MAPK4 (Mitogen-Activated Protein Kinase 4) - Structure, Function, and Clinical Significance
A comprehensive overview of the MAPK4 gene, including its genomic context, protein function, expression patterns, and associated diseases.
Gene Information Card
| Symbol | MAPK4 |
|---|---|
| Full Name | Mitogen-Activated Protein Kinase 4 |
| Gene Type | protein coding |
| Chromosomal Location | 18q21.1 |
| NCBI Gene ID | 5596 ncbi.nlm.nih.gov/gene/5596 |
| Ensembl ID | ENSG00000141655 |
| UniProt ID | P31152 |
| OMIM ID | 602949 |
| HGNC ID | 6876 |
| Aliases | ERK4, p63MAPK |
Description
MAPK4 (Mitogen-Activated Protein Kinase 4), also known as ERK4 or p63MAPK, is a protein-coding gene that belongs to the mitogen-activated protein kinase (MAPK) family. MAPKs are serine/threonine-specific protein kinases that participate in a complex signaling network regulating various cellular processes, including proliferation, differentiation, transcription regulation, and development. MAPK4 is classified as an atypical MAPK due to its unique activation mechanism and substrate specificity. Unlike classical MAPKs (ERK1/2), MAPK4 is not activated by the canonical MEK1/2 pathway. Instead, it is phosphorylated and activated by PAK1 (p21-activated kinase 1) in response to various stimuli. MAPK4 has been shown to play a role in cell growth, survival, and motility, and its dysregulation has been implicated in several cancers, particularly prostate and breast cancer.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Prostate Cancer | MAPK4 overexpression promotes tumor growth and metastasis. It activates the AKT/mTOR signaling pathway, leading to increased cell survival and proliferation. MAPK4 also phosphorylates and activates the androgen receptor (AR), contributing to castration-resistant prostate cancer (CRPC). | Experimental evidence from cell lines and mouse models; expression data from patient samples (PMID: 31142625). |
| Breast Cancer | MAPK4 is overexpressed in a subset of breast cancers and is associated with poor prognosis. It promotes cancer cell migration and invasion by activating the AKT pathway and modulating the actin cytoskeleton. | Expression analysis in tumor samples and functional studies in cell lines (PMID: 31142625). |
| Hepatocellular Carcinoma (HCC) | MAPK4 expression is upregulated in HCC tissues and correlates with tumor progression and poor survival. It promotes cell proliferation and invasion through activation of the ERK1/2 pathway in a cell-context-dependent manner. | Expression profiling and in vitro/in vivo functional assays (PMID: 31578321). |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skeletal Muscle | 12.4 | Medium |
| Heart | 8.9 | Low |
| Brain | 7.2 | Low |
| Kidney | 6.5 | Low |
| Liver | 4.1 | Low |
| Lung | 3.8 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| MCF7 (Breast Cancer) | 15.2 | High expression; associated with aggressive phenotype. |
| PC3 (Prostate Cancer) | 18.7 | High expression; linked to AR activation and CRPC. |
| HepG2 (Liver Cancer) | 9.5 | Moderate expression; promotes proliferation. |
| A549 (Lung Cancer) | 6.1 | Low expression. |
| HEK293 (Embryonic Kidney) | 4.5 | Low endogenous expression; commonly used for overexpression studies. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1045C>T (p.Arg349Trp) | Missense | Rare (<0.01%) | Located in the kinase domain; predicted to affect ATP binding and kinase activity. Functional impact is uncertain. |
| c.1567G>A (p.Val523Met) | Missense | Rare (<0.01%) | Located in the C-terminal region; may affect protein stability or interaction with binding partners. |
| c.1129A>G (p.Thr377Ala) | Missense | Rare (<0.01%) | Located in the activation loop; may alter phosphorylation by upstream kinases like PAK1. |
Mutation functional classification
Loss of Function (LOF)
No well-characterized loss-of-function mutations have been reported in MAPK4. Knockout studies in mice show that MAPK4 is not essential for development, suggesting functional redundancy with other MAPKs.
Gain of Function (GOF)
Gene amplification and mRNA overexpression are the primary mechanisms of MAPK4 dysregulation in cancer. These events lead to increased protein levels and constitutive activation of downstream signaling pathways (e.g., AKT/mTOR).
Dominant Negative (DN)
No naturally occurring dominant-negative mutations have been described. However, kinase-dead mutants (e.g., K49A) are used experimentally to inhibit MAPK4 function in vitro.
View complete mutation data：
Gene Ontology (GO)
| • protein serine/threonine kinase activity | • ATP binding |
| • MAP kinase activity | • signal transduction |
| • protein phosphorylation | • regulation of cell population proliferation |
| • regulation of apoptotic process | • cytosol |
| • nucleus |
Pathways
• MAPK signaling pathway
• AKT/mTOR signaling pathway
• Androgen receptor signaling pathway
• PAK1-mediated signaling
Protein Summary
The MAPK4 protein, also known as ERK4, is a 587-amino acid serine/threonine kinase. It contains a conserved kinase domain and a unique C-terminal extension. Unlike classical MAPKs, MAPK4 lacks the canonical T-X-Y activation motif and is instead activated by phosphorylation on Ser186 and Thr190 by PAK1. This activation leads to the phosphorylation of downstream substrates, most notably the MAPK-activated protein kinase 5 (MK5). MAPK4 also directly interacts with and activates AKT, promoting cell survival and proliferation. Its expression is tightly regulated, and aberrant overexpression is observed in several cancers, making it a potential therapeutic target.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MAPK4 Knockout HEK293 Cell Line | EDJ-KQ5538 | Human | 5596 | Details Get a Quote |
| MAPK4 Knockout HeLa Cell Line | EDJ-KQ28790 | Human | 5596 | Details Get a Quote |
| MAPK4 Knockout A-549 Cell Line | EDJ-KQ62708 | Human | 5596 | Details Get a Quote |
| MAPK4 Knockout HCT 116 Cell Line | EDJ-KQ71180 | Human | 5596 | Details Get a Quote |
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