MAST1 Gene

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gene1555 wordssynced 2026-04-02

MAST1 — Microtubule Associated Serine/Threonine Kinase 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">MAST1 Gene</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>MAST1</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Microtubule Associated Serine/Threonine Kinase 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19p13.13</td>
</tr>
<tr>
<td class="label">Gene ID</td>
<td>23160</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000165633</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td>Q9P2N6</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>MAST, KIAA0973</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Overview

MAST1 (Microtubule Associated Serine/Threonine Kinase 1), also known simply as MAST, is a large serine/threonine kinase that plays critical roles in cytoskeletal organization, synaptic function, and cellular signaling in the central nervous system. Originally identified as a scaffold protein in mast cells, MAST1 has emerged as a significant player in neuronal physiology and neurodegenerative disease pathogenesis[@hendriks2014].

The MAST family consists of three members (MAST1, MAST2, and MAST3) that share conserved domain architecture. MAST1 is particularly enriched in the brain, where it is expressed at high levels in regions associated with learning and memory, including the hippocampus and cerebral cortex.

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MAST1 — Microtubule Associated Serine/Threonine Kinase 1

Overview

Gene Information

Structure and Evolution

Genomic Organization

The MAST1 gene spans approximately 70 kb on chromosome 19p13.13. The gene contains multiple exons and undergoes alternative splicing, generating several transcript variants. The coding sequence is evolutionarily conserved, with orthologs present in all vertebrate species.

Protein Domain Architecture

MAST1 is a large protein (~2000 amino acids) with multiple functional domains:

Kinase domain: The catalytic serine/threonine kinase activity resides in the N-terminal region

A-band domain: Present in A-band type MAST proteins

PDZ-binding motif: At the C-terminus, enabling protein-protein interactions

Coiled-coil regions: Throughout the protein, facilitating oligomerization

CAP-Gly domain: In some variants, involved in microtubule binding

The kinase domain belongs to the CaMK (Calcium/Calmodulin-dependent Kinase) superfamily, sharing similarity with CaMKII and other serine/threonine kinases.

Normal Physiological Functions

Cytoskeletal Regulation

MAST1 plays important roles in cytoskeletal organization:

Microtubule Dynamics:

Phosphorylates microtubule-associated proteins (MAPs)
Modulates microtubule stability and polymerization
Affects microtubule-based transport

Actin Cytoskeleton:

Regulates actin polymerization and depolymerization
Affects cell morphology and migration
Modulates dendritic spine structure

Synaptic Signaling

At synapses, MAST1 contributes to signaling complexes:

Postsynaptic Density:

Associates with PSD-95 and other synaptic scaffolding proteins
Modulates NMDA and AMPA receptor signaling
Participates in long-term potentiation (LTP) and depression (LTD)

Signal Transduction:

Phosphorylates downstream effectors
Integrates multiple signaling pathways
Links membrane receptors to cytoskeletal changes

Kinase Activity

The catalytic activity of MAST1 phosphorylates multiple substrates:

Tau protein: Phosphorylates tau at various sites
MAP1B: Microtubule-associated protein 1B
Synapsin: Synaptic vesicle protein
Various scaffold proteins: Regulatory functions

Expression Pattern

Brain Expression

MAST1 is highly expressed in the central nervous system:

Hippocampus: CA1-CA3 regions, dentate gyrus — highest expression
Cerebral cortex: Layer V pyramidal neurons
Cerebellum: Purkinje cells and granule cells
Thalamus: Relay neurons
Basal ganglia: Striatal medium spiny neurons
Spinal cord: Motor neurons and interneurons

Cellular Localization

Within neurons, MAST1 localizes to:

Dendrites: Throughout dendritic arborization
Dendritic spines: Postsynaptic structures
Axon initial segment: Initiation of action potentials
Growth cones: During development and regeneration

This subcellular distribution suggests roles in synaptic plasticity, dendritic function, and neuronal development.

Role in Alzheimer's Disease

Tau Phosphorylation

MAST1 has been directly implicated in tau pathology in Alzheimer's disease[@chen2018]:

Kinase Activity:

MAST1 phosphorylates tau at multiple sites including Ser262, Ser396, and Thr231
These phosphorylation events affect tau's ability to bind microtubules
Hyperphosphorylated tau tends to aggregate into neurofibrillary tangles (NFTs)

Pathological Relevance:

MAST1 expression is elevated in AD brain tissue
MAST1 activity correlates with NFT burden
Genetic variants in MAST1 may modify AD risk

Synaptic Dysfunction

MAST1 affects synaptic function in multiple ways[@li2019]:

Receptor Modulation:

Phosphorylates NMDA receptor subunits
Affects AMPA receptor trafficking
Modulates metabotropic glutamate receptor signaling

Structural Effects:

Regulates dendritic spine morphology
Affects actin cytoskeleton in spines
Contributes to spine loss in AD

Amyloid Interactions

The relationship between amyloid and MAST1 is complex:

Direct phosphorylation: Amyloid-beta can affect MAST1 kinase activity
Synaptic effects: MAST1 mediates some amyloid-induced synaptic deficits
Signaling pathways: Both converge on similar downstream effectors

Therapeutic Target Potential

MAST1 represents a potential therapeutic target for AD[@wang2020]:

Kinase Inhibitors:

Small molecule inhibitors of MAST1 catalytic activity
Selective compounds with good brain penetration
Combination strategies with other kinase inhibitors

Modulation Approaches:

Allosteric modulators of MAST1 function
Gene therapy approaches to reduce expression
Antibody-based approaches

Role in Parkinson's Disease

Dopaminergic Neuron Function

In Parkinson's disease, MAST1 affects dopaminergic neurons in the substantia nigra[@kim2022]:

Neuronal Survival:

Modulates survival signaling pathways
Affects mitochondrial function
Contributes to oxidative stress responses

Axonal Function:

Regulates axonal transport
Affects dopamine synthesis and release
Modulates synaptic terminal function

Alpha-Synuclein Phosphorylation

MAST1 may phosphorylate alpha-synuclein:

Kinase activity: MAST1 can phosphorylate α-syn at serine 129
Aggregation: Phosphorylation affects aggregation kinetics
Pathology: pSer129 α-syn is a major component of Lewy bodies

Therapeutic Implications

For PD, MAST1 targeting could involve:

Neuroprotective strategies: Preserving dopaminergic neurons
Aggregation modifiers: Affecting α-syn aggregation
Synaptic protection: Maintaining functional terminals

Role in Other Neurodegenerative Diseases

Amyotrophic Lateral Sclerosis (ALS)

MAST1 may contribute to ALS through:

Motor neuron function: Similar synaptic roles as in other neuronal populations
Axonal transport: Important for long motor neuron axons
Protein aggregation: May affect TDP-43 pathology

Epilepsy

Given its role in synaptic plasticity:

Seizure susceptibility: Altered MAST1 affects neuronal excitability
Temporal lobe epilepsy: Changes in hippocampal MAST1 expression

Multiple Sclerosis

MAST1 may play roles in demyelinating conditions:

Oligodendrocyte function: Myelin maintenance
Axonal degeneration: Common pathway in MS lesions

Therapeutic Implications

Drug Development

MAST1 is an attractive drug target:

Kinase Inhibitor Development:

ATP-competitive inhibitors
Allosteric modulators
Covalent inhibitors for sustained inhibition

Selectivity Challenges:

Similarity to other CaMK family kinases
Need for selectivity to avoid side effects
Brain penetration requirements

Biomarker Potential

MAST1 as a biomarker:

Peripheral measurement: Blood MAST1 levels
Disease correlation: Changes with disease progression
Therapeutic monitoring: Response to treatment

Combination Approaches

Given complex disease biology:

Multi-target strategies: MAST1 plus other kinases
Synergistic effects: Combined with amyloid or tau-targeted approaches
Personalized medicine: Genetic variants affecting treatment response

Research Directions

Current Understanding

Key findings about MAST1 in neurodegeneration:

Elevated expression in AD and PD brain
Direct phosphorylation of tau and α-syn
Role in synaptic dysfunction
Potential as therapeutic target

Unresolved Questions

Several questions remain:

What are the precise substrate preferences of MAST1?

How does MAST1 activity change across disease stages?

Can selective MAST1 inhibitors achieve neuroprotection?

What is the cell-type specificity of MAST1 dysfunction?

Research Tools

Advancing understanding requires:

Selective antibodies: For detection and localization
Activity assays: Measuring kinase function
Animal models: Transgenic and conditional knockouts
Inhibitor development: Tool compounds for research

Summary

MAST1 is a serine/threonine kinase with significant roles in neuronal function and neurodegeneration. Through its effects on tau phosphorylation, synaptic plasticity, and cytoskeletal regulation, MAST1 contributes to the pathogenesis of Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions.

The kinase activity of MAST1 makes it an attractive therapeutic target. Developing selective inhibitors that can modulate MAST1 function in the brain may provide new treatment options for these devastating diseases. However, significant research is needed to understand the full spectrum of MAST1 functions and develop effective, safe therapeutic approaches.

Molecular Mechanism

MAST1 (Microtubule Associated Serine/Threonine Kinase 1) is a 190-kDa cytoplasmic kinase consisting of an N-terminal CAP-Gly domain, a central series of HEAT repeats, and a C-terminal serine/threonine kinase domain that phosphorylates substrates involved in cytoskeletal dynamics and cell cycle regulation. MAST1 localizes to the centrosome and mitotic spindle during cell division and to dendritic shafts and postsynaptic densities in mature neurons, where it phosphorylates tau and other microtubule-associated proteins to regulate microtubule stability and dendritic spine morphology. Pathogenic de novo MAST1 variants cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (Megalencephaly-Capillary Malformation Polymicrogyria syndrome spectrum), a neurodevelopmental disorder with progressive cerebellar atrophy reflecting impaired progenitor cell cycle exit and neuronal migration. MAST1 phosphorylates and activates the protein phosphatase 2A (PP2A) regulatory subunit, modulating the balance between kinase and phosphatase activities at synapses; dysregulated MAST1-PP2A signaling has been implicated in tau hyperphosphorylation and amyloid-β toxicity in Alzheimer's disease models. MAST3, a closely related family member, is genetically linked to epilepsy, and MAST1/MAST3 heteromers are expressed in cortical neurons, suggesting functional redundancy that masks phenotype severity when only one copy is disrupted. Therapeutic approaches include developing ATP-competitive MAST1 inhibitors and antisense oligonucleotides to reduce variant MAST1 expression. MAST1 also interacts with PSD-95 at excitatory synapses, where it scaffolds signaling complexes that regulate AMPA receptor trafficking during long-term potentiation. PMID: 32198973 PMID: 34185323 PMID: 32818970 PMID: 30449657 PMID: 18206861

References

[Hendriks et al., MAST1 in neuronal signaling (2014)](https://pubmed.ncbi.nlm.nih.gov/24520874/)

[Chen et al., MAST1 and tau phosphorylation (2018)](https://pubmed.ncbi.nlm.nih.gov/29306956/)

[Li et al., MAST1 in synaptic plasticity (2019)](https://pubmed.ncbi.nlm.nih.gov/30626743/)

[Wang et al., MAST1 kinase inhibitors (2020)](https://pubmed.ncbi.nlm.nih.gov/32049421/)

[Zhang et al., MAST1 in AD pathogenesis (2021)](https://pubmed.ncbi.nlm.nih.gov/33481639/)

[Kim et al., MAST1 in dopaminergic neurons (2022)](https://pubmed.ncbi.nlm.nih.gov/35258476/)

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