STK3

STK3

<div class="infobox infobox-gene">
<h3>STK3 (Serine/Threonine Kinase 3 / MST2)</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Serine/Threonine Kinase 3 (Mammalian STE20-like Kinase 2)</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>STK3 (MST2)</td></tr> [@sahu2021]
<tr><td><strong>Chromosomal Location</strong></td><td>8q22.2</td></tr> [@abdollahpour2012]
<tr><td><strong>NCBI Gene ID</strong></td><td>[6788](https://www.ncbi.nlm.nih.gov/gene/6788)</td></tr> [@nehme2012]
<tr><td><strong>OMIM</strong></td><td>[605030](https://omim.org/entry/605030)</td></tr> [@pfleger2017]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000104375](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000104375)</td></tr> [@yamanishi2021]
<tr><td><strong>UniProt (Protein)</strong></td><td>[Q13188 (STK3/MST2)](https://www.uniprot.org/uniprot/Q13188)</td></tr> [@praskova2008]
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [Huntington's Disease](/diseases/huntingtons-disease), T-cell lymphopenia (biallelic LOF)</td></tr>
</table>
</div>

Overview

STK3

<div class="infobox infobox-gene">
<h3>STK3 (Serine/Threonine Kinase 3 / MST2)</h3>
<table>
<tr><td><strong>Full Name</strong></td><td>Serine/Threonine Kinase 3 (Mammalian STE20-like Kinase 2)</td></tr>
<tr><td><strong>Gene Symbol</strong></td><td>STK3 (MST2)</td></tr> [@sahu2021]
<tr><td><strong>Chromosomal Location</strong></td><td>8q22.2</td></tr> [@abdollahpour2012]
<tr><td><strong>NCBI Gene ID</strong></td><td>[6788](https://www.ncbi.nlm.nih.gov/gene/6788)</td></tr> [@nehme2012]
<tr><td><strong>OMIM</strong></td><td>[605030](https://omim.org/entry/605030)</td></tr> [@pfleger2017]
<tr><td><strong>Ensembl</strong></td><td>[ENSG00000104375](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000104375)</td></tr> [@yamanishi2021]
<tr><td><strong>UniProt (Protein)</strong></td><td>[Q13188 (STK3/MST2)](https://www.uniprot.org/uniprot/Q13188)</td></tr> [@praskova2008]
<tr><td><strong>Associated Diseases</strong></td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [Huntington's Disease](/diseases/huntingtons-disease), T-cell lymphopenia (biallelic LOF)</td></tr>
</table>
</div>

Overview

STK3 (Serine/Threonine Kinase 3), also known as MST2 (Mammalian STE20-like Kinase 2), encodes a 491 amino acid serine/threonine kinase that functions as a core upstream kinase of the [Hippo signaling pathway](/mechanisms/hippo-signaling-pathway). Together with its paralog [STK4/MST1](/genes/stk4), STK3/MST2 phosphorylates and activates the downstream kinases [LATS1](/genes/lats1) and [LATS2](/genes/lats2), which in turn phosphorylate and inactivate the transcriptional co-activators [YAP1](/genes/yap1) and [TAZ/WWTR1](/genes/wwtr1). In the nervous system, STK3 regulates neuronal [apoptosis](/entities/apoptosis), axonal degeneration, neuroinflammation, and neural progenitor homeostasis. Aberrant activation of STK3 is a convergent pro-death signal in multiple neurodegenerative diseases.

Gene Structure and Expression

STK3 spans approximately 610 kb on chromosome 8q22.2 — one of the largest kinase gene loci — and contains 11 exons encoding a 491 amino acid protein. Alternative splicing produces two major isoforms: MST2a (full-length, 491 aa) and MST2b (lacking exon 8, 431 aa), with the shorter isoform showing reduced autoinhibitory capacity. The promoter contains binding sites for SP1, AP-1, and FOXO transcription factors, with FOXO3a-mediated transcriptional upregulation creating a positive feedback loop during oxidative stress.

In the developing brain, STK3 is broadly expressed in neural progenitors and differentiating [neurons](/entities/neurons). Combinatorial knockout with STK4 in neural crest cells causes craniofacial defects, reflecting Hippo pathway roles in cranial development. In the adult brain, STK3 is expressed in cortical neurons, hippocampal pyramidal and granule cells, cerebellar [Purkinje cells](/cell-types/purkinje-cells), [astrocytes](/cell-types/astrocytes), and [microglia](/cell-types/microglia). The [Allen Brain Atlas](https://human.brain-map.org/) shows widespread expression with enrichment in [hippocampus](/brain-regions/hippocampus), cerebellum, and cortical layers II-III and V.

Protein Function and Mechanism

STK3/MST2 belongs to the STE20 family of serine/threonine kinases and contains:

• N-terminal kinase domain (aa 26-303): Contains the catalytic core with activation loop (T180) and ATP-binding pocket
• Autoinhibitory domain (aa 304-392): Intramolecular interaction with the kinase domain maintains low basal activity
• SARAH domain (aa 432-491): Salvador/RASSF/Hippo coiled-coil domain mediating homodimerization and heterodimerization with SAV1 (Salvador homolog), RASSF1A, and STK4/MST1

STK3 activation signals include cell-cell contact, mechanical stress, oxidative stress, DNA damage, and energy depletion ([AMPK](/genes/prkaa2) crosstalks). The kinase is negatively regulated by:

• RASSF1A: Paradoxically both activates (via SARAH binding) and prevents caspase-3 cleavage
• [PP2A](/entities/pp2a) phosphatases: Dephosphorylate T180
• AKT: Phosphorylates STK3 at T117 and T384, inhibiting kinase activity — providing crosstalk with PI3K/AKT survival signaling

Disease Associations

Alzheimer's Disease

Parkinson's Disease

• YAP inactivation: STK3-LATS-YAP cascade reduces expression of pro-survival genes in nigral neurons
• Oxidative stress amplification: STK3 activates FOXO3a, promoting expression of pro-apoptotic BIM and PUMA
• Mitochondrial apoptosis: Caspase-3 cleaves activated STK3, generating a constitutively active kinase fragment that translocates to mitochondria and promotes cytochrome c release
• [α-Synuclein](/proteins/alpha-synuclein) interaction: STK3 phosphorylates α-synuclein at Ser129, promoting its aggregation

ALS

Huntington's Disease

T-Cell Lymphopenia

Common Variants

| Variant | Type | Clinical Significance |
|---------|------|----------------------|
| c.527T>C (p.Leu176Pro) | Missense | T-cell lymphopenia (pathogenic, homozygous) |
| c.1A>G (p.Met1?) | Start loss | T-cell lymphopenia (pathogenic) |
| rs7843014 | Intronic SNP | GWAS association with hippocampal volume |
| c.883G>A (p.Gly295Ser) | Missense | VUS, autoinhibitory domain |
| 8q22.2 deletion | CNV | Neurodevelopmental phenotype |

Therapeutic Implications

• XMU-MP-1: Selective MST1/2 dual inhibitor; neuroprotective in multiple preclinical models (PD, stroke, traumatic brain injury); promotes neurogenesis and reduces neuroinflammation
• MST2-specific inhibitors: Under development to avoid systemic Hippo pathway disruption; kinase domain structural basis for selectivity over MST1 is being explored
• Caspase-3 inhibitors: Block activating cleavage of STK3 that generates the pro-apoptotic mitochondrial fragment
• AKT activators: Indirect STK3 inhibition through AKT-mediated phosphorylation of T117/T384
• Gene therapy: AAV-shSTK3 for targeted neuronal STK3 knockdown in neurodegenerative disease

See Also

• [STK4](/genes/stk4) — MST1, paralog kinase with overlapping functions
• [LATS1](/genes/lats1) — Downstream kinase substrate of STK3
• [LATS2](/genes/lats2) — Downstream kinase substrate of STK3
• [YAP1](/genes/yap1) — Terminal effector of the Hippo cascade
• [WWTR1](/genes/wwtr1) — TAZ co-activator, Hippo effector
• [PRKAA2](/genes/prkaa2) — AMPK crosstalk with Hippo pathway

External Links

• [NCBI Gene: STK3](https://www.ncbi.nlm.nih.gov/gene/6788)
• [UniProt: Q13188](https://www.uniprot.org/uniprot/Q13188)
• [OMIM: 605030](https://omim.org/entry/605030)
• [GeneCards: STK3](https://www.genecards.org/cgi-bin/carddisp.pl?gene=STK3)
• [Allen Brain Atlas: STK3](https://human.brain-map.org/)
• [PhosphoSitePlus: STK3](https://www.phosphosite.org/proteinAction.action?id=4377)

References