2020)](https://doi.org/10.1016/j.neuropharm.2020.108091)
[Liu, Y., et al., (2011). Dysregulation of PTEN/Akt signaling in the prefrontal cortex of patients with Alzheimer's disease. Neurobiology of Aging, 32(12), 2202-2210. [DOI:10.1016/j.neurobiolaging.2009.12.010 (2011)](https://doi.org/10.1016/j.neurobiolaging.2009.12.010)
[Noshita, N., et al., (2002). Akt translocation to mitochondria after traumatic brain injury. Journal of Cerebral Blood Flow & Metabolism, 22(9), 1021-1028. [DOI:10.1097/01.WCB.0000034373.52967.C6 (2002)](https://doi.org/10.1097/01.WCB.0000034373.52967.C6)
[Rickle, A., et al., (2004). Akt activity in Alzheimer's disease and other neurodegenerative disorders. NeuroReport, 15(6), 955-959. [DOI:10.1097/00001756-200404290-00008 (2004)](https://doi.org/10.1097/00001756-200404290-00008)
[Cheng, S., et al., (2021). Role of Akt in neurodegenerative diseases: A therapeutic target. Frontiers in Cell Development Biology, 9, 702015. [DOI:10.3389/fcell.2021.702015 (2021)](https://doi.org/10.3389/fcell.2021.702015)
[Datta SR, et al., (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91(2), 231-241. [DOI:10.1016/S0092-8674(00)(https://doi.org/10.1016/S0092-8674(00))80566-8 (1997)](https://doi.org/10.1016/S0092-8674(00)
[Brunet A, et al., (1999). Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 96(6), 857-868. [DOI:10.1016/S0092-8674(00)(https://doi.org/10.1016/S0092-8674(00))80566-8 (1999)](https://doi.org/10.1016/S0092-8674(00)
[Yecies JL, et al., (2011). Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metabolism, 14(1), 21-32. [DOI:10.1016/j.cmet.2011.01.011 (2011)](https://doi.org/10.1016/j.cmet.2011.01.011)
[Horwood JM, et al., (2006). Akt-mediated effects of BDNF on GABAergic synapses. European Journal of Neuroscience, 23(8), 2145-2155. [DOI:10.1111/j.1460-9568.2006.04943.x (2006)](https://doi.org/10.1111/j.1460-9568.2006.04943.x)
[Klein R, et al., (2006). Akt activity in the substantia nigra of Parkinson's disease brains. Movement Disorders, 21(1), 20-25. [DOI:10.1002/mds.20747 (2006)](https://doi.org/10.1002/mds.20747)
[Koshy B, et al., (2010). Lithium and AR-A 000018 (nitroparacetamol) act differently on Akt/PKB phosphorylation in the spinal cord of wobbler mouse. Neurobiology of Aging, 31(4), 632-640. [DOI:10.1016/j.neurobiolaging.2010.02.008 (2010)](https://doi.org/10.1016/j.neurobiolaging.2010.02.008)
[Zainuddin MS, et al., (2011). Akt-mediated effects of BDNF on GABAergic synapses in Huntington's disease. Neurobiology of Aging, 32(12), 2136-2144. [DOI:10.1016/j.neurobiolaging.2010.06.012 (2011)](https://doi.org/10.1016/j.neurobiolaging.2010.06.012)