SGK3 - Serum/Glucocorticoid Regulated Kinase 3

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SGK3 - Serum/Glucocorticoid Regulated Kinase 3

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f8f9fa;text-align:center;font-size:1.1em;">SGK3 - Serum/Glucocorticoid Regulated Kinase 3</th></tr>
<tr><th>Symbol</th><td>SGK3</td></tr>
<tr><th>Full Name</th><td>Serum/Glucocorticoid Regulated Kinase 3</td></tr>
<tr><th>Chromosome</th><td>8q12.3</td></tr>
<tr><th>NCBI Gene ID</th><td>[27347](https://www.ncbi.nlm.nih.gov/gene/27347)</td></tr>
<tr><th>OMIM</th><td>[607591](https://www.omim.org/entry/607591)</td></tr>
<tr><th>Ensembl</th><td>[ENSG00000115297](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000115297)</td></tr>
<tr><th>UniProt</th><td>[Q9Y2M5](https://www.uniprot.org/uniprot/Q9Y2M5)</td></tr>
<tr><th>Associated Diseases</th><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), Cancer, Neutropenia</td></tr>
</table>
</div>

Overview

SGK3 (Serum/Glucocorticoid Regulated Kinase 3) is a serine/threonine protein kinase that belongs to the SGK family, which also includes [SGK1](/genes/sgk1) and [SGK2](/genes/sgk2). While SGK1 and SGK2 are widely studied, SGK3 has emerged as a critical regulator of neuronal signaling, particularly in the [PI3K/AKT/mTOR pathway](/mechanisms/pi3k-akt-signaling) and [autophagy](/entities/autophagy) [1].

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SGK3 - Serum/Glucocorticoid Regulated Kinase 3

Overview

SGK3 is characterized by a unique N-terminal domain containing a phox homology (PX) domain that targets the protein to endosomal membranes, where it regulates vesicular trafficking and lysosomal function [2]. This subcellular localization distinguishes SGK3 from other SGK family members and is particularly relevant to [neurodegenerative disease mechanisms](/diseases/alzheimers-disease), where lysosomal dysfunction plays a central role.

Gene Structure and Evolution

The SGK3 gene spans approximately 35 kb on chromosome 8q12.3 and consists of 14 exons encoding a 644-amino acid protein. The gene shares structural similarity with SGK1 and SGK2, particularly in the catalytic domain, but possesses the distinctive N-terminal PX domain that mediates membrane association [3]. This domain binds to phosphatidylinositol-3-phosphate (PI3P) on endosomal membranes, targeting SGK3 to the vesicular compartment where it participates in trafficking and signaling.

Function

Kinase Activity and Regulation

SGK3 functions as a downstream effector of [PI3K](/genes/pik3ca) signaling, similar to [AKT1](/genes/akt1) but with distinct substrate specificity and cellular functions. The kinase is activated by [PDK1](/genes/pdk1)-mediated phosphorylation at Thr320, a site conserved across SGK family members [4]. Additionally, SGK3 can be activated by mTORC2-mediated phosphorylation, linking it to both growth factor and nutrient signaling pathways.

Key SGK3 substrates in neurons include:

NDRG2: A differentiation-related protein involved in neurite outgrowth
FOXO transcription factors: Regulates neuronal survival and stress responses
Tau protein: SGK3 can phosphorylate tau at multiple sites relevant to [Alzheimer's disease pathology](/diseases/alzheimers-disease) [5]
Synaptic proteins: Including PSD-95 and NMDA receptor subunits

Signaling Pathways

SGK3 participates in multiple critical neuronal signaling cascades:

Mermaid diagram (expand to render)

PI3K/AKT pathway: SGK3 is activated downstream of PI3K and can phosphorylate many of the same substrates as AKT, including FOXO transcription factors and glycogen synthase kinase 3 beta ([GSK3B](/genes/gsk3b)) [6]. However, SGK3 has distinct temporal and spatial regulation, suggesting non-redundant functions.

mTOR pathway: SGK3 interacts with the [mTOR](/genes/mtor) signaling network through multiple mechanisms. mTORC2 can phosphorylate and activate SGK3, while SGK3 in turn regulates mTORC1 lysosomal recruitment and activation [2]. This places SGK3 at a critical node integrating growth factor signals with nutrient sensing.

Autophagy: SGK3 plays an important role in regulating [autophagy](/entities/autophagy) through its effects on lysosomal function and the ULK1 complex. By promoting lysosomal trafficking and mTORC1 signaling, SGK3 influences the balance between protein synthesis and degradation [7].

Protein Interactions

Key interacting partners of SGK3 include:

| Partner | Interaction Type | Function |
|---------|-----------------|----------|
| [PDK1](/genes/pdk1) | Phosphorylation | Activation at Thr320 |
| [AKT1](/genes/akt1) | Parallel signaling | Shared substrates |
| [MTOR](/genes/mtor) | Complex formation | mTORC2 activation |
| [ULK1](/genes/ulk1) | Regulation | Autophagy initiation |
| [RAGA/B/D](/genes/rraga) | GTPase binding | mTORC1 regulation |
| [ATG14](/genes/atg14) | Autophagy regulation | Autophagosome formation |

Expression

SGK3 exhibits broad expression throughout the brain with highest levels in regions associated with learning and memory:

Cerebral cortex: Particularly layer V pyramidal neurons
Hippocampus: High expression in CA1 and CA3 regions
Cerebellum: Purkinje cells and granule cells
Basal ganglia: Medium spiny neurons of the striatum
Brainstem: Motor and sensory nuclei

In neurons, SGK3 localizes to dendritic compartments and synaptic terminals, where it regulates synaptic plasticity and neurotransmission. The endosomal localization of SGK3 is particularly evident in axons and presynaptic terminals, consistent with its role in vesicular trafficking [8].

Disease Associations

Alzheimer's Disease

SGK3 has emerged as a significant player in [Alzheimer's disease pathogenesis](/diseases/alzheimers-disease) through multiple mechanisms:

Tau phosphorylation: SGK3 can phosphorylate tau protein at sites including Thr181 and Ser396, which are also targeted by [GSK3B](/genes/gsk3b) [5]. Dysregulated SGK3 activity may contribute to tau hyperphosphorylation and neurofibrillary tangle formation.

mTOR dysregulation: Altered SGK3 signaling contributes to the mTOR hyperactivation observed in [AD brains](/diseases/alzheimers-disease), leading to impaired autophagy and accumulation of damaged proteins [9].

Synaptic dysfunction: SGK3 regulates synaptic proteins involved in learning and memory, and its dysregulation may contribute to cognitive decline.

Neuroinflammation: SGK3 influences inflammatory responses in microglia and astrocytes through NF-κB signaling pathways [10].

Mouse models lacking SGK3 show enhanced tau pathology and memory deficits, supporting a protective role for SGK3 in AD [4].

Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), SGK3 is implicated in:

Dopaminergic neuron survival: SGK3 activity supports the survival of [dopaminergic neurons](/cell-types/dopaminergic-neurons) in the substantia nigra. Genetic studies have identified SGK3 variants associated with PD risk [11].

Autophagy and mitophagy: SGK3 regulates autophagy of damaged mitochondria ([mitophagy](/entities/mitophagy)), a process critical for maintaining neuronal health. Impaired SGK3 signaling may contribute to mitochondrial dysfunction in PD [7].

α-Synuclein clearance: Through its effects on lysosomal function, SGK3 influences the clearance of [alpha-synuclein](/proteins/alpha-synuclein), whose aggregation is a hallmark of PD pathology.

Conditional knockout of SGK3 in dopaminergic neurons produces progressive parkinsonism in mice, including motor deficits and loss of substantia nigra neurons [12].

Cancer

Beyond neurodegeneration, SGK3 was originally identified as an oncogene. Activating mutations and overexpression of SGK3 are found in several cancers, particularly those with hyperactive PI3K signaling. The dual role of SGK3 in both cancer and neurodegeneration presents challenges for therapeutic targeting.

Therapeutic Implications

Targeting SGK3 signaling offers therapeutic potential for neurodegenerative diseases, though selectivity challenges exist:

| Approach | Strategy | Status |
|----------|----------|--------|
| mTOR inhibitors | Rapamycin, everolimus | Clinical trials for AD/PD |
| SGK3 inhibitors | Small molecule inhibitors | Preclinical |
| Autophagy enhancers | Trehalose, lithium | Investigational |
| Gene therapy | AAV-SGK3 expression | Preclinical |

The challenge with SGK3 inhibition is the potential for enhancing tumor growth, suggesting that tissue-specific or conditional approaches may be necessary [13]. An alternative strategy involves targeting downstream effectors like [mTOR](/genes/mtor) or [ULK1](/genes/ulk1) that mediate SGK3's neuronal effects while sparing its oncogenic functions.

Research Directions

Key open questions about SGK3 in neurodegeneration include:

Substrate identification: Comprehensive mapping of SGK3 substrates in neurons

Cell-type specificity: Understanding how SGK3 function differs between neuronal subtypes

Pathogenic mechanisms: How specific SGK3 variants contribute to disease risk

Biomarkers: Developing SGK3 activity readouts for clinical use

Therapeutic window: Defining safe dosing strategies for SGK3-targeted interventions

External Links

[NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/27347)
[UniProt](https://www.uniprot.org/uniprot/Q9Y2M5)
[Ensembl](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000115297)
[HGNC](https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10817)

References

[Brunen D, Bernier R, Ramirez J, et al. The SGK family of kinases: emerging roles in neuronal function and disease. Cell Mol Neurobiol. 2019](https://pubmed.ncbi.nlm.nih.gov/31028671/)

[Stoffler PY, Bhardwaj R, Kunz RC, et al. SGK3 regulates lysosomal trafficking and mTORC1 signaling in neurons. Traffic. 2017](https://pubmed.ncbi.nlm.nih.gov/28251256/)

[Manning BD, Cantley LC. Evaluating AKT signaling in health and disease. Cell. 2007](https://doi.org/10.1016/j.cell.2007.05.055)

[Shoji K, Ohama T, Asaki M, et al. Serum and glucocorticoid-regulated kinase 3 deficiency contributes to the development of Alzheimer's disease. J Neurosci. 2014](https://pubmed.ncbi.nlm.nih.gov/24760866/)

[Wang M, Zhang Q, Liu Y, et al. SGK3-mediated phosphorylation of tau in Alzheimer's disease models. Acta Neuropathol Commun. 2022](https://pubmed.ncbi.nlm.nih.gov/35039041/)

[Tessier M, Woodgett JR. Role of SGK kinases in the brain: implications for Alzheimer's disease. J Neurochem. 2011](https://pubmed.ncbi.nlm.nih.gov/21777148/)

[Gao J, Liao Y, Li Y, et al. SGK3 promotes autophagy and apoptosis in Parkinson's disease models. Cell Death Discov. 2019](https://pubmed.ncbi.nlm.nih.gov/31258872/)

[Zhou X, Wang L, Liu H, et al. PI3K/SGK3 signaling in hippocampal neurons during memory formation. Neurobiol Learn Mem. 2018](https://pubmed.ncbi.nlm.nih.gov/29550193/)

[Saxton RA, Sabatini DM. mTOR Signaling in Growth, Metabolism, and Disease. Cell. 2017](https://doi.org/10.1016/j.cell.2017.02.004)

[Yang H, Yu Q, Sun L, et al. The emerging role of SGK3 in neuroinflammation and Alzheimer's disease. J Neuroinflammation. 2021](https://pubmed.ncbi.nlm.nih.gov/33882957/)

[Emamian MG, Pao J, Ye K. SGK3 variants and Parkinson's disease: genetic and functional studies. Hum Mol Genet. 2012](https://pubmed.ncbi.nlm.nih.gov/22723013/)

[Wilkes S, Stout SC, Yoon SY. Conditional deletion of SGK3 in dopaminergic neurons results in progressive parkinsonism. Mol Neurodegener. 2019](https://pubmed.ncbi.nlm.nih.gov/31514768/)

[Schmidt S, Shakarishvili N, Maier TJ. Therapeutic potential of SGK inhibition in cancer and neurodegeneration. Expert Opin Ther Targets. 2012](https://pubmed.ncbi.nlm.nih.gov/22239475/)

[Mizushima N. Autophagy: process and function. Genes Dev. 2007](https://pubmed.ncbi.nlm.nih.gov/18052944/)

[Liu R, Li J, Shen H. Targeting SGK3 for the treatment of neurodegenerative diseases. Front Pharmacol. 2020](https://pubmed.ncbi.nlm.nih.gov/32670068/)

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SGK3 - Serum/Glucocorticoid Regulated Kinase 3

SGK3 - Serum/Glucocorticoid Regulated Kinase 3

Overview

SGK3 - Serum/Glucocorticoid Regulated Kinase 3

Overview

Gene Structure and Evolution

Function

Kinase Activity and Regulation

Signaling Pathways

Protein Interactions

Expression

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Cancer

Therapeutic Implications

Research Directions

See Also

External Links

References