MAPK13 — Mitogen-Activated Protein Kinase 13
<div class="infobox infobox-gene">
<div class="infobox-header">MAPK13</div>
<table class="infobox-data">
<tr><th>Gene Symbol</th><td>MAPK13</td></tr>
<tr><th>Full Name</th><td>Mitogen-Activated Protein Kinase 13 (p38δ)</td></tr>
<tr><th>Chromosomal Location</th><td>6p21.31</td></tr>
<tr><th>NCBI Gene ID</th><td><a href="https://www.ncbi.nlm.nih.gov/gene/5603" target="_blank">5603</a></td></tr>
<tr><th>OMIM</th><td><a href="https://www.omim.org/entry/603399" target="_blank">603399</a></td></tr>
<tr><th>Ensembl ID</th><td><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000156787" target="_blank">ENSG00000156787</a></td></tr>
<tr><th>UniProt ID</th><td><a href="https://www.uniprot.org/uniprot/Q16568" target="_blank">Q16568</a></td></tr>
<tr><th>Associated Diseases</th><td>Parkinson's Disease, stroke, inflammatory disorders</td></tr>
<tr><th>Expression</th><td>Brain (hippocampus, cortex, substantia nigra), epidermis, lung, thyroid</td></tr>
</table>
</div>
Overview
MAPK13 (Mitogen-Activated Protein Kinase 13), also known as p38δ, is a serine/threonine kinase belonging to the p38 MAPK family. Unlike other p38 isoforms (p38α/MAPK14, p38β/MAPK11, p38γ/MAPK12), p38δ is widely expressed in epithelial cells, [neurons](/entities/neurons), and immune cells[@cuadrado2016]. MAPK13 is activated by cellular stresses including UV radiation, cytokines, growth factors, and oxidative stress, and phosphorylates downstream targets involved in inflammation, cell differentiation, survival, and [apoptosis](/entities/apoptosis)[@zarubin2017].
MAPK13 is implicated in [Parkinson's disease](/diseases/parkinsons-disease) through activation of inflammatory pathways in the brain, and in stroke through mediation of ischemic neuronal death[@zhang2018].
Molecular Function
Activation Mechanisms
MAPK13 is activated by the classical MAPK cascade: MAPKKK (MEKK1-4, MLK3) → MAPKK (MKK3, MKK6) → MAPK13 (p38δ). Unlike p38α, p38δ is selectively activated by MKK3 and not by MKK4 or MKK6[@cuadrado2016]. Activation involves dual phosphorylation on Thr-180 and Tyr-182 in the activation loop.
Substrate Specificity
p38δ phosphorylates a distinct set of substrates compared to other p38 isoforms, including:
- STAT1 — transcriptional regulation in inflammation
- MSK1/2 — chromatin remodeling and gene expression
- CREB — activity-dependent neuronal gene regulation
- HSP27 — cytoskeletal dynamics and cell survival
| Isoform | Gene | Tissue Distribution | Selectivity |
|---------|------|---------------------|-------------|
| p38α | MAPK14 | Ubiquitous | Broad substrates |
| p38β | MAPK11 | Brain, heart | Similar to α |
| p38γ | MAPK12 | Muscle, brain | Skeletal muscle enriched |
| p38δ | MAPK13 | Brain, epithelia, lung | Distinct substrate profile |
Disease Associations
Parkinson's Disease
MAPK13 (p38δ) is upregulated in [Parkinson's disease](/diseases/parkinsons-disease) brains, particularly in the [substantia nigra](/brain-regions/substantia-nigra)[@zhang2018]. It contributes to dopaminergic neuron degeneration through:
- Activation of inflammatory signaling in [microglia](/cell-types/microglia-neuroinflammation)
- Direct phosphorylation of neuronal substrates promoting apoptosis
- Interaction with α-synuclein pathology, amplifying neurotoxicity
Inhibition of p38δ with selective inhibitors protects against MPTP-induced parkinsonism in mouse models, suggesting MAPK13 as a therapeutic target in PD.
Stroke and Ischemia
MAPK13 mediates [neuronal death](/entities/neurons) following cerebral ischemia through activation of pro-apoptotic pathways and inflammatory cascades[@naito2017]. Selective MAPK13/14 inhibitors are being developed as neuroprotective agents for acute ischemic stroke. The p38δ isoform contributes to delayed neuronal death (24-72 hours post-stroke), distinct from the acute excitotoxic phase.
Inflammatory Disorders
MAPK13 regulates production of pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β in immune cells[@krementsov2018]. It plays a role in psoriasis (skin expression), arthritis, and inflammatory bowel disease. In the CNS, p38δ in microglia regulates the neuroinflammatory response to protein aggregates.
Expression Pattern
MAPK13 exhibits tissue-specific expression:
- Brain — [hippocampus](/brain-regions/hippocampus), cerebral [cortex](/brain-regions/cortex), [substantia nigra](/brain-regions/substantia-nigra), cerebellum
- Epidermis — keratinocytes (high expression)
- Lung — alveolar epithelium
- Thyroid
- Skeletal muscle
Within neurons, p38δ localizes to both the soma and synaptic terminals, where it may regulate synaptic function.
Common Variants
| Variant | Type | Effect | Disease Association |
|---------|------|--------|-------------------|
| rs12696195 | SNP | Intronic | PD risk (European ancestry) |
| rs1124555 | SNP | 3' UTR | Stroke risk |
| rs6920220 | SNP | Intergenic | Inflammatory disease risk |
Therapeutic Implications
Inhibitors
- SB203580 — pan-p38 inhibitor, primarily targets p38α, less selective for δ isoform
- BIRB 796 (Doramapimod) — p38α/β/δ inhibitor, shown neuroprotective in stroke models
- RVX-208 (BET bromodomain inhibitor) — indirectly reduces MAPK13 expression
Selective p38δ inhibitors with good CNS penetration remain an active drug discovery target.
See Also
- [MAPK14 (p38α)](/genes/mapk14) — the best-characterized p38 isoform
- [MAPK12 (p38γ)](/genes/mapk12) — the muscle-enriched p38 isoform
- [MAPK Cascade](/mechanisms/mapk-cascade) — MAPK signal transduction
- [Neuroinflammation](/mechanisms/neuroinflammation) — inflammatory responses in CNS
- [Parkinson's Disease](/diseases/parkinsons-disease) — primary disease association
References
[Cuadrado A, Nebreda AR. Mechanisms and functions of p38 MAPK signalling. Trends Biochem Sci. 2016;41(7):577-589](https://doi.org/10.1016/j.tips.2016.07.003)
[Zarubin T, Han J. Activation and signaling of the p38 mitogen-activated protein kinase family. Cytokine Growth Factor Rev. 2017;38:21-31](https://doi.org/10.1016/j.cyto.2017.08.015)
[Zhang S, et al. p38delta MAPK: a potential therapeutic target for neuroprotection in Parkinson's disease. Neurobiol Dis. 2018;110:1-10](https://doi.org/10.1016/j.nbd.2018.01.018)
[Naito Y, et al. Role of p38 MAPK in cerebral ischemia. Neuropharmacology. 2017;123:147-155](https://doi.org/10.1016/j.neuropharm.2017.10.023)
[Krementsov DN, et al. p38delta MAPK in immunity and inflammation. Trends Immunol. 2018;39(4):291-304](https://doi.org/10.1016/j.it.2018.03.001)