MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

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MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

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MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

Introduction

MAP3K5 (also known as ASK1 — Apoptosis Signal-regulating Kinase 1) is a critical MAP3K that activates the JNK and p38 MAPK pathways in response to cellular stress. Located on chromosome 6q26, this gene encodes a serine/threonine protein kinase that serves as a central mediator of oxidative stress, ER stress, and inflammatory signaling in neurons. [@kadowaki2005]

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MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

Introduction

MAP3K5 (also known as ASK1 — Apoptosis Signal-regulating Kinase 1) is a critical MAP3K that activates the JNK and p38 MAPK pathways in response to cellular stress. Located on chromosome 6q26, this gene encodes a serine/threonine protein kinase that serves as a central mediator of oxidative stress, ER stress, and inflammatory signaling in neurons. [@kadowaki2005]

<div class="infobox infobox-gene"> [@sakauchi2011]
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">MAP3K5 (ASK1)</th></tr>
<tr><td>Gene Symbol</td><td>MAP3K5</td></tr>
<tr><td>Protein Name</td><td>ASK1 (Apoptosis Signal-regulating Kinase 1)</td></tr>
<tr><td>Full Name</td><td>Mitogen-Activated Protein Kinase Kinase Kinase 5</td></tr>
<tr><td>Chromosome</td><td>6q26</td></tr>
<tr><td>NCBI Gene ID</td><td>[4217](https://www.ncbi.nlm.nih.gov/gene/4217)</td></tr>
<tr><td>OMIM</td><td>602476</td></tr>
<tr><td>Ensembl ID</td><td>ENSG00000197442</td></tr>
<tr><td>UniProt ID</td><td>[Q9UHD6](https://www.uniprot.org/uniprot/Q9UHD6)</td></tr>
<tr><td>Protein Length</td><td>1,374 amino acids</td></tr>
<tr><td>Molecular Weight</td><td>~155 kDa</td></tr>
<tr><td>Associated Diseases</td><td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ALS, Stroke</td></tr>
</table>
</div>

Gene Structure and Expression

Genomic Organization

The MAP3K5 gene spans approximately 54 kb on chromosome 6q26 and contains multiple exons encoding the full-length protein. The gene is ubiquitously expressed with particularly high levels in the brain, heart, and liver. [@kuroda2011]

Brain Expression

In the central nervous system, ASK1 is highly expressed in:

Cerebral cortex — pyramidal neurons
Hippocampus — CA1-CA3 regions, dentate gyrus
Substantia nigra — dopaminergic neurons
Spinal cord — motor neurons

This neuronal expression pattern makes ASK1 particularly relevant to neurodegenerative processes. [@kadowaki2005]

Protein Structure and Regulation

Domain Architecture

ASK1 contains several functional domains:

N-terminal regulatory domain — Contains binding sites for thioredoxin (Trx) and 14-3-3 proteins

Kinase domain — Catalytic Ser/Thr kinase domain (aa 682-937)

C-terminal regulatory domain — Contains binding sites for TRAF proteins and negative regulators

Regulation Mechanisms

ASK1 activity is tightly controlled through multiple mechanisms:

| Regulator | Mechanism | Effect |
|-----------|-----------|--------|
| Thioredoxin (Trx) | Covalent binding to N-terminal | Inhibits activation [@thioredoxin2005] |
| 14-3-3 proteins | Phosphorylation-dependent binding | Sequesters in cytoplasm |
| Hsp90 | Chaperone binding | Stabilizes protein |
| TRAF2/6 | K63-linked ubiquitination | Activates in response to TNF-α |

Activation Mechanism

Under non-stressed conditions, ASK1 is held in an inactive state through:

Direct interaction with thioredoxin (Trx) at the N-terminus
Binding to 14-3-3 proteins
Formation of inactive complexes with negative regulators

Upon stress exposure, these inhibitory interactions are disrupted, leading to ASK1 autophosphorylation and activation. [@kuroda2011]

Signaling Pathways

Downstream Kinase Cascades

Mermaid diagram (expand to render)

JNK Pathway

ASK1 → MKK4/7 → JNK1/2/3 → c-Jun/ATF2 → AP-1 → Apoptosis

Key substrates:

c-Jun (transcription factor)
ATF2 (transcription factor)
Bcl-2 family proteins (mitochondrial pathway)
Synaptic proteins (synaptic dysfunction)

p38 Pathway

ASK1 → MKK3/6 → p38α/β/γ/δ → ATF2/CREB/MSK → Inflammation

Key functions:

Pro-inflammatory cytokine production
Microglial activation
Tau phosphorylation
Synaptic plasticity impairment

Role in Alzheimer's Disease

Amyloid-β Mediated Activation

Aβ activates ASK1 through multiple mechanisms:

Direct oxidative stress — Aβ generates ROS that activate ASK1

Glial activation — Aβ triggers inflammatory signaling via microglia

ER stress — Aβ disrupts calcium homeostasis causing UPR activation

Neuronal Apoptosis

Aβ-induced ASK1 activation mediates neuronal death through:

JNK3-mediated pathway — Neuron-specific JNK3 phosphorylates c-Jun
Mitochondrial apoptosis — ASK1 promotes Bax translocation
Caspase activation — Upstream of caspase-3 activation

Synaptic Dysfunction

ASK1-JNK pathway impairs synaptic plasticity:

Inhibits LTP in hippocampal neurons
Promotes AMPA receptor internalization
Disrupts dendritic spine morphology

Tau Pathology

The ASK1-p38 pathway contributes to tau hyperphosphorylation:

p38 directly phosphorylates tau at AD-relevant sites (Thr181, Ser396)
ASK1 deletion reduces tau pathology in animal models [@tau2022]

Therapeutic Implications

ASK1 represents a promising therapeutic target:

Small molecule inhibitors (e.g., Selonsertib/GS-4997) in development
Genetic deletion protects against Aβ toxicity in mice
PET tracer [18F]ASK1-IN-6 enables visualization of ASK1 in AD brain [@ask1pet2024]

Role in Parkinson's Disease

Dopaminergic Neuron Vulnerability

SNc dopaminergic neurons show particular susceptibility to ASK1 activation:

High basal oxidative stress — Due to dopamine metabolism

Mitochondrial vulnerability — Complex I defects

Calcium influx — Pacemaker activity increases ROS

Toxin-Induced Models

In MPTP and 6-OHDA models:

ASK1 is rapidly activated in dopaminergic neurons
JNK3 mediates apoptotic cell death
Inhibition protects against toxin-induced degeneration [@mptp2009]

α-Synuclein Toxicity

α-Syn aggregation activates ASK1-JNK pathway:

Promotes neuronal apoptosis
Contributes to spreading of pathology
Synergizes with mitochondrial dysfunction

Mitochondrial Pathway

ASK1 links mitochondrial dysfunction to apoptosis:

Directly interacts with mitochondrial proteins
Promotes cytochrome c release
Activates intrinsic apoptosis cascade

Therapeutic Potential

ASK1 inhibition may protect dopaminergic neurons:

Preclinical studies show neuroprotection
Broad therapeutic window
Addresses multiple PD pathways

Role in ALS

Motor Neuron Vulnerability

Motor neurons are particularly susceptible to ASK1 activation:

SOD1 mutations — Activate ASK1-JNK pathway [@sod1als2009]
TDP-43 pathology — Triggers ER stress and ASK1
Glutamate excitotoxicity — Activates via calcium dysregulation

Mutant SOD1 Models

In SOD1 transgenic mice:

ASK1 activation precedes motor neuron loss
Genetic deletion prolongs survival
JNK3 mediates axonal degeneration

Therapeutic Targeting

ASK1 inhibitors:

Protect motor neurons in culture
Delay disease onset in animal models
Could complement other therapeutic approaches

Role in Stroke/Ischemia

Ischemic Injury

ASK1 is strongly activated in ischemic brain:

Rapid activation within hours of stroke
Mediates neuronal death in penumbra
Contributes to blood-brain barrier disruption

Therapeutic Window

ASK1 inhibition may provide:

Neuroprotection if administered early
Reduced infarct size
Improved functional recovery

PET Imaging Tracer Development

[18F]ASK1-IN-6

A landmark development in ASK1 research is the first fluorine-18 PET radiotracer for ASK1 neuroimaging: [@ask1pet2024]

Key characteristics:

First-in-class ASK1 radioligand
High purity (>95%)
Specific binding to ASK1 protein
Higher binding in AD model mice

Preclinical results:

Good binding specificity in vitro
High binding across brain regions
Potential for AD diagnosis
Future applications in PD and MS

Clinical potential:

Non-invasive ASK1 quantification
Disease progression monitoring
Therapeutic response assessment
Patient stratification for ASK1 inhibitors

Therapeutic Targeting

Small Molecule Inhibitors

| Compound | Target | Stage | Notes |
|----------|--------|-------|-------|
| Selonsertib (GS-4997) | ASK1 | Phase II | Originally for NASH [@selonsertib2021] |
| 5Z-7-Oxozeaenol | ASK1 | Preclinical | Natural product analog |
| K811 | ASK1 | Preclinical | Selective inhibitor |

Challenges

Achieving brain penetration
Selectivity over other MAP3Ks
Sustained inhibition vs. pathway modulation

Clinical Trials

Selonsertib (GS-4997) has been evaluated in:

Non-alcoholic steatohepatitis (NASH) — Phase II/III
Diabetic kidney disease — Phase II
Potential for neurodegenerative disease trials

Cross-Links

[JNK/p38 MAPK Signaling Pathway](/mechanisms/jnk-p38-mapk-neurodegeneration)
[Apoptosis Pathway](/entities/apoptosis)
[Oxidative Stress](/entities/oxidative-stress)
[ER Stress/Unfolded Protein Response](/mechanisms/unfolded-protein-response)
[Mitochondrial Dysfunction](/entities/mitochondrial-dysfunction)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)

Disease Associations

Top DisGeNET gene-disease associations for this gene are listed below. Scores are numeric DisGeNET association scores (`score_max`) from the consolidated DisGeNET disease-gene association table; higher values indicate stronger aggregated evidence.

| Disease | DisGeNET score | Evidence sources | Supporting PMID count |
|---|---:|---|---:|
| Parkinson's disease | 0.213 | CTD_human/LHGDN | 2 |
| melanoma | 0.211 | BeFree/CTD_human | 2 |
| pancreatic cancer | 0.003 | BeFree/LHGDN | 2 |
| bone cancer | 0.003 | BeFree/LHGDN | 2 |
| type 2 diabetes mellitus | 0.003 | BeFree/GAD | 1 |

Source: DisGeNET-derived consolidated disease-gene associations (`dhimmel/disgenet`, gene symbol `MAP3K5`).

References

[Tobiume et al., ASK1 in apoptosis (2001)](https://doi.org/10.1038/sj.cdd.4400858)

[Kadowaki et al., ASK1 in neurodegeneration (2005)](https://doi.org/10.1111/j.1471-4159.2005.03248.x)

[Sakauchi et al., ASK1 in ALS (2011)](https://doi.org/10.1016/j.neuroscience.2011.04.027)

[Zhang et al., [18F]ASK1-IN-6 PET tracer (2024)](https://doi.org/10.1038/s41386-024-01990-8)

[Hayashi et al., ASK1 mediates neuronal death (2003)](https://doi.org/10.1523/jneurosci.23-22-07405.2003)

[Nagai et al., ASK1 in Parkinson's disease models (2007)](https://doi.org/10.1523/jneurosci.3110-06.2007)

[Ryu et al., ASK1 in Alzheimer's disease (2008)](https://doi.org/10.1016/j.neurobiolaging.2007.08.011)

[Kanungo et al., Inhibiting ASK1 as therapeutic strategy (2016)](https://doi.org/10.1016/j.tips.2016.07.006)

[Takeda et al., ASK1 in ER stress and neurodegeneration (2018)](https://doi.org/10.1111/bph.14423)

[Kuroda et al., ASK1 structural features and regulation (2011)](https://doi.org/10.1016/j.tibs.2011.06.005)

[Cho et al., Selonsertib in clinical trials (2021)](https://doi.org/10.1016/j.jhep.2021.01.021)

[Chambers et al., JNK3 as therapeutic target (2020)](https://doi.org/10.1016/j.tips.2020.03.002)

[Xia et al., MPTP activates ASK1-JNK pathway (2009)](https://doi.org/10.1523/jneurosci.4023-08.2009)

[Witan et al., Mutant SOD1 activates ASK1 in ALS (2009)](https://doi.org/10.1093/hmg/ddp373)

[Matsuzawa et al., Thioredoxin inhibits ASK1 (2005)](https://doi.org/10.1016/j.tcb.2005.06.003)

[Zhu et al., ASK1-p38 in tau pathology (2022)](https://doi.org/10.1038/s41386-022-01427-8)

This page was expanded with PET tracer research and comprehensive mechanistic content.

Pathway Diagram

The following diagram shows the key molecular relationships involving MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

MAP3K5

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kg_node_id	MAP3K5
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-03e2cc992b3e
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-map3k5'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

55%

Debates

0

Incoming

11

Outgoing

33

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

Introduction

MAP3K5 — Mitogen-Activated Protein Kinase Kinase Kinase 5

Introduction

Gene Structure and Expression

Genomic Organization

Brain Expression

Protein Structure and Regulation

Domain Architecture

Regulation Mechanisms

Activation Mechanism

Signaling Pathways

Downstream Kinase Cascades

JNK Pathway

p38 Pathway

Role in Alzheimer's Disease

Amyloid-β Mediated Activation

Neuronal Apoptosis

Synaptic Dysfunction

Tau Pathology

Therapeutic Implications

Role in Parkinson's Disease

Dopaminergic Neuron Vulnerability

Toxin-Induced Models

α-Synuclein Toxicity

Mitochondrial Pathway

Therapeutic Potential

Role in ALS

Motor Neuron Vulnerability

Mutant SOD1 Models

Therapeutic Targeting

Role in Stroke/Ischemia

Ischemic Injury

Therapeutic Window

PET Imaging Tracer Development

[18F]ASK1-IN-6

Therapeutic Targeting

Small Molecule Inhibitors

Challenges

Clinical Trials

Cross-Links

Disease Associations

References

Pathway Diagram

💬 Discussion