| Gene Symbol | MAPK4 |
|---|---|
| Full Name | Mitogen-Activated Protein Kinase 4 |
| Protein Name | ERK4 (Extracellular Signal-Regulated Kinase 4) |
| Chromosomal Location | 18q12.2 |
| NCBI Gene ID | 5595 |
| OMIM | 617957 |
| Ensembl ID | ENSG00000116539 |
| UniProt | P31196 |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, Cancer, Neuroinflammation |
| Expression | Brain (neurons, astrocytes), various tissues |
MAPK4 encodes ERK4 (Extracellular Signal-Regulated Kinase 4), a member of the mitogen-activated protein kinase (MAPK) family. Unlike classical MAPKs such as ERK1/2 (MAPK3/MAPK1), ERK4 is classified as an "atypical" MAPK because it lacks canonical activation-loop phosphorylation sites and does not require dual phosphorylation for activity. This distinctive regulation, combined with its expression in neurons and astrocytes, positions MAPK4 as an important regulator of brain function and a potential contributor to neurodegenerative disease pathogenesis[1].
The MAPK family includes several subfamilies:
ERK4 is expressed throughout the brain with particularly high levels in the cortex, hippocampus, and basal ganglia. It participates in diverse signaling pathways controlling neuronal survival, synaptic function, stress responses, and inflammatory processes[2].
The human MAPK4 gene has a complex genomic organization that reflects its multiple transcript variants and regulatory mechanisms.
| Feature | Details |
|---|---|
| Chromosome | 18q12.2 |
| Genomic Span | ~77 kb |
| Exons | 16 coding exons |
| Transcript Length | ~4.0 kb |
| Protein Length | 632 amino acids |
| Molecular Weight | ~65 kDa |
| Kinase | Gene | Size (aa) | Phosphorylation Sites | Activation |
|---|---|---|---|---|
| ERK1 | MAPK3 | 384 | T202/Y204 | Dual phosphorylation |
| ERK2 | MAPK1 | 360 | T185/Y187 | Dual phosphorylation |
| ERK3 | MAPK6 | 398 | S189 (unique) | Single site |
| ERK4 | MAPK4 | 632 | None canonical | Kinase-independent |
| ERK5 | MAPK7 | 816 | T218/Y220 | Dual phosphorylation |
| JNK1 | MAPK8 | 384 | T183/Y185 | Dual phosphorylation |
| p38α | MAPK14 | 360 | T180/Y182 | Dual phosphorylation |
ERK4 has a distinctive structure that reflects its atypical nature:
| Property | Conventional MAPKs | ERK4 |
|---|---|---|
| Activation loop | Requires dual phosphorylation | No phosphorylation required |
| Catalytic activity | Low without activation | Constitutively active |
| Regulation | By upstream kinases | By protein interactions |
| Substrate specificity | Phosphorylation-dependent | Interaction-dependent |
Despite being classified as an atypical MAPK, ERK4 has genuine kinase activity:
ERK4 participates in multiple neuronal signaling pathways[3]:
ERK4 responds to various cellular stresses:
| Stress Type | ERK4 Response | Outcome |
|---|---|---|
| Oxidative Stress | Activation | Adaptive response |
| DNA Damage | Involvement | Cell cycle control |
| ER Stress | Modulation | Unfolded protein response |
| Osmotic Stress | Response | Volume regulation |
ERK4 in glial cells regulates inflammatory responses[4]:
| Brain Region | ERK4 Expression | Cell Type |
|---|---|---|
| Cerebral Cortex | High | Pyramidal neurons, interneurons |
| Hippocampus | High | CA1-CA3 pyramidal cells, dentate granule cells |
| Basal Ganglia | Moderate | Medium spiny neurons |
| Cerebellum | Moderate | Purkinje cells |
| Brainstem | Moderate | Various neuron types |
ERK4 is implicated in Alzheimer's disease pathogenesis through multiple mechanisms[5]:
ERK4 involvement in Parkinson's disease:
ERK4 has complex, often oncogenic roles in cancer[6]:
| Cancer Type | ERK4 Role | Evidence |
|---|---|---|
| Breast Cancer | Oncogenic | Overexpression, promotes proliferation |
| Lung Cancer | Context-dependent | Both pro- and anti-tumorigenic |
| Colorectal Cancer | Oncogenic | Amplification, high expression |
| Glioma | Oncogenic | Promotes growth and invasion |
ERK4 contributes to excessive inflammation in:
A key study demonstrates the neuroprotective potential of ERK4 deficiency[2:1]:
| Approach | Status | Considerations |
|---|---|---|
| ATP-competitive inhibitors | Preclinical | May not inhibit all functions |
| Allosteric inhibitors | Preclinical | Better selectivity potential |
| Protein-protein interaction blockers | Discovery | Challenge of drugability |
| Gene therapy (knockdown) | Preclinical | Long-lasting effect |
Last updated: 2026-03-25
Kim EK, Choi EJ. Compromised MAPK signaling in human diseases. Arch Toxicol. 2015. ↩︎
Huang CY, et al. ERK4 deficiency attenuates neuroinflammation and protects against neurodegenerative diseases. J Neuroinflammation. 2020. ↩︎ ↩︎
Kim JH, et al. Role of MAPK4 in neuronal survival and synaptic function. Mol Neurobiol. 2020. ↩︎
Caruso A, et al. ERK4 signaling in astrocytes and neuroinflammation. Glia. 2022. ↩︎
Sun J, et al. MAPK4 and neurodegenerative disease mechanisms. Prog Neuropsychopharmacol Biol Psychiatry. 2021. ↩︎
Zhou Y, et al. MAPK4 promotes tumor progression and chemoresistance. Oncogene. 2017. ↩︎