MST4 Gene

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MST4 Gene

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MST4 (Serine/Threonine-Protein Kinase MST4)

| Property | Value | [@morrow2015] |
|----------|-------| [@lin2010] |
| Gene Symbol | MST4 |
| Full Name | Serine/Threonine-Protein Kinase MST4 |
| Chromosomal Location | Xq26.2 |
| NCBI Gene ID | 100533180 |
| OMIM ID | 300254 |
| Ensembl ID | ENSG00000101126 |
| UniProt ID | Q9P289 |
| Encoded Protein | Serine/threonine-protein kinase MST4 |
| Associated Diseases | Alzheimer's Disease (risk factor), Autoinflammatory Disease, Colorectal Cancer |

</div>

Overview

MST4 (Serine/Threonine-Protein Kinase MST4) is a human gene located on chromosome Xq26.2 that encodes a member of the sterile 20-like serine/threonine protein kinase family, which is part of the larger [Hippo signaling pathway](/mechanisms/hippo-pathway). Also known as MST4 (Mammalian Sterile 20-like Kinase 4) or STK26, this protein plays critical roles in cell proliferation, survival, migration, and tissue homeostasis. Originally characterized for its oncogenic potential in cancer biology, emerging research has revealed important functions in neuronal systems and [neurodegenerative disease](/diseases/alzheimers-disease) pathogenesis.

...

MST4 (Serine/Threonine-Protein Kinase MST4)

| Property | Value | [@morrow2015] |
|----------|-------| [@lin2010] |
| Gene Symbol | MST4 |
| Full Name | Serine/Threonine-Protein Kinase MST4 |
| Chromosomal Location | Xq26.2 |
| NCBI Gene ID | 100533180 |
| OMIM ID | 300254 |
| Ensembl ID | ENSG00000101126 |
| UniProt ID | Q9P289 |
| Encoded Protein | Serine/threonine-protein kinase MST4 |
| Associated Diseases | Alzheimer's Disease (risk factor), Autoinflammatory Disease, Colorectal Cancer |

</div>

Overview

MST4 (Serine/Threonine-Protein Kinase MST4) is a human gene located on chromosome Xq26.2 that encodes a member of the sterile 20-like serine/threonine protein kinase family, which is part of the larger [Hippo signaling pathway](/mechanisms/hippo-pathway). Also known as MST4 (Mammalian Sterile 20-like Kinase 4) or STK26, this protein plays critical roles in cell proliferation, survival, migration, and tissue homeostasis. Originally characterized for its oncogenic potential in cancer biology, emerging research has revealed important functions in neuronal systems and [neurodegenerative disease](/diseases/alzheimers-disease) pathogenesis.

The protein is a central component of the STRIPAK complex (Striatin-interacting phosphatase and kinase), a highly conserved signaling hub that integrates environmental cues to regulate [cell death](/mechanisms/apoptosis-pathways), [autophagy](/mechanisms/autophagy-pathway), [cytoskeletal dynamics](/cell-types/neurons), and [immune responses](/cell-types/microglia). This connection to fundamental cellular processes positions MST4 as a protein of significant interest in understanding [Alzheimer's Disease](/diseases/alzheimers-disease) and [Parkinson's Disease](/diseases/parkinsons-disease) pathogenesis.

Gene Structure and Evolution

The MST4 gene spans approximately 32 kb on chromosome Xq26.2. The gene comprises 13 exons that encode a 436-amino acid protein with a molecular weight of approximately 48 kDa.

Evolutionary Conservation

MST4 belongs to the MST/STS family (Mammalian Sterile 20-like Kinases), which includes:

MST1 (STK4) - Apoptosis regulator
MST2 (STK3) - Hippo pathway core kinase
MST3 (STK24) - Neuronal function
MST4 (STK26) - This gene

The kinase domain shows high conservation across species, reflecting fundamental roles in [cell growth regulation](/mechanisms/cell-cycle-regulation).

Protein Structure and Function

Catalytic Domain Architecture

MST4 possesses the canonical serine/threonine kinase structure:

N-terminal catalytic domain (aa 1-280): Contains the activation loop and ATP-binding pocket

C-terminal regulatory domain (aa 281-436): Contains dimerization motifs and interaction surfaces

The protein adopts an active conformation when phosphorylated at:

Thr178 (activation loop) - Primary activation site
Thr385 (hydrophobic motif) - Enhances catalytic activity

Kinase Activity and Substrates

MST4 phosphorylates numerous substrates involved in diverse cellular processes:

| Substrate | Function | Reference |
|-----------|----------|-----------|
| PI3K (p85) | Cell survival signaling | [@hwang2011] |
| LKB1 | Energy sensing | [@fang2019] |
| TAOK1/2 | Cytoskeletal regulation | [@gu2018] |
| MOB1 | Hippo pathway coordination | [@chen2019] |
| AMPK | Metabolic regulation | [@fang2019] |

The STRIPAK Complex

MST4 is a core component of the STRIPAK complex, a macromolecular signaling assembly comprising:

Striatin (STRN1-4) - Scaffold protein
PP2A (PPP2R1A/B) - Phosphatase subunit
CCM2 - Cerebral cavernous malformation protein
MST3/4 - Kinase subunits
TAOK1/2 - Upstream kinases
MOB1 - Hippo pathway adapter

This complex serves as a signal integration hub that:

Coordinates kinase and phosphatase activities
Links membrane signaling to [cytoskeletal remodeling](/cell-types/neurons)
Regulates [autophagy](/mechanisms/autophagy-pathway) and [apoptosis](/mechanisms/apoptosis-pathways)
Controls [mitochondrial dynamics](/mechanisms/mitochondrial-function) in neurons

Normal Physiological Functions

Cell Growth and Proliferation

MST4 regulates [cell cycle progression](/mechanisms/cell-cycle-regulation) through multiple mechanisms:

Hippo pathway modulation: MST4 phosphorylates MOB1, promoting YAP/TAZ inhibition

PI3K/AKT crosstalk: Direct phosphorylation of PI3K p85 subunit enhances [AKT signaling](/genes/akt1)

Cell cycle checkpoints: Modulates G1/S transition through CDK inhibitor regulation

Cell Survival and Apoptosis

Through its position in the STRIPAK complex, MST4 integrates pro-survival and pro-death signals:

Anti-apoptotic signaling: Activates [PI3K/AKT pathway](/mechanisms/pi3k-akt-pathway), inhibiting [caspase](/mechanisms/apoptosis-pathways) activation
Stress response: Coordinates DNA damage response through [CHEK2](/genes/chek2) interactions
Mitochondrial regulation: Controls [Bcl-2 family](/genes/bcl2) protein localization

Cell Migration and Cytoskeleton

MST4 plays essential roles in [cytoskeletal dynamics](/cell-types/neurons) through:

Actin polymerization: Phosphorylates downstream effectors that reorganize F-actin
Microtubule stability: Modulates tubulin dynamics
Cell polarity: Partners with Par complex for asymmetric cell division

Immune Regulation

As demonstrated in [@morrow2015], MST4 modulates [immune cell](/cell-types/microglia) function:

T cell activation: Controls TCR signaling strength and duration
Cytokine production: Regulates NF-κB and MAPK pathways
Inflammatory responses: Modulates macrophage polarization

Epithelial Integrity

MST4 maintains [tissue barrier function](/cell-types/epithelial-cells) through:

Tight junction assembly: Coordinates claudin and occludin localization
Cell-cell adhesion: Regulates E-cadherin dynamics
Wound healing: Promotes collective migration

Disease Associations

Alzheimer's Disease

MST4 has emerged as a protein of interest in [Alzheimer's Disease](/diseases/alzheimers-disease) pathogenesis through multiple mechanisms:

Genetic Evidence

GWAS hits: SNPs in the MST4 locus show marginal association with AD risk
Expression quantitative trait loci (eQTLs): Genetic variants correlate with MST4 expression in [brain](/brain-regions/cortex)

Molecular Mechanisms in AD

Neuroinflammation [@liu2020]:

MST4 regulates [microglial](/cell-types/microglia) activation state
Modulates [TNF-α](/genes/tnfa) and [IL-1β](/genes/il1b) production
Altered in AD brain regions showing neuroinflammation

Neuronal survival:

MST4/AKT axis protects against [β-amyloid](/mechanisms/amyloid-cascade)-induced toxicity
Loss of MST4 signaling may contribute to [synaptic loss](/mechanisms/synaptic-loss)

Autophagy dysregulation [@gu2018]:

MST4 regulates [autophagosome](/mechanisms/autophagy-pathway) formation
Impaired autophagy is a hallmark of AD
MST4 dysfunction may exacerbate protein aggregate clearance

Mitochondrial dysfunction [@zhang2021]:

MST4 localizes to [mitochondria](/mechanisms/mitochondrial-function) in neurons
Controls [mitochondrial fission/fusion](/mechanisms/mitochondrial-dynamics)
Altered in AD [brain](/brain-regions/hippocampus) showing energy deficits

Therapeutic Implications

Targeting MST4 in AD may offer several benefits:

Neuroprotective strategies: Enhancing MST4/AKT signaling
Anti-inflammatory approaches: Modulating microglial MST4
Autophagy enhancement: Restoring protein clearance pathways

Parkinson's Disease

While less studied, MST4 may contribute to [Parkinson's Disease](/diseases/parkinsons-disease) through:

Dopaminergic neuron survival: MST4 signaling protects [dopaminergic neurons](/cell-types/dopaminergic-neurons)
α-Synuclein handling: Potential role in [autophagy](/mechanisms/autophagy-pathway) of protein aggregates
Mitochondrial health: Maintaining [mitochondrial dynamics](/mechanisms/mitochondrial-dynamics) in neurons

Autoinflammatory Diseases

MST4 variants affect [immune](/cell-types/microglia) function and predispose to:

Chronic inflammatory conditions: Altered cytokine regulation
Autoimmune associations: Potential for autoantibody generation
Inflammatory bowel disease: MST4 expression in gut epithelium

Cancer Associations

As characterized in [@lin2010], MST4 shows oncogenic potential:

Colorectal cancer: Overexpression drives proliferation and metastasis
Breast cancer: Associated with poor prognosis
Therapeutic targeting: Small molecule inhibitors under development [@yu2022]

Expression Patterns

Tissue Distribution

MST4 shows broad expression across tissues:

| Tissue | Expression Level | Notable Regions |
|--------|-----------------|-----------------|
| Brain | High | [Cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), cerebellum, basal ganglia |
| Immune system | High | T cells, B cells, [macrophages](/cell-types/microglia), dendritic cells |
| Epithelial | Moderate-high | Intestine, lung, breast |
| Heart | Moderate | Cardiac myocytes |
| Liver | Moderate | Hepatocytes |
| Muscle | Low-moderate | Skeletal muscle |

Brain Expression

Within the [central nervous system](/brain-regions/cortex), MST4 is expressed in:

Neurons: Particularly in [pyramidal cells](/cell-types/pyramidal-neurons) of cortex and hippocampus
Astrocytes: [Astrocytic](/cell-types/astrocytes) support of neuronal function
Microglia: [Microglial](/cell-types/microglia) immune surveillance

Subcellular Localization

MST4 exhibits dynamic subcellular distribution:

Cytoplasm: Primary location, associated with cytoskeletal elements
Membrane: Transient localization at plasma membrane
Mitochondria: Identified in neuronal mitochondria
Nucleus: Low levels, potential transcription regulation

Signaling Pathways

Hippo Pathway Integration

MST4 connects to the [Hippo signaling pathway](/mechanisms/hippo-pathway) through:

MST4 → MOB1 → LATS1/2 → YAP/TAZ inhibition
↓
Cell growth control

This axis is critical for:

Contact inhibition
Organ size control
[Cell death](/mechanisms/apoptosis-pathways) regulation

PI3K/AKT Cross-talk

As described in [@hwang2011], MST4 directly phosphorylates PI3K p85:

Enhances AKT activation
Promotes cell survival
Integrates growth factor signals

MAPK/ERK Cascade

MST4 interacts with the [MAPK pathway](/mechanisms/mapk-signaling):

Activates ERK1/2
Promotes cell proliferation
Regulates stress responses

Clinical Significance

Diagnostic Markers

MST4 expression may serve as:

Prognostic biomarker: Higher expression correlates with cancer progression
Disease activity marker: Inflammatory conditions show altered MST4
Therapeutic target indicator: Cancer subtypes with MST4 dependency

Therapeutic Targeting

Current therapeutic approaches include:

Kinase inhibitors [@yu2022]:

ATP-competitive inhibitors in development
Specificity challenges due to MST family conservation

Activation strategies (for neurodegeneration):

Small molecule activators of MST4 signaling
Gene therapy approaches

Combination therapies:

MST4 inhibition with standard chemotherapy
Synergy with immune checkpoint inhibitors

Research Directions

Unresolved Questions

Key questions remain regarding MST4 in neurodegeneration:

Mechanism specificity: How does MST4 selectively affect neuronal survival?

Pathology timing: Is MST4 dysregulation cause or consequence of AD?

Therapeutic window: Can MST4 be safely modulated in the brain?

Biomarker potential: Does MST4 have utility in diagnosis or monitoring?

Emerging Areas

Single-cell analysis: Defining MST4 roles in specific [cell types](/cell-types/neurons)
Structural biology: MST4-inhibitor complexes for drug design
Systems biology: Network mapping of MST4 signaling

Interactions and Pathways

Protein-Protein Interactions

MST4 participates in numerous protein interactions:

| Interactor | Interaction Type | Function |
|------------|-----------------|----------|
| STRN3 | Structural | STRIPAK complex scaffold |
| PPP2R1A | Enzymatic | PP2A phosphatase subunit |
| MST3/STK24 | Homologous | Kinase dimerization |
| MOB1 | Substrate | Hippo pathway adapter |
| CCM2 | Structural | Complex anchoring |
| TAOK1 | Enzymatic | Upstream activation |

Genetic Interactions

MST4 genetically interacts with:

[AKT1](/genes/akt1): Synthetic lethal in certain contexts
[MAP3K7](/genes/map3k7): TAK1-MST4 axis in inflammation
[STK11](/genes/stk11): LKB1-MST4 in energy sensing

External Links

[Ensembl: ENSG00000101126](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000101126)
[NCBI Gene: MST4](https://www.ncbi.nlm.nih.gov/gene/?term=MST4)
[GeneCards: MST4](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MST4)
[UniProt: Q9P289](https://www.uniprot.org/uniprot/Q9P289)
[OMIM: 300254](https://omim.org/search?search=MST4)
[Allen Brain Atlas: MST4](https://human.brain-map.org/microarray/search/show?search_term=MST4)
[STRING: MST4 Interactions](https://string-db.org/network/9606/ENSG00000101126)

References

[Wan et al., MST4 and cell growth (2004)](https://doi.org/10.1016/j.cell.2004.09.024)

[Morrow et al., MST4 in inflammation (2015)](https://doi.org/10.1016/j.coi.2015.01.007)

[Lin et al., MST4 and cancer (2010)](https://doi.org/10.1038/onc.2010.13)

[Hwang et al., MST4 phosphorylates PI3K in cell survival (2011)](https://doi.org/10.1016/j.cell.2011.03.013)

[Fang et al., STRIPAK complex in neuronal development (2019)](https://doi.org/10.1016/j.tcb.2019.03.001)

[Gu et al., MST4 in autophagy regulation (2018)](https://doi.org/10.1038/s41418-018-0121-0)

[Chen et al., Hippo pathway crosstalk with MST4 (2019)](https://doi.org/10.1038/s41418-019-0340-7)

[Liu et al., MST4 and neuroinflammation in AD (2020)](https://doi.org/10.1016/j.neurobiolaging.2020.02.015)

[Zhang et al., MST4 regulates mitochondrial dynamics in neurons (2021)](https://doi.org/10.1016/j.mito.2021.01.005)

[Yu et al., MST4 kinase inhibitors in disease therapy (2022)](https://doi.org/10.1016/j.tips.2022.01.003)

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Related Entities

MST4

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slug	genes-mst4
kg_node_id	MST4
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-a4d8462fcfc5
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-mst4'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

25%

Debates

0

Incoming

5

Outgoing

9

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

MST4 Gene

MST4 (Serine/Threonine-Protein Kinase MST4)

Overview

MST4 (Serine/Threonine-Protein Kinase MST4)

Overview

Gene Structure and Evolution

Evolutionary Conservation

Protein Structure and Function

Catalytic Domain Architecture

Kinase Activity and Substrates

The STRIPAK Complex

Normal Physiological Functions

Cell Growth and Proliferation

Cell Survival and Apoptosis

Cell Migration and Cytoskeleton

Immune Regulation

Epithelial Integrity

Disease Associations

Alzheimer's Disease

Genetic Evidence

Molecular Mechanisms in AD

Therapeutic Implications

Parkinson's Disease

Autoinflammatory Diseases

Cancer Associations

Expression Patterns

Tissue Distribution

Brain Expression

Subcellular Localization

Signaling Pathways

Hippo Pathway Integration

PI3K/AKT Cross-talk

MAPK/ERK Cascade

Clinical Significance

Diagnostic Markers

Therapeutic Targeting

Research Directions

Unresolved Questions

Emerging Areas

Interactions and Pathways

Protein-Protein Interactions

Genetic Interactions

See Also

Related Pathways

Related Diseases

Related Genes

External Links

References

💬 Discussion