SGK3 - Serum/Glucocorticoid Regulated Kinase 3

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].

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].

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:

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

Disease Associations

Alzheimer's Disease

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

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:

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:

See Also

• [PI3K/AKT Signaling](/mechanisms/pi3k-akt-signaling)
• [mTOR Pathway](/mechanisms/mtor-neurodegeneration)
• [Autophagy in Neurodegeneration](/mechanisms/autophagy)
• [Lysosomal Dysfunction](/mechanisms/lysosomal-dysfunction)
• [Tau Phosphorylation](/mechanisms/tau-phosphorylation)
• [Alpha-Synuclein Pathogenesis](/mechanisms/alpha-synuclein-pathogenesis)

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