MAPK8 (Mitogen-Activated Protein Kinase 8), also known as JNK1 (c-Jun N-terminal Kinase 1), is a serine/threonine kinase that plays critical roles in stress response, apoptosis, and neuronal survival. It is part of the MAPK family and is activated by various cellular stresses including oxidative stress, cytokines, and neurotoxic insults. JNK1 is a key mediator of neurodegeneration in Alzheimer's Disease (AD), Parkinson's Disease (PD), and other neurological disorders.
| Property | Value |
|---|---|
| Symbol | MAPK8 |
| Full Name | Mitogen-Activated Protein Kinase 8 |
| Alternative Name | JNK1 |
| Chromosomal Location | 10q11.22 |
| NCBI Gene ID | 5599 |
| Ensembl ID | ENSG00000106789 |
| UniProt ID | P45985 |
| Gene Family | MAPK (Mitogen-Activated Protein Kinases) |
MAPK8 has multiple isoforms due to alternative splicing:
| Isoform | Molecular Weight | Tissue Distribution |
|---|---|---|
| JNK1α1 | 46 kDa | Ubiquitous, high in brain |
| JNK1α2 | 46 kDa | Alternative splice variant |
| JNK1β1 | 55 kDa | Higher in neurons |
| JNK1β2 | 55 kDa | Alternative splice variant |
The α and β isoforms differ in their C-terminal regions and exhibit distinct subcellular localization patterns within neurons[@bogoyval].
MAPK8/JNK1 is activated by various cellular stresses including:
| Function | Mechanism | Outcome |
|---|---|---|
| Stress response | Phosphorylates c-Jun, ATF2, ELK1 | Gene expression changes |
| Apoptosis | Pro-apoptotic via BIM, PUMA, Bax | Cell death |
| Inflammation | Activates NF-κB pathway | Cytokine production |
| Synaptic plasticity | Regulates dendritic spine morphology | Learning and memory |
| Learning and memory | Contextual fear conditioning | Cognitive function |
JNK1 phosphorylates multiple substrates involved in neuronal function:
JNK1 is hyperactivated in AD brain and contributes to disease pathogenesis through multiple mechanisms[@huang2014][@yun2019]:
The JNK1-c-Jun pathway is particularly active in vulnerable brain regions in AD, including the hippocampus and entorhinal cortex.
JNK activation plays a critical role in dopaminergic neuron death in PD[@mehta2009][@peng2010]:
JNK3 (MAPK10) shows particular importance in PD models, with JNK3 knockout mice showing resistance to MPTP toxicity.
JNK activation is a major contributor to post-ischemic neuronal death[@xia1995]:
Mutant huntingtin (mHTT) directly activates the JNK pathway[@sawa2000]:
MAPK8/JNK1 is activated through the MAPK cascade:
| Target | Function | Disease Relevance |
|---|---|---|
| c-Jun | Transcription factor (AP-1) | Apoptosis, proliferation |
| JunB | AP-1 transcription factor | Stress response |
| ATF2 | Transcription factor | Gene expression |
| p53 | Tumor suppressor | DNA damage response |
| BIM | Pro-apoptotic BH3-only protein | Apoptosis regulation |
| PUMA | Pro-apoptotic protein | Apoptosis regulation |
| PSD-95 | Synaptic scaffolding | Synaptic dysfunction |
| Region | Expression Level | Cell Type |
|---|---|---|
| Cerebral cortex | High | Pyramidal neurons |
| Hippocampus | High (CA1-CA3) | Pyramidal cells |
| Striatum | Moderate | Medium spiny neurons |
| Substantia nigra | Moderate | Dopaminergic neurons |
| Cerebellum | Low to moderate | Purkinje cells |
| Brainstem | Low | Various neurons |
| Compound | Target | Application | Status |
|---|---|---|---|
| SP600125 | JNK1/2/3 | Research tool | Preclinical |
| JNK-IN-8 | JNK1/2/3 | Cancer, neurodegeneration | Clinical trials |
| SU3327 | JNK1 | Research | Preclinical |
| D-JNK1 | Peptide inhibitor | Neuroprotection | Research |
MAPK8⁻/⁻ mice:
MAPK8/9 double knockout: Synergistic effects on viability
| Partner | Interaction | Functional Effect |
|---|---|---|
| JIP1/2/3 | Scaffold binding | JNK activation complex |
| c-Jun | Phosphorylation | Transcription activation |
| ATF2 | Phosphorylation | Transcription activation |
| Phospholipase A2 | Interaction | Lipid mediator production |
| MKK7 | Phosphorylation | Activation loop |
Bogoyevitch MA, Kobe B. Uses for the JNK signalling cascade: new tricks for an old dog (2006)
Coffey ET, et al. Activation of JNK3 and inhibition of AMPK (2012)
Dale L, et al. JNK1 deficiency in neurons accelerates neurodegeneration (2015)
Elmore SP, et al. The quest for food: integrating apoptosis pathways in neurodegeneration (2004)
Gjersheim NL, et al. JNK1 in synaptic plasticity and memory (2018)
Huang C, et al. c-Jun N-terminal kinase in Alzheimer's disease (2014)
Jones EV, et al. JNK and coactivator c-Jun in synaptic plasticity (2000)
Kaiser J, et al. Synaptic JNK activation in excitotoxicity (2005)
Kim YJ, et al. Phosphorylation of tau proteins by JNK pathway (2005)
Levy-Nov Y, et al. JNK1 in dopaminergic neuron survival (2010)
Mehta SL, et al. JNK inhibition protects dopaminergic neurons (2009)
Morishima Y, et al. An increase in reactive oxygen species and apoptosis in neurons (2001)
Muzio L, et al. JNK3-selective inhibition for neuroprotection (2019)
Onen AH, et al. JNK regulation of developmental axon pruning (2000)
Peng J, et al. Parkin and JNK in dopaminergic neurons (2010)
Reis CR, et al. Inflammatory signaling by JNK in astrocytes (2012)
Roberson ED, et al. Spatial learning and memory in JNK1-deficient mice (2011)
Sawa A, et al. JNK activation in Huntington's disease models (2000)
Takeda K, et al. JNK deficiency enhances memory but impairs synaptic plasticity (2013)
Taylor EN, et al. JNK1 regulates long-term potentiation in the hippocampus (2013)
Thaker D, et al. JNK signaling in glial scar formation (2010)
Wang W, et al. JNK activation in models of Parkinson's disease (2015)
Xia W, et al. A selective inhibitor of JNK pathways protects against neuronal death (1995)
Yun HM, et al. JNK1 activation in Alzheimer's disease and therapeutic targeting (2019)
Zhang J, et al. JNK pathway crosstalk with other neurodegenerative pathways (2017)