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. [1]
| MAP3K5 (ASK1) | |
|---|---|
| Gene Symbol | MAP3K5 |
| Protein Name | ASK1 (Apoptosis Signal-regulating Kinase 1) |
| Full Name | Mitogen-Activated Protein Kinase Kinase Kinase 5 |
| Chromosome | 6q26 |
| NCBI Gene ID | [4217](https://www.ncbi.nlm.nih.gov/gene/4217) |
| OMIM | 602476 |
| Ensembl ID | ENSG00000197442 |
| UniProt ID | [Q9UHD6](https://www.uniprot.org/uniprot/Q9UHD6) |
| Protein Length | 1,374 amino acids |
| Molecular Weight | ~155 kDa |
| Associated Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), ALS, Stroke |
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. [2]
In the central nervous system, ASK1 is highly expressed in:
This neuronal expression pattern makes ASK1 particularly relevant to neurodegenerative processes. [1:1]
ASK1 contains several functional domains:
ASK1 activity is tightly controlled through multiple mechanisms:
| Regulator | Mechanism | Effect |
|---|---|---|
| Thioredoxin (Trx) | Covalent binding to N-terminal | Inhibits activation [3] |
| 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 |
Under non-stressed conditions, ASK1 is held in an inactive state through:
Upon stress exposure, these inhibitory interactions are disrupted, leading to ASK1 autophosphorylation and activation. [2:1]
ASK1 → MKK4/7 → JNK1/2/3 → c-Jun/ATF2 → AP-1 → Apoptosis
Key substrates:
ASK1 → MKK3/6 → p38α/β/γ/δ → ATF2/CREB/MSK → Inflammation
Key functions:
Aβ activates ASK1 through multiple mechanisms:
Aβ-induced ASK1 activation mediates neuronal death through:
ASK1-JNK pathway impairs synaptic plasticity:
The ASK1-p38 pathway contributes to tau hyperphosphorylation:
ASK1 represents a promising therapeutic target:
SNc dopaminergic neurons show particular susceptibility to ASK1 activation:
In MPTP and 6-OHDA models:
α-Syn aggregation activates ASK1-JNK pathway:
ASK1 links mitochondrial dysfunction to apoptosis:
ASK1 inhibition may protect dopaminergic neurons:
Motor neurons are particularly susceptible to ASK1 activation:
In SOD1 transgenic mice:
ASK1 inhibitors:
ASK1 is strongly activated in ischemic brain:
ASK1 inhibition may provide:
A landmark development in ASK1 research is the first fluorine-18 PET radiotracer for ASK1 neuroimaging: [5:1]
Key characteristics:
Preclinical results:
Clinical potential:
| Compound | Target | Stage | Notes |
|---|---|---|---|
| Selonsertib (GS-4997) | ASK1 | Phase II | Originally for NASH [8] |
| 5Z-7-Oxozeaenol | ASK1 | Preclinical | Natural product analog |
| K811 | ASK1 | Preclinical | Selective inhibitor |
Selonsertib (GS-4997) has been evaluated in:
Kadowaki et al. ASK1 in neurodegeneration (2005). 2005. ↩︎ ↩︎
Kuroda et al. ASK1 structural features and regulation (2011). 2011. ↩︎ ↩︎
Matsuzawa et al. Thioredoxin inhibits ASK1 (2005). 2005. ↩︎
Zhu et al. ASK1-p38 pathway in tau pathology (2022). 2022. ↩︎
Zhang et al. [18F]ASK1-IN-6 is the first Fluorine-18 PET radiotracer for ASK1 neuroimaging. 2024. ↩︎ ↩︎
Xia et al. MPTP activates ASK1-JNK pathway in PD (2009). 2009. ↩︎
Witan et al. Mutant SOD1 activates ASK1 in ALS (2009). 2009. ↩︎
Cho et al. Selonsertib (GS-4997) in clinical trials (2021). 2021. ↩︎