MAPK8 (mitogen-activated protein kinase 8)

2003-01-01   Fei Chen 

Health Effects Laboratory Division, NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505, USA

Identity

HGNC
LOCATION
10q11.22
LOCUSID
ALIAS
JNK,JNK-46,JNK1,JNK1A2,JNK21B1/2,PRKM8,SAPK1,SAPK1c
FUSION GENES

DNA/RNA

Atlas Image

Description

The JNK1 gene maps on chromosome 10q11.21 spanning 130089bp. It contains 22 confirmed introns, 20 of which are alternative.

Transcription

By alternative splicing, JNK1 gene encodes 13 different transcripts that translate to 13 JNK1 isoforms. The predicted molecular weight of JNK1 protein is 44.2 kD.

Proteins

Description

All JNK proteins contain a protein kinase domain that belong to a very extensive family of eukaryotic serine/threonine proteins kinase. A number of conserved regions have been identified in the catalytic domain of JNKs. In the N-terminal extremity of the catalytic domain there is a glycine-rich motif in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. A conserved aspartic acid reside that is critical for the catalytic activity of kinase has also been identified in the central part of the catalytic domain.

Expression

JNK1 is ubiquitously expressed.

Localisation

Cytoplasmic and nuclear

Function

The members of JNK family act as an integration point for multiple intracellular biochemical signals governing a wide variety of cellular processes such as proliferation, differentiation, apoptosis, migration, transcriptional regulation, and development JNK targets specific transcription factors and thus mediates immediate-early gene expression in response to various stress signals including ultraviolet (UV) radiation, oxidative stress, protein malfolding in endoplasmic reticulum, osmotical shock, and inflammatory mediators. These transcription factors include AP-1, ATF-2, Elk-1, p53, etc... Several upstream dual specific protein kinases, such as MKK4/SEK1 and MKK7, can activate JNK through phosphorylation of the conversed Thr-Pro-Tyr motif on JNK proteins. In mammalian cells, activated JNK can phosphorylate the N-terminus of c-Jun, which contains both JNK docking site and JNK phosphorylation site (ser63 and ser73), orJunD, which lacks a JNK docking site but contains a JNK phosphorylation site. JNK is unable to phosphorylate JunB due to the lack of a JNK phosphorylation site inJunB, despite there is a functional JNK docking site. Comparison of the binding activity of JNK isoforms demonstrates that JNK2 bind c-Jun approximately 25 times more efficiently than did JNK1. Therefore, individual members of the JNK family may selectively target specific transcription factors in vivo. One of the most important functions of JNK is the regulation of apoptosis. Emerging evidence indicates that JNK activation is obligatory for apoptosis induced by both receptor-mediated "extrinsic" pathway or mitochondria-mediated "intrinsic" pathway. JNK activation may contribute to the initiation of Fas-induced apoptosis, possibly through the amplification of autocrine or paracrine Fas signaling by JNK-dependent Fas ligand (FasL) gene expression. In addition, JNK has been indicated in the apoptosis induced by Daxx, a Fas death domain (FADD) interaction protein. Through its serine/threonine kinase activity, JNK may contribute to mitochondria-mediated apoptosis by phosphorylating pro- or anti-apoptoticBcl-2 family proteins. Finally, JNK has also been indicated as an important kinase phosphorylating p53 and subsequently facilitating p53-dependent apoptotic responses. Sustained JNK activation may be responsible for the enhanced apoptosis observed in RelA-/- or Ikkb-/- mouse embryonic fibroblasts treated with TNFa. It was suggested that deficiency of RelA or IKKb caused a decreased expression of XIAP or GADD45b, which may antagonize the activation of JNK activation. However, such speculation contradicts the previous observations indicating that both GADD45b and XIAP are activators, rather than inhibitors for JNK activation. Moreover, gene profiling in our recent studies indicated no substantial difference of basal or inducible GADD45b and XIAP mRNA in wild type cells and Ikkb-/- cells.

Implicated in

Entity name
Obesity, insulin resistance, neurodegenerative diseases, inflammation, cancer.

Bibliography

Pubmed IDLast YearTitleAuthors
110578972000Signal transduction by the JNK group of MAP kinases.Davis RJ et al
117135302001Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling.De Smaele E et al
97106251998Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter.Faris M et al
97322641998JNK targets p53 ubiquitination and degradation in nonstressed cells.Fuchs SY et al
99256411999Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase.Jacobs D et al
114472972001Ubiquitin-protein ligase activity of X-linked inhibitor of apoptosis protein promotes proteasomal degradation of caspase-3 and enhances its anti-apoptotic effect in Fas-induced cell death.Suzuki Y et al
98278041998A family of stress-inducible GADD45-like proteins mediate activation of the stress-responsive MTK1/MEKK4 MAPKKK.Takekawa M et al
117135312001Inhibition of JNK activation through NF-kappaB target genes.Tang G et al
92156291997Daxx, a novel Fas-binding protein that activates JNK and apoptosis.Yang X et al

Other Information

Locus ID:

NCBI: 5599
MIM: 601158
HGNC: 6881
Ensembl: ENSG00000107643

Variants:

dbSNP: 5599
ClinVar: 5599
TCGA: ENSG00000107643
COSMIC: MAPK8

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000107643ENST00000360332P45983
ENSG00000107643ENST00000374176P45983
ENSG00000107643ENST00000374176A1L4K2
ENSG00000107643ENST00000374179P45983
ENSG00000107643ENST00000374182P45983
ENSG00000107643ENST00000374189P45983
ENSG00000107643ENST00000395611P45983
ENSG00000107643ENST00000395611A1L4K2
ENSG00000107643ENST00000426557C9J762
ENSG00000107643ENST00000429041C9JWQ4
ENSG00000107643ENST00000432379C9J762
ENSG00000107643ENST00000476134A0A3B3IRW7

Expression (GTEx)

0
5
10
15
20
25
30
35

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Autophagy - animalKEGGko04140
ApoptosisKEGGko04210
Wnt signaling pathwayKEGGko04310
Focal adhesionKEGGko04510
Tight junctionKEGGko04530
Toll-like receptor signaling pathwayKEGGko04620
Fc epsilon RI signaling pathwayKEGGko04664
Insulin signaling pathwayKEGGko04910
GnRH signaling pathwayKEGGko04912
Progesterone-mediated oocyte maturationKEGGko04914
Adipocytokine signaling pathwayKEGGko04920
Type II diabetes mellitusKEGGko04930
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
Colorectal cancerKEGGko05210
Pancreatic cancerKEGGko05212
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Autophagy - animalKEGGhsa04140
ApoptosisKEGGhsa04210
Wnt signaling pathwayKEGGhsa04310
Focal adhesionKEGGhsa04510
Tight junctionKEGGhsa04530
Toll-like receptor signaling pathwayKEGGhsa04620
Fc epsilon RI signaling pathwayKEGGhsa04664
Insulin signaling pathwayKEGGhsa04910
GnRH signaling pathwayKEGGhsa04912
Adipocytokine signaling pathwayKEGGhsa04920
Type II diabetes mellitusKEGGhsa04930
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
ShigellosisKEGGhsa05131
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Pancreatic cancerKEGGhsa05212
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
Progesterone-mediated oocyte maturationKEGGhsa04914
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Protein processing in endoplasmic reticulumKEGGko04141
Protein processing in endoplasmic reticulumKEGGhsa04141
ToxoplasmosisKEGGko05145
ToxoplasmosisKEGGhsa05145
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
TuberculosisKEGGko05152
TuberculosisKEGGhsa05152
Influenza AKEGGko05164
Influenza AKEGGhsa05164
PertussisKEGGko05133
PertussisKEGGhsa05133
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Salmonella infectionKEGGko05132
Salmonella infectionKEGGhsa05132
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Retrograde endocannabinoid signalingKEGGhsa04723
Retrograde endocannabinoid signalingKEGGko04723
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Hepatitis BKEGGhsa05161
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Ras signaling pathwayKEGGhsa04014
FoxO signaling pathwayKEGGhsa04068
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Choline metabolism in cancerKEGGhsa05231
Choline metabolism in cancerKEGGko05231
MAPK (JNK) signalingKEGGhsa_M00688
MAPK (JNK) signalingKEGGM00688
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1REACTOMER-HSA-450321
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
Activation of the AP-1 family of transcription factorsREACTOMER-HSA-450341
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Signal TransductionREACTOMER-HSA-162582
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
Cell death signalling via NRAGE, NRIF and NADEREACTOMER-HSA-204998
NRAGE signals death through JNKREACTOMER-HSA-193648
NRIF signals cell death from the nucleusREACTOMER-HSA-205043
Cell-Cell communicationREACTOMER-HSA-1500931
DSCAM interactionsREACTOMER-HSA-376172
Programmed Cell DeathREACTOMER-HSA-5357801
ApoptosisREACTOMER-HSA-109581
Intrinsic Pathway for ApoptosisREACTOMER-HSA-109606
Activation of BH3-only proteinsREACTOMER-HSA-114452
Activation of BIM and translocation to mitochondriaREACTOMER-HSA-111446
Activation of BMF and translocation to mitochondriaREACTOMER-HSA-139910
DNA RepairREACTOMER-HSA-73894
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Oxidative Stress Induced SenescenceREACTOMER-HSA-2559580
Insulin resistanceKEGGhsa04931
DNA Double-Strand Break RepairREACTOMER-HSA-5693532
DNA Double Strand Break ResponseREACTOMER-HSA-5693606
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaksREACTOMER-HSA-5693565
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Apoptosis - multiple speciesKEGGko04215
Apoptosis - multiple speciesKEGGhsa04215
Endocrine resistanceKEGGko01522
Endocrine resistanceKEGGhsa01522
Th1 and Th2 cell differentiationKEGGko04658
Th1 and Th2 cell differentiationKEGGhsa04658
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
IL-17 signaling pathwayKEGGko04657
Fluid shear stress and atherosclerosisKEGGko05418
IL-17 signaling pathwayKEGGhsa04657
Fluid shear stress and atherosclerosisKEGGhsa05418
Mitophagy - animalKEGGko04137
Mitophagy - animalKEGGhsa04137

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA134963361MAFAGenePathwayassociated23922006
PA162392499JDP2GenePathwayassociated23922006
PA248NFKB1GenePathwayassociated
PA25084ATF2GenePathwayassociated23922006
PA25085ATF3GenePathwayassociated23922006
PA25268BATFGenePathwayassociated23922006
PA27749ELK1GenePathwayassociated
PA28212FOSGenePathwayassociated23922006
PA28213FOSBGenePathwayassociated23922006
PA28214FOSL1GenePathwayassociated23922006
PA28215FOSL2GenePathwayassociated23922006
PA284MAP2K7GenePathwayassociated20124951, 23922006
PA296RELAGenePathwayassociated
PA30006JUNGenePathwayassociated23922006
PA30007JUNBGenePathwayassociated23922006
PA30008JUNDGenePathwayassociated23922006
PA30534MAFGenePathwayassociated23922006
PA30535MAFBGenePathwayassociated23922006
PA30538MAFFGenePathwayassociated23922006
PA30539MAFGGenePathwayassociated23922006
PA30540MAFKGenePathwayassociated23922006
PA30584MAP2K1GenePathwayassociated20124951
PA30587MAP2K2GenePathwayassociated20124951
PA30588MAP2K3GenePathwayassociated20124951
PA30589MAP2K4GenePathwayassociated20124951, 23922006
PA30590MAP2K5GenePathwayassociated20124951
PA30591MAP2K6GenePathwayassociated20124951
PA31353MYCGenePathwayassociated
PA31600NFKB2GenePathwayassociated
PA31781NRLGenePathwayassociated23922006
PA337STAT3GenePathwayassociated
PA338STAT5AGenePathwayassociated
PA36042SP1GenePathwayassociated
PA36183STAT1GenePathwayassociated
PA36184STAT2GenePathwayassociated
PA36185STAT4GenePathwayassociated
PA36186STAT5BGenePathwayassociated
PA7000sorafenibChemicalPathwayassociated20124951

References

Pubmed IDYearTitleCitations
185708712008JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy.487
189224732008TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta.217
119317682002The N-CoR-HDAC3 nuclear receptor corepressor complex inhibits the JNK pathway through the integral subunit GPS2.192
180827452008Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease.177
145320032003A JNK-dependent pathway is required for TNFalpha-induced apoptosis.176
187691112008Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation.138
185477512008The apoptotic effect of nanosilver is mediated by a ROS- and JNK-dependent mechanism involving the mitochondrial pathway in NIH3T3 cells.122
201036472010Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62/SQSTM1 expression and AMPK activation.117
182193132008NLRX1 is a mitochondrial NOD-like receptor that amplifies NF-kappaB and JNK pathways by inducing reactive oxygen species production.113
190336642008Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation.112

Citation

Fei Chen

MAPK8 (mitogen-activated protein kinase 8)

Atlas Genet Cytogenet Oncol Haematol. 2003-01-01

Online version: http://atlasgeneticsoncology.org/gene/196/mapk8