| Mitogen-Activated Protein Kinase Kinase 3 | |
|---|---|
| Gene Symbol | MAP2K3 |
| Full Name | Mitogen-Activated Protein Kinase Kinase 3 |
| Chromosome | 6p21.3 |
| NCBI Gene ID | [5606](https://www.ncbi.nlm.nih.gov/gene/5606) |
| OMIM | [602314](https://www.omim.org/entry/602314) |
| Ensembl ID | ENSG00000099695 |
| UniProt ID | [P46734](https://www.uniprot.org/uniprot/P46734) |
| Associated Diseases | Alzheimer's Disease, Parkinson's Disease, ALS, Cancer |
MAP2K3 (Mitogen-Activated Protein Kinase Kinase 3), also known as MEK3, is a dual-specificity protein kinase that serves as a critical upstream activator of the p38 MAPK signaling pathway.[1] It phosphorylates and activates p38 alpha, beta, and gamma MAP kinases in response to cellular stresses including oxidative stress, inflammatory cytokines, UV radiation, and ischemic injury.[2] The MAP2K3/p38 pathway plays pivotal roles in regulating cellular processes such as proliferation, differentiation, apoptosis, and inflammatory responses, all of which are dysregulated in neurodegenerative diseases.[3] In the brain, MAP2K3 is expressed in both neurons and glial cells, where its activation contributes to neuroinflammation, tau pathology, and synaptic dysfunction in Alzheimer's disease (AD), dopaminergic neuron death in Parkinson's disease (PD), and motor neuron degeneration in amyotrophic lateral sclerosis (ALS).[4]
MAP2K3 (MEK3) is a mitogen-activated protein kinase kinase that activates p38 MAP kinase signaling pathways. It is a dual-specificity kinase that phosphorylates and activates MAP kinase 14 (p38-alpha), MAP kinase 11 (p38-beta), and MAP kinase 12 (p38-gamma). MAP2K3 is activated by various cellular stresses including oxidative stress, inflammatory cytokines, and UV radiation. It plays important roles in cell proliferation, differentiation, apoptosis, and inflammatory responses. MAP2K3 is itself activated by MAP3Ks including MEKK1-4 and TAK1.
The MAP2K3/p38 signaling cascade:
Cellular Stress → MAP3K Activation → MAP2K3 (MEK3) Activation → p38 MAPK Phosphorylation → Cellular Responses
Key downstream effects include:
In Alzheimer's disease, MAP2K3/p38 signaling is activated in neurons surrounding amyloid plaques and contributes to disease pathogenesis through multiple mechanisms:[4][5]
In Parkinson's disease, MAP2K3/p38 signaling contributes to dopaminergic neuron degeneration:[6]
In amyotrophic lateral sclerosis, MAP2K3/p38 activation in motor neurons and glial cells contributes to:
MAP2K3 and its downstream p38 MAPK represent important therapeutic targets:
MAP2K3 is expressed in most tissues, with high expression in brain, heart, and skeletal muscle. In the brain, it is expressed in neurons and glia. Expression and activation are increased in various brain regions affected by neurodegenerative diseases, including:
While MAP2K3 is not typically mutated in familial neurodegenerative diseases, polymorphisms in the MAP2K3 gene have been associated with:
MAP2K3/p38 pathway activation markers in cerebrospinal fluid (CSF) and blood are being studied as potential biomarkers: