| Full Name | Serine/Threonine Kinase 3 (Mammalian STE20-like Kinase 2) |
| Gene Symbol | STK3 (MST2) |
| Chromosomal Location | 8q22.2 |
| NCBI Gene ID | [6788](https://www.ncbi.nlm.nih.gov/gene/6788) |
| OMIM | [605030](https://omim.org/entry/605030) |
| Ensembl | [ENSG00000104375](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000104375) |
| UniProt (Protein) | [Q13188 (STK3/MST2)](https://www.uniprot.org/uniprot/Q13188) |
| Associated Diseases | [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) |
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. Together with its paralog STK4/MST1, STK3/MST2 phosphorylates and activates the downstream kinases LATS1 and LATS2, which in turn phosphorylate and inactivate the transcriptional co-activators YAP1 and TAZ/WWTR1. In the nervous system, STK3 regulates neuronal apoptosis, axonal degeneration, neuroinflammation, and neural progenitor homeostasis. Aberrant activation of STK3 is a convergent pro-death signal in multiple neurodegenerative diseases.
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. 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, astrocytes, and microglia. The Allen Brain Atlas shows widespread expression with enrichment in hippocampus, cerebellum, and cortical layers II-III and V.
STK3/MST2 belongs to the STE20 family of serine/threonine kinases and contains:
Activation of STK3 involves:
STK3 activation signals include cell-cell contact, mechanical stress, oxidative stress, DNA damage, and energy depletion (AMPK crosstalks). The kinase is negatively regulated by:
STK3/MST2 is activated in AD 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/PS1 transgenic mice, STK3 activation precedes neuronal loss in CA1 and correlates with cognitive decline. STK3 also phosphorylates tau at disease-relevant sites (T231, S262) independently of the canonical Hippo cascade, directly contributing to tau pathology. Genetic reduction of STK3 in APP/PS1 mice reduces tau hyperphosphorylation and amyloid plaque burden.
In PD, STK3 activation contributes to dopaminergic neuron death through multiple mechanisms:
In MPTP-treated mice, pharmacological inhibition of MST1/2 kinases (XMU-MP-1) protects dopaminergic neurons and improves motor behavior.
STK3 activation has been observed in motor neurons of SOD1-G93A mice and in sporadic ALS patient spinal cord. TDP-43 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.
Mutant huntingtin activates the MST1/MST2-LATS-YAP cascade in striatal medium spiny neurons. In HD 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.
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.
| 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 |