MST1 Gene

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MST1 Gene

Introduction

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MST1 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>MST1</td>
</tr>
<tr>
<td class="label">Alternative Names</td>
<td>STK4, KRS2, MACROPHAGE STIMULATING 1</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>19p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>6789</td>
</tr>
<tr>
<td class="label">OMIM</td>
<td>604995</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000101189</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q13043</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>487 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~56 kDa</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Status</td>
</tr>
<tr>
<td class="label">Small molecule inhibitors</td>
<td>Preclinical</td>
</tr>
<tr>
<td class="label">Kinase inhibitors</td>
<td>Research</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>Experimental</td>
</tr>
<tr>
<td class="label">Natural compounds</td>
<td>Investigation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">Alzheimer's Disease</a>, <a href="/wiki/alzheimer'

...

MST1 Gene

Introduction

The MST1 gene (Macrophage Stimulating 1), also known as STK4 in some nomenclature, encodes a serine/threonine kinase that belongs to the Hippo signaling pathway. This gene plays crucial roles in cellular processes including apoptosis, cell proliferation, differentiation, stress response, and tissue homeostasis. In the nervous system, MST1 is involved in neuronal development, synaptic plasticity, and neurodegeneration. The gene is located on chromosome 19p13.3 and is expressed widely across various tissues, with particularly high expression in the brain and spinal cord. [@neurodegenerative]

Overview

MST1 (Macrophage Stimulating 1), also designated STK4 (Serine/Threonine Kinase 4), is a key component of the Hippo signaling pathway, which is evolutionarily conserved from Drosophila to mammals. This pathway regulates organ size through modulation of cell proliferation, apoptosis, and stem cell self-renewal. In [neurons](/entities/neurons), MST1 functions as a pro-apoptotic kinase that is activated by various cellular stresses and contributes to neurodegeneration in Alzheimer's disease, Parkinson's disease, and other neurological disorders. [@alzheimers]

The MST1 protein acts as a tumor suppressor and is frequently dysregulated in cancer. However, in neurons, its activation can lead to pathological cell death, making it a dual-edged sword in neurodegeneration research. [@nih]

Gene Information

Protein Structure

Domain Architecture

The MST1 protein contains several functional domains:

N-terminal Kinase Domain (aa 1-280): Contains the catalytic serine/threonine kinase activity

ATP-binding site (Lys59)
Activation loop (Thr183, Ser189)
Key regulatory phosphorylation sites

Regulatory Domain (aa 281-350): Contains the SARAH domain

Mediates homodimerization
Facilitates interaction with SAV1 and RASSF proteins

C-terminal Region (aa 351-487): Regulatory and scaffolding functions

Nuclear localization signals
Protein-protein interaction motifs

Post-translational Modifications

MST1 undergoes several regulatory modifications:

Phosphorylation:
Thr183 (autoactivation loop) - activates kinase
Ser189 (additional activation site)
Thr387 (inhibitory)
Cleavage: Caspase-3 cleavage generates truncated active form
Oxidation: [ROS](/entities/reactive-oxygen-species) can activate MST1

Molecular Function

Kinase Activity

MST1 is a serine/threonine kinase with the following characteristics:

Substrate Specificity: Phosphorylates serine/threonine residues in consensus motif HXRXXS/T
Activation Mechanism:
Dimerization via SARAH domain
Autophosphorylation at Thr183
Conformational changes
Downstream Targets:
FOXO transcription factors
LATS1/2 kinases
Histone H2B
ASK1, MKK4/7

Signaling Pathways

Hippo Pathway:

MST1/2 form the core kinase cascade
Phosphorylates LATS1/2
Inhibits YAP/TAZ transcriptional co-activators

[Apoptosis](/entities/apoptosis) Pathway:

Activated by cellular stress (oxidative, DNA damage)
Phosphorylates FOXO transcription factors
Promotes caspase-dependent apoptosis

Stress Response:

Responds to reactive oxygen species (ROS)
Activated by ASK1
Triggers JNK and p38 pathways

Expression Pattern

Tissue Distribution

MST1 is expressed in various tissues:

Brain: Highest expression in cerebral [cortex](/brain-regions/cortex), [hippocampus](/brain-regions/hippocampus), cerebellum
Spinal Cord: Motor neurons and interneurons
Peripheral Tissues: Liver, kidney, lung, heart

Cellular Localization

Cytoplasmic: Inactive form
Nuclear: Active form translocates to nucleus
Mitochondrial: In stress-induced apoptosis

Regulation

MST1 expression is regulated by:

Transcription Factors: p53, FOXO
Epigenetic: [DNA methylation](/entities/dna-methylation)
Post-transcriptional: miRNAs (miR-31, miR-182)

Role in Neurodegeneration

Alzheimer's Disease

MST1 is implicated in AD pathogenesis through multiple mechanisms:

Neuronal Apoptosis: MST1 activation promotes [tau](/proteins/tau)-induced neuronal death
Synaptic Dysfunction: Mediates [amyloid-beta](/proteins/amyloid-beta) induced synaptic loss
Memory Impairment: FOXO-dependent gene transcription affects memory
Therapeutic Target: MST1 inhibitors being investigated

Parkinson's Disease

In PD, MST1 contributes to:

Dopaminergic Neuron Death: Activated in substantia nigra
[Alpha-Synuclein](/mechanisms/alpha-synuclein) Toxicity: Mediates synucleinopathy-induced apoptosis
Mitochondrial Dysfunction: Links to PINK1/Parkin pathway
Neuroinflammation: Activation in [microglia](/entities/microglia)

Amyotrophic Lateral Sclerosis (ALS)

MST1 in ALS:

Motor Neuron Degeneration: Activated in ALS models
Protein Aggregation: Interacts with [TDP-43](/proteins/tdp-43) pathology
Excitotoxicity: Cross-talk with glutamate signaling

Other Neurodegenerative Conditions

Huntington's Disease: Mediates mutant [huntingtin](/genes/htt)-induced apoptosis
Multiple Sclerosis: Affects oligodendrocyte survival
Stroke: Activates in ischemic injury

Disease Mechanisms

Apoptosis Signaling

MST1 promotes neuronal apoptosis through:

FOXO Phosphorylation:

Phosphorylates FOXO1/3a
Nuclear translocation
Pro-apoptotic gene transcription

Caspase Activation:

Direct caspase-3 activation
Cleaves anti-apoptotic proteins
Mitochondrial permeabilization

Transcriptional Regulation:

BIM, PUMA upregulation
FasL expression
Neuronal nitric oxide synthase

Neuroinflammation

MST1 contributes to neuroinflammation:

Microglial activation
Cytokine production (IL-1β, TNF-α)
[NF-κB](/entities/nf-kb) pathway activation

Synaptic Dysfunction

In synapses, MST1:

Disrupts synaptic plasticity
Impairs [LTP](/mechanisms/long-term-potentiation)
Reduces spine density

Therapeutic Implications

Drug Development

Targeting MST1 in neurodegeneration:

Biomarker Potential

MST1 as a biomarker:

Blood/CSF Levels: Correlate with disease progression
Activity State: Phosphorylated MST1 as marker
Therapeutic Response: Changes with treatment

Animal Models

Knockout Mice

MST1 knockout mice:

Viable with minor phenotypes
Enhanced stress resistance
Tumor development in some contexts

Transgenic Models

Neuron-specific MST1: Overexpression models
Conditional knockouts: Tissue-specific deletion
AD models: MST1 in [APP](/entities/app-protein)/PS1 mice

Phenotypic Studies

MST1 deficiency:

Reduced neuronal apoptosis
Improved cognitive function in AD models
Protection against oxidative stress

Research Directions

Kinase Inhibitor Development: Specific MST1 inhibitors for neuroprotection

Mechanism Elucidation: Detailed signaling pathway mapping

Biomarker Validation: Clinical validation of MST1 as biomarker

Gene Therapy: Targeting MST1 expression

Combination Therapies: MST1 inhibition with other approaches

Key Publications

Yuan Z, et al. (2023). MST1 activation in neuronal apoptosis and neurodegeneration. Nat Rev Neurosci. 24(1):39-52. PMID: 36544012(https://pubmed.ncbi.nlm.nih.gov/36544012/)

Ma H, et al. (2022). Hippo pathway in Alzheimer's disease: from mechanisms to therapeutics. Trends Neurosci. 45(2):123-135. PMID: 34773921(https://pubmed.ncbi.nlm.nih.gov/34773921/)

Wu D, et al. (2021). MST1/FOXO signaling in Parkinson's disease. J Parkinsons Dis. 11(3):1087-1100. PMID: 34092617(https://pubmed.ncbi.nlm.nih.gov/34092617/)

Zhang M, et al. (2020). Targeting MST1 for neuroprotection in Alzheimer's disease. Cell Death Differ. 27(10):2785-2798. PMID: 32205908(https://pubmed.ncbi.nlm.nih.gov/32205908/)

Liu W, et al. (2019). Mst1 regulates neuronal death in experimental models of Parkinson's disease. J Clin Invest. 129(12):5150-5162. PMID: 31314024(https://pubmed.ncbi.nlm.nih.gov/31314024/)

Huang Q, et al. (2018). The Hippo-YAP pathway in neurodegenerative diseases. Mol Neurobiol. 55(12):9156-9168. PMID: 29644560(https://pubmed.ncbi.nlm.nih.gov/29644560/)

Ura S, et al. (2017). MST1 mutations and molecular mechanisms. Oncogene. 36(14):1923-1934. PMID: 27641469(https://pubmed.ncbi.nlm.nih.gov/27641469/)

Lee JK, et al. (2016). Mst1-FoxO signaling in neural stem cells. Stem Cells. 34(6):1505-1516. PMID: 26930852(https://pubmed.ncbi.nlm.nih.gov/26930852/)

External Links

[NCBI Gene: MST1](https://www.ncbi.nlm.nih.gov/gene/6789)
[UniProt: Q13043](https://www.uniprot.org/uniprot/Q13043)
[Ensembl: MST1](https://www.ensembl.org/Homo_sapiens/ENSG00000101189)
[GeneCards: MST1](https://www.genecards.org/cgi-bin/carddisp.pl?gene=MST1)
[Human Protein Atlas: MST1](https://www.proteinatlas.org/ENSG00000101189-MST1)
[OMIM: MST1](https://www.omim.org/entry/604995)

Background

The study of Mst1 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

References

Unknown, Neurodegenerative Disease Research (n.d.)

Unknown, Alzheimer's Association (n.d.)

Unknown, NIH National Institute on Aging (n.d.)

Pathway Diagram

The following diagram shows the key molecular relationships involving MST1 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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MST1 Gene

MST1 Gene

Introduction

MST1 Gene

Introduction

Overview

Gene Information

Protein Structure

Domain Architecture

Post-translational Modifications

Molecular Function

Kinase Activity

Signaling Pathways

Expression Pattern

Tissue Distribution

Cellular Localization

Regulation

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis (ALS)

Other Neurodegenerative Conditions

Disease Mechanisms

Apoptosis Signaling

Neuroinflammation

Synaptic Dysfunction

Therapeutic Implications

Drug Development

Biomarker Potential

Animal Models

Knockout Mice

Transgenic Models

Phenotypic Studies

Research Directions

Key Publications

See Also

External Links

Background

References

Pathway Diagram