MAPK8

The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha induced apoptosis. This kinase is also involved in UV radiation induced apoptosis, which is thought to be related to cytochrom c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Apr 2016]

Mitogen-Activated Protein Kinase 8

Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as pro-inflammatory cytokines or physical stress stimulate the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. In this cascade, two dual specificity kinases MAP2K4/MKK4 and MAP2K7/MKK7 phosphorylate and activate MAPK8/JNK1. In turn, MAPK8/JNK1 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN, JDP2 and ATF2 and thus regulates AP-1 transcriptional activity (PubMed:18307971).
Phosphorylates the replication licensing factor CDT1, inhibiting the interaction between CDT1 and the histone H4 acetylase HBO1 to replication origins (PubMed:21856198).
Loss of this interaction abrogates the acetylation required for replication initiation (PubMed:21856198).
Promotes stressed cell apoptosis by phosphorylating key regulatory factors including p53/TP53 and Yes-associates protein YAP1 (PubMed:21364637).
In T-cells, MAPK8 and MAPK9 are required for polarized differentiation of T-helper cells into Th1 cells. Contributes to the survival of erythroid cells by phosphorylating the antagonist of cell death BAD upon EPO stimulation (PubMed:21095239).
Mediates starvation-induced BCL2 phosphorylation, BCL2 dissociation from BECN1, and thus activation of autophagy (PubMed:18570871).
Phosphorylates STMN2 and hence regulates microtubule dynamics, controlling neurite elongation in cortical neurons (By similarity).
In the developing brain, through its cytoplasmic activity on STMN2, negatively regulates the rate of exit from multipolar stage and of radial migration from the ventricular zone (By similarity).
Phosphorylates several other substrates including heat shock factor protein 4 (HSF4), the deacetylase SIRT1, ELK1, or the E3 ligase ITCH (PubMed:20027304, PubMed:16581800, PubMed:17296730).
Phosphorylates the CLOCK-ARNTL/BMAL1 heterodimer and plays a role in the regulation of the circadian clock (PubMed:22441692).
Phosphorylates the heat shock transcription factor HSF1, suppressing HSF1-induced transcriptional activity (PubMed:10747973).
Phosphorylates POU5F1, which results in the inhibition of POU5F1's transcriptional activity and enhances its proteosomal degradation (By similarity).
Phosphorylates JUND and this phosphorylation is inhibited in the presence of MEN1 (PubMed:22327296).
In neurons, phosphorylates SYT4 which captures neuronal dense core vesicles at synapses (By similarity).
Phosphorylates EIF4ENIF1/4-ET in response to oxidative stress, promoting P-body assembly (PubMed:22966201).
Phosphorylates SIRT6 in response to oxidative stress, stimulating its mono-ADP-ribosyltransferase activity (PubMed:27568560).
JNK1 isoforms display different binding patterns: beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta-2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms.

Cellular response to amino acid starvationManual Assertion Based On ExperimentIDA:CAFA
Cellular response to cadmium ionManual Assertion Based On ExperimentIMP:CAFA
Cellular response to lipopolysaccharideManual Assertion Based On ExperimentIDA:MGI
Cellular response to mechanical stimulusManual Assertion Based On ExperimentIEP:UniProtKB
Cellular response to reactive oxygen speciesManual Assertion Based On ExperimentIMP:CAFA
Cellular senescenceTAS:Reactome
Fc-epsilon receptor signaling pathwayTAS:Reactome
Intracellular signal transductionManual Assertion Based On ExperimentIBA:GO_Central
JNK cascadeManual Assertion Based On ExperimentIDA:UniProtKB
JUN phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of protein bindingManual Assertion Based On ExperimentIDA:UniProtKB
Peptidyl-serine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Peptidyl-threonine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of apoptotic processManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of cell killingTAS:Reactome
Positive regulation of cyclase activityManual Assertion Based On ExperimentIMP:CACAO
Positive regulation of deacetylase activityManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of gene expressionManual Assertion Based On ExperimentIMP:BHF-UCL
Positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathwayTAS:Reactome
Positive regulation of protein metabolic processManual Assertion Based On ExperimentIMP:CACAO
Protein phosphorylationManual Assertion Based On ExperimentIDA:CAFA
Regulation of circadian rhythmISS:UniProtKB
Regulation of DNA replication origin bindingManual Assertion Based On ExperimentIMP:CAFA
Regulation of DNA-binding transcription factor activityTAS:Reactome
Regulation of macroautophagyManual Assertion Based On ExperimentTAS:ParkinsonsUK-UCL
Regulation of protein localizationManual Assertion Based On ExperimentIDA:BHF-UCL
Response to mechanical stimulusManual Assertion Based On ExperimentIBA:GO_Central
Response to oxidative stressManual Assertion Based On ExperimentIDA:UniProtKB
Response to UVManual Assertion Based On ExperimentIDA:MGI
Rhythmic processIEA:UniProtKB-KW
Stress-activated MAPK cascadeManual Assertion Based On ExperimentIDA:CAFA

Cytoplasm
Nucleus
Cell junction, synapse
In the cortical neurons, predominantly cytoplasmic and associated with the Golgi apparatus and endosomal fraction. Increased neuronal activity increases phosphorylated form at synapses (By similarity).
Colocalizes with POU5F1 in the nucleus.

Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme (PubMed:11062067).
Phosphorylated by TAOK2 (PubMed:17158878).
May be phosphorylated at Thr-183 and Tyr-185 by MAP3K1/MEKK1 (PubMed:17761173).
Phosphorylated form is more concentrated at synapses than none-phosphorylated (By similarity).