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
Activation of STK3 involves:
Dimerization-induced trans-autophosphorylation: STK3 homodimers or STK3-STK4 heterodimers trans-phosphorylate the activation loop (T180), generating full kinase activity
SAV1 scaffold binding: SAV1 binds the SARAH domain and recruits LATS1/2 for efficient phosphorylation
MOB1 phosphorylation: STK3 phosphorylates MOB1 at T12/T35, enabling MOB1 to bind and co-activate LATS1/2
LATS1/2 phosphorylation: STK3 directly phosphorylates LATS1 (T1079) and LATS2 (S872) at the hydrophobic motif
Downstream cascade: Activated LATS1/2 phosphorylate YAP/TAZ, sequestering them in the cytoplasmSTK3 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
STK3/MST2 is activated in [AD](/diseases/alzheimers-disease) brain, with elevated phospho-T180 levels detected in hippocampal and cortical lysates from AD patients compared to age-matched controls. Amyloid-β oligomers activate STK3 through oxidative stress-dependent mechanisms, triggering the LATS1/2-YAP cascade and promoting neuronal apoptosis. In [APP](/entities/app-protein)/PS1 transgenic mice, STK3 activation precedes neuronal loss in CA1 and correlates with cognitive decline. STK3 also phosphorylates [tau](/proteins/tau) at disease-relevant sites (T231, S262) independently of the canonical Hippo cascade, directly contributing to [tau pathology](/mechanisms/tau-pathology). Genetic reduction of STK3 in APP/PS1 mice reduces tau hyperphosphorylation and amyloid plaque burden.
Parkinson's Disease
In [PD](/diseases/parkinsons-disease), STK3 activation contributes to dopaminergic neuron death through multiple mechanisms:
- 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
In MPTP-treated mice, pharmacological inhibition of MST1/2 kinases (XMU-MP-1) protects dopaminergic neurons and improves motor behavior.
ALS
STK3 activation has been observed in motor neurons of SOD1-G93A mice and in sporadic [ALS](/diseases/amyotrophic-lateral-sclerosis) patient spinal cord. [TDP-43](/genes/tardbp) aggregation activates STK3 through disruption of nuclear MST2-PP2A complexes, shifting the phosphorylation balance toward active STK3. STK3-mediated YAP inactivation impairs motor neuron survival, and genetic STK3 reduction extends survival in SOD1-G93A mice.
Huntington's Disease
Mutant [huntingtin](/proteins/huntingtin) activates the MST1/MST2-LATS-YAP cascade in striatal medium spiny neurons. In [HD](/diseases/huntingtons) mouse models, STK3 activation correlates with striatal atrophy and motor symptom onset. MST1/2 inhibition restores YAP nuclear localization and TEAD-dependent survival gene expression.
T-Cell Lymphopenia
Biallelic loss-of-function mutations in STK3 (MST2) cause autosomal recessive T-cell lymphopenia with recurrent infections (OMIM 614868). This immunodeficiency phenotype reflects the essential role of Hippo signaling in T-cell homeostasis and apoptosis regulation.
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
[Meng Z et al., Mechanisms of Hippo pathway regulation (2016) (2016)](https://doi.org/10.1101/gad.274027.115)
[Lee JK et al., MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS (2013) (2013)](https://doi.org/10.1073/pnas.1300894110)
[Yuan F et al., MST1 promotes apoptosis through regulating Sirt1-dependent p53 deacetylation (2011) (2011)](https://doi.org/10.1074/jbc.M111.246280)
[Fan F et al., Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration (2016) (2016)](https://doi.org/10.1126/scitranslmed.aaf2304)
[Unknown, Sahu MR & Bhatt R, Hippo signaling in neurodegeneration (2021) (2021)](https://doi.org/10.1016/j.tins.2021.05.002)
[Abdollahpour H et al., The phenotype of human STK4 deficiency (2012) (2012)](https://doi.org/10.1182/blood-2011-09-378158)
[Nehme NT et al., MST1 mutations in autosomal recessive primary immunodeficiency (2012) (2012)](https://doi.org/10.1084/jem.20120583)
[Unknown, Pfleger CM, The Hippo pathway: DRASSFically different signal integration in brain development (2017) (2017)](https://doi.org/10.4161/fly.22016)
[Yamanishi E et al., Lats1/2 control cortical and hippocampal development through YAP and TAZ (2021) (2021)](https://doi.org/10.1523/JNEUROSCI.2619-20.2021)
[Praskova M et al., MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation (2008) (2008)](https://doi.org/10.1016/j.cub.2008.02.006)