Affinage

MAPK9

Mitogen-activated protein kinase 9 · UniProt P45984

Length
424 aa
Mass
48.1 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 37 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAPK9/JNK2 is a stress-activated MAP kinase that integrates diverse extracellular signals—including cytokines, UV irradiation, ER stress, and metabolic cues—into phosphorylation of transcription factors, apoptosis regulators, and structural proteins to control cell fate decisions, immune activation, lipid metabolism, and cell cycle progression. Activated by the upstream kinases MKK4/SEK1 and MKK7, JNK2 binds c-Jun with ~25-fold higher affinity than JNK1 owing to a specificity-determining β-strand near the catalytic pocket, and its crystal structure reveals a MAP kinase insert that stabilizes an activation-inhibitory conformation of the activation loop (PMID:8001819, PMID:18801372). JNK2 phosphorylates substrates including p53 (Ser6/Ser34), Bcl-xL (Thr47/Thr115), TIF-IA (Thr200), GRASP65 (Ser277), SIRT1 (Ser27), SR-A, c-Src, and ABCG1, thereby regulating apoptosis, rRNA transcription, Golgi disassembly at G2/M, foam cell formation, intestinal barrier integrity, and autophagy (PMID:10617621, PMID:15805466, PMID:25948586, PMID:15567863, PMID:25377781, PMID:18838864). Isoform-specific knockout studies demonstrate non-redundant roles: JNK2 is required for efficient T-cell activation and anti-CD3-induced thymocyte apoptosis, promotes CaMKIIδ-dependent atrial arrhythmogenesis in aging, and mediates TNF-induced hepatotoxic caspase-8 activation, while cooperating with JNK1 in hepatoprotection and brain development (PMID:10021384, PMID:29352041, PMID:16571730, PMID:26708719, PMID:10230788).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1994 High

    Molecular cloning of JNK2 resolved how two closely related JNK isoforms achieve differential substrate selectivity, establishing that JNK2 binds c-Jun with ~25-fold higher affinity than JNK1 through a specificity-determining β-strand region.

    Evidence Molecular cloning, in vitro kinase assays with Km determination, and structural modeling

    PMID:8001819

    Open questions at the time
    • No crystal structure at this stage to validate the modeled β-strand interaction
    • Physiological relevance of affinity difference untested in vivo
  2. 1994 High

    Identification of SEK1/MKK4 as the direct upstream activator of JNK1/JNK2 established the three-tiered MAP kinase cascade for stress signaling, with later identification of MKK7 as a JNK-specific activating kinase particularly important in TNFα signaling.

    Evidence In vitro kinase assays, dominant-negative SEK1 blocking SAPK activation; MKK7 cloned and shown to specifically activate JNK but not p38

    PMID:7997269 PMID:9384583

    Open questions at the time
    • Relative contributions of MKK4 vs MKK7 to JNK2 activation in different physiological contexts not fully resolved
  3. 1997 Medium

    Demonstration that JNK2 associates with and phosphorylates p53 at Ser34 (and later Ser6) established p53 as a direct JNK2 substrate, linking stress kinase signaling to tumor suppressor regulation.

    Evidence In vitro kinase assays, co-immunoprecipitation in 293T cells; later confirmed by JNK1→JNK2→p53 sequential phosphorylation studies

    PMID:17525747 PMID:9393873

    Open questions at the time
    • In vivo physiological relevance of p53 Ser6/Ser34 phosphorylation by JNK2 not demonstrated in knockout animals
    • Relative contribution of JNK2 vs JNK3 to p53 regulation unclear
  4. 1999 High

    Jnk2-knockout mice revealed non-redundant functions: JNK2 is required for efficient T-cell activation and stimulus-specific thymocyte apoptosis, while compound Jnk1/Jnk2 knockouts showed embryonic lethality with region-specific brain apoptosis dysregulation.

    Evidence Jnk2−/− and Jnk1/Jnk2 double-KO mouse models with T-cell activation assays and developmental histology

    PMID:10021384 PMID:10230788 PMID:10559486

    Open questions at the time
    • Molecular substrates mediating JNK2-dependent T-cell activation not identified
    • Whether pro- vs anti-apoptotic roles in brain reflect distinct substrates or context-dependent signaling unresolved
  5. 2000 High

    Discovery that JNK translocates to mitochondria and phosphorylates Bcl-xL at Thr47/Thr115 to promote apoptosis established a direct mechanistic link between JNK signaling and the mitochondrial death pathway.

    Evidence Subcellular fractionation, co-immunoprecipitation, in vitro kinase assay, and phosphosite mutagenesis showing enhanced anti-apoptotic function of non-phosphorylatable Bcl-xL

    PMID:10617621

    Open questions at the time
    • Relative contributions of JNK1 vs JNK2 to Bcl-xL phosphorylation not dissected isoform-specifically
  6. 2004 High

    JNK2 was shown to have isoform-specific roles in both mitotic progression (anaphase spindle formation) and macrophage foam cell formation, demonstrating functional divergence from JNK1 in cell cycle control and lipid metabolism.

    Evidence DN-JNK2, RNAi, and pharmacological inhibition causing G2 arrest and polyploidy; Jnk2−/− macrophages showing reduced SR-A phosphorylation and foam cell formation in ApoE−/− mice

    PMID:15262983 PMID:15567863

    Open questions at the time
    • Direct phosphorylation targets mediating JNK2's anaphase role not identified
    • Whether SR-A is a direct JNK2 substrate or phosphorylated indirectly not fully resolved
  7. 2005 High

    Identification of TIF-IA Thr200 as a direct JNK2 phosphorylation site that disrupts Pol I transcription initiation complex assembly revealed how stress signals silence rRNA synthesis, with Jnk2-KO preventing TIF-IA inactivation.

    Evidence In vitro kinase assay, Thr200Val mutagenesis, Jnk2 KO cells, co-IP, and nucleolar fractionation

    PMID:15805466

    Open questions at the time
    • Whether JNK1 can partially compensate for JNK2 in TIF-IA regulation under prolonged stress unknown
  8. 2005 Medium

    A scaffold-dependent sequential activation model was established: during glucose deprivation, SEK1 phosphorylates JNK2 on Tyr185 on JIP3, then JNK2 transfers to JIP1 for Thr183 phosphorylation, followed by JNK2-mediated JIP1-Thr103 phosphorylation releasing Akt1 for negative feedback.

    Evidence Co-immunoprecipitation, phosphosite mapping, site-directed mutagenesis, kinase assays

    PMID:15911620

    Open questions at the time
    • Sequential scaffold transfer model not validated by live-cell imaging or reconstitution with purified components
    • Generalizability beyond glucose deprivation not tested
  9. 2006 High

    Isoform-specific hepatic studies established that JNK2 mediates TNF-induced toxic liver injury through caspase-8 activation and the mitochondrial pathway (Bid cleavage, cytochrome c release), while also revealing regulatory crosstalk where JNK2 loss paradoxically increases total JNK activity.

    Evidence Jnk2−/− mice protected from GalN/LPS-induced liver injury; compound Jnk1+/−Jnk2−/− mice showing improved metabolic parameters

    PMID:16571730 PMID:16818881

    Open questions at the time
    • Mechanism of JNK2-dependent caspase-8 activation (direct phosphorylation vs scaffolding) not resolved
    • How JNK2 constrains JNK1 activation at the biochemical level unknown
  10. 2008 High

    The crystal structure of JNK2 revealed a novel activation-loop conformation incompatible with upstream kinase phosphorylation, stabilized by the MAP kinase insert through induced-fit interaction, providing a structural basis for JNK2's regulation.

    Evidence X-ray crystallography with surface-site mutagenesis

    PMID:18801372

    Open questions at the time
    • No structure of JNK2 in complex with MKK4/MKK7 to show how the inhibitory conformation is overcome
    • Whether the MAP kinase insert conformation is dynamically regulated by post-translational modifications unknown
  11. 2008 Medium

    JNK2 was identified as an isoform-specific regulator of SIRT1 protein stability through Ser27 phosphorylation, extending JNK2's substrate repertoire to epigenetic regulators.

    Evidence RNAi-mediated JNK2 depletion reducing SIRT1 half-life from >9 h to <2 h; phosphorylation site mapping

    PMID:18838864

    Open questions at the time
    • Direct in vitro phosphorylation of SIRT1 Ser27 by purified JNK2 not demonstrated
    • Downstream consequences of SIRT1 destabilization upon JNK2 loss not explored
  12. 2009 Medium

    Multiple studies converged to show JNK2 regulates lipid homeostasis at multiple levels: promoting ABCG1 degradation, mediating insulin-induced SREBP-1 nuclear accumulation for fatty acid synthesis, and activating pro-survival autophagy in hepatocytes exposed to lipotoxic stress.

    Evidence JNK isoform-specific KO macrophages, co-IP of JNK2-SREBP-1, siRNA in human adipocytes, and autophagy marker analysis

    PMID:19713213 PMID:23515281 PMID:24608675

    Open questions at the time
    • Direct phosphorylation sites on ABCG1 and SREBP-1 by JNK2 not mapped
    • Whether JNK2's pro-autophagic role is Beclin1-dependent or independent not established
  13. 2009 Medium

    JNK2 was found to constitutively suppress basal apoptosis in cancer cells and to interact with β-catenin signaling by enhancing GSK3β-mediated β-catenin degradation, revealing tumor-context-dependent pro-survival and Wnt-suppressive functions.

    Evidence RNAi/KO with ChIP showing c-Jun regulation of Bcl-3; co-IP, mammalian two-hybrid, and JNK2−/− intestinal cells for β-catenin regulation

    PMID:19675674 PMID:19806201

    Open questions at the time
    • Whether JNK2 directly phosphorylates GSK3β or acts through an intermediary not determined
    • Generalizability of anti-apoptotic role across cancer types not systematically tested
  14. 2010 Medium

    JNK2 localization to RPA-coated ssDNA during UV damage and genomic instability in jnk2−/− tumor cells revealed an unexpected role in the DNA damage response and replicative stress management.

    Evidence Immunofluorescence, comparative genomic hybridization, BrdU incorporation, and Chk1/CDT1 analysis in JNK2 KO mammary tumor cells

    PMID:20454618

    Open questions at the time
    • Direct phosphorylation substrates at DNA damage sites not identified
    • Whether JNK2 is recruited to damage sites via RPA interaction or other scaffolds unknown
  15. 2015 High

    JNK2 phosphorylation of GRASP65 at Ser277 was established as a requirement for Golgi stack separation at G2, mechanistically linking JNK2 to cell cycle-coupled organelle remodeling and explaining the G2 arrest phenotype upon JNK2 inhibition.

    Evidence RNAi, pharmacological inhibition, cell cycle analysis, FRAP, and epistasis with brefeldin A/GRASP65 depletion

    PMID:25948586

    Open questions at the time
    • How JNK2 is specifically activated at G2 for Golgi disassembly not determined
    • Whether GRASP65 Ser277 phosphorylation suffices or additional substrates are required unknown
  16. 2015 High

    JNK2 was placed in the intestinal epithelial barrier integrity pathway through direct phosphorylation and activation of c-Src downstream of ASK1/MKK7, and combined hepatocyte-specific JNK1/JNK2 deletion revealed cooperative hepatoprotective functions against chemical liver injury.

    Evidence In vitro kinase assay with recombinant JNK2 and c-Src; conditional double-KO mice with phosphoproteomic and transcriptomic analysis

    PMID:25377781 PMID:26708719

    Open questions at the time
    • c-Src phosphorylation site(s) by JNK2 not mapped
    • Hepatoprotective mechanism downstream of JNK-dependent AMPK/JunD activation not fully delineated
  17. 2018 High

    JNK2 was identified as a driver of age-dependent atrial fibrillation through transcriptional upregulation of CaMKIIδ (via c-Jun binding to its promoter), leading to diastolic SR Ca2+ leak through RyR2, with validation in human atrial tissue.

    Evidence Transgenic/KO mouse models, atrial electrophysiology, ChIP showing c-Jun binding to CaMKIIδ promoter, dominant-negative JNK2, and human donor heart analysis

    PMID:29352041 PMID:29360953

    Open questions at the time
    • Whether JNK2 directly phosphorylates CaMKIIδ protein in addition to transcriptional regulation unknown
    • Therapeutic window for JNK2 inhibition in atrial fibrillation not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive substrate identification, a unified structural model explaining how JNK2 selects among its many substrates in different cellular contexts, and the full spectrum of JNK2-specific vs JNK1-redundant functions in vivo, remain unresolved.
  • No co-crystal structure of JNK2 with any substrate or scaffold protein
  • Isoform-specific substrate selectivity determinants beyond c-Jun not structurally characterized
  • Quantitative contribution of JNK2 vs JNK1 to total JNK signaling output in most tissues not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 5
Localization
GO:0005739 mitochondrion 2 GO:0005634 nucleus 1 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 2 R-HSA-9612973 Autophagy 2
Partners
GRASP65JIP1JIP4MAVSMKK4MKK7SREBF1TP53

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 JNK2 (55 kDa form of JNK) was molecularly cloned and shown to bind c-Jun approximately 25 times more efficiently than JNK1, with a lower Km toward c-Jun; a specificity-determining beta-strand-like region near the catalytic pocket was identified as the structural basis for this differential substrate recognition. Molecular cloning, in vitro kinase assay, structural modeling, binding studies Genes & development High 8001819
1994 SEK1 (MKK4) was identified as an immediate upstream activator of SAPKs (JNK1/JNK2) in vitro and in vivo; a kinase-dead SEK1 mutant blocks SAPK activation by extracellular stimuli without interfering with the MAPK/ERK pathway. In vitro kinase assay, dominant-negative overexpression in cells Nature High 7997269
1997 MKK7 was identified as a novel SAPK/JNK-specific kinase; unlike SEK1/MKK4 which activates both JNK and p38, MKK7 specifically activates the SAPK/JNK subgroup and is a major JNK-activating kinase in TNFα signaling. Molecular cloning, immunochemical kinase assays, column fractionation, reporter assays The EMBO journal High 9384583
1997 JNK1, JNK2, and JNK3 all phosphorylate mouse p53 at serine 34 in vitro; JNK2 and JNK3 associate with p53 in vivo, indicating they are p53 N-terminal serine 34 kinases. In vitro kinase assay, co-immunoprecipitation, dominant-negative mutant expression in 293T cells Oncogene Medium 9393873
1999 JNK2 is required for efficient T-cell activation; jnk2-/- mice show reduced peripheral T-cell proliferation and cytokine production upon anti-CD3 stimulation, and immature thymocytes lacking JNK2 are resistant to anti-CD3-induced apoptosis but not to Fas-, dexamethasone-, or UVC-induced apoptosis. Gene knockout mouse model, T-cell activation assays, apoptosis assays Current biology : CB High 10021384
1999 JNK1 and JNK2 together regulate region-specific apoptosis during early brain development; compound Jnk1/Jnk2 double-mutant mice are embryonic lethal with dysregulation of apoptosis in specific brain regions, demonstrating both pro- and anti-apoptotic roles depending on brain region. Gene knockout mouse model, developmental analysis, histology Neuron High 10230788 10559486
2000 SAPK/JNK translocates to mitochondria upon ionizing radiation and associates with Bcl-xL; SAPK phosphorylates Bcl-xL on Thr-47 and Thr-115 in vitro and in vivo, and a Bcl-xL mutant with both threonines replaced by alanines is a more potent inhibitor of apoptosis. Subcellular fractionation, co-immunoprecipitation, in vitro kinase assay, mutagenesis The Journal of biological chemistry High 10617621
2004 JNK2 is required for scavenger receptor A (SR-A)-mediated foam cell formation in atherogenesis; JNK2 promotes phosphorylation of SR-A in macrophages, enhancing uptake and degradation of modified lipoproteins; macrophage-restricted deletion of JNK2 is sufficient to decrease atherosclerosis in ApoE-/- mice. Gene knockout mouse model, macrophage-specific deletion, foam cell assays, SR-A phosphorylation analysis Science (New York, N.Y.) High 15567863
2005 JNK2 phosphorylates the RNA polymerase I-specific transcription factor TIF-IA at Thr-200 in response to stress, impairing its interaction with Pol I and TIF-IB/SL1, abrogating transcription initiation complex formation, and causing TIF-IA translocation from nucleolus to nucleoplasm; Jnk2 knockout prevents TIF-IA inactivation and stress-dependent repression of rRNA synthesis. In vitro kinase assay, mutagenesis (Thr200Val), Jnk2 knockout, co-immunoprecipitation, nucleolar fractionation Genes & development High 15805466
2006 JNK1 but not JNK2 is responsible for JNK activation in MCD diet-induced steatohepatitis; jnk1 null mice have significantly reduced hepatic triglyceride accumulation, inflammation, lipid peroxidation, and apoptosis, while jnk2-/- mice show no such protection. Isoform-specific knockout mouse model, dietary liver injury model, biochemical and histological analysis Hepatology (Baltimore, Md.) High 16374858
2006 JNK2 mediates TNF-induced toxic liver injury by promoting caspase-8 activation and the mitochondrial death pathway (Bid cleavage, cytochrome c release); jnk2-/- mice are protected from GalN/LPS-induced liver injury independently of c-Jun kinase activity. Isoform-specific knockout mouse model, caspase activation assays, Bid cleavage, cytochrome c release The Journal of biological chemistry High 16571730
2006 JNK2 deficiency in Jnk2-/- mice leads to higher-than-normal JNK activation, particularly in the liver, indicating regulatory crosstalk between JNK1 and JNK2 isoforms; combined Jnk1+/- Jnk2-/- mice show reduced body weight and improved insulin sensitivity, demonstrating JNK2 participates in metabolic regulation. Compound isoform-specific knockout mouse models, metabolic phenotyping, cytokine measurement Proceedings of the National Academy of Sciences of the United States of America High 16818881
2007 JNK2, but not JNK1, physically associates with p53 and directly phosphorylates p53 at Ser6 in response to FDH induction; JNK1 first phosphorylates JNK2, which then phosphorylates p53; knockdown of either JNK1 or JNK2 prevents p53 Ser6 phosphorylation and protects cells from apoptosis. Pull-down/co-IP assay, siRNA knockdown, phosphorylation analysis, apoptosis assay Oncogene Medium 17525747
2008 JNK2 (but not JNK1) regulates SIRT1 protein stability; RNAi-mediated depletion of JNK2 reduces SIRT1 half-life from >9h to <2h and abolishes SIRT1 phosphorylation at serine 27. RNAi knockdown, protein half-life measurement, phosphorylation site mapping Cell cycle (Georgetown, Tex.) Medium 18838864
2008 The crystal structure of human JNK2 was determined, revealing a novel activation-loop conformation incompatible with phosphorylation by upstream kinases; the MAP kinase insert interacts with the activation loop in an induced-fit manner to stabilize this activation-inhibitory conformation, suggesting the MAP kinase insert regulates JNK2 activation. X-ray crystallography, surface-site mutagenesis, high-throughput protein engineering Journal of molecular biology High 18801372
2009 JNK1 promotes palmitic acid-induced lipoapoptosis, whereas JNK2 activates pro-survival autophagy in hepatocytes; specific knockdown of JNK2, but not JNK1, suppresses PA-induced autophagy and enhances apoptosis. isoform-specific siRNA knockdown, autophagy markers (LC3-II, Beclin1, Atg5), apoptosis assays Acta pharmacologica Sinica Medium 24608675
2009 JNK2 regulates ABCG1 protein stability via serine phosphorylation and subsequent proteasomal degradation; JNK2-deficient (but not JNK1-deficient) macrophages are resistant to 12S-HETE-mediated ABCG1 downregulation and show increased cholesterol efflux. JNK-isoform-specific knockout macrophages, proteasomal inhibitor experiments, dominant-negative constructs, phosphorylation analysis The Journal of biological chemistry High 19713213
2009 JNK2 coimmunoprecipitates with SREBP-1 and mediates insulin-induced nuclear accumulation of active SREBP-1 and upregulation of SREBP-1c; depletion of JNK2 attenuates insulin-induced fatty acid synthesis in human adipocytes. Co-immunoprecipitation, siRNA knockdown, microarray, reporter assays, radiolabeled fatty acid synthesis Journal of lipid research Medium 23515281
2009 JNK2 constitutively suppresses basal apoptosis in cancer cells; JNK2 silencing leads to JNK1-dependent apoptosis via accumulation of hypo-phosphorylated c-Jun, which suppresses Bcl-3 expression and activates the TNFα response pathway. RNAi, gene knockout, chromatin immunoprecipitation, phosphorylation mutant expression PloS one Medium 19806201
2009 JNK2 interacts with and suppresses beta-catenin signaling by increasing GSK3β activity; activated JNK2 promotes proteasomal degradation of beta-catenin through GSK3β-mediated phosphorylation at Ser33/Ser37. Co-immunoprecipitation, mammalian two-hybrid assay, confocal microscopy, mutagenesis, JNK2-/- mouse intestinal epithelial cells PloS one Medium 19675674
2010 JNK2 localizes to RPA-coated single-stranded DNA strands during UV-induced DNA damage; jnk2-/- mammary tumor cells exhibit replicative stress, impaired DNA damage response (reduced pH2AX/53BP1 foci), and increased genomic instability, supporting a role for JNK2 in coordinating cell cycle progression and DNA damage repair. JNK2 knockout mice, immunofluorescence, comparative genomic hybridization, BrdU incorporation, Chk1/CDT1 analysis PloS one Medium 20454618
2011 JNK2 promotes mammary cancer cell migration through inhibition of EPS8 expression; in the absence of JNK2, EPS8 expression increases and promotes EPS8/RN-Tre association that inhibits EGFR endocytic trafficking, whereas JNK2 enhances the EPS8-Abi-1-Sos-1 complex to augment EGFR-Akt/ERK signaling. Jnk2-/- mouse models, EPS8 knockdown rescue, co-immunoprecipitation, cell migration assays The Journal of biological chemistry Medium 21357683
2011 JNK2-selective peptide inhibitors (JIP-based) with ~90 nM IC50 and 10-fold selectivity over JNK1/JNK3 inhibit JNK2-dependent mammary tumor cell migration, demonstrating JNK2-specific contribution to cell motility. In vitro kinase assay with isoform selectivity, cell-based migration assays with jnk2-/- controls and GFP-JNK2 rescue ACS chemical biology Medium 21438496
2012 JNK2 and JNK3 are the major isoforms activated in injured RGC axons; combined deficiency of Jnk2 and Jnk3 provides robust long-term protection against axonal injury-induced RGC death and prevents JUN phosphorylation; JUN-dependent pathways are required for RGC death. Isoform-specific KO mice, optic nerve crush model, immunohistochemistry, long-term survival analysis Neurobiology of disease High 22353563
2012 JNK2 is activated during ER stress, upregulates BiP expression, prevents accumulation of the acidic compartment, and promotes autophagic flux; pharmacological or RNAi inhibition of JNK2 causes p62 accumulation, caspase-3 activation, and apoptosis in stressed cells. Pharmacological inhibition, siRNA knockdown, UPR marker analysis, autophagy flux assays Cell death & disease Medium 23171849
2012 EGFR inhibition by cetuximab induces JNK2 phosphorylation through JIP-4; JIP-4 was identified as a JNK2-interacting protein by immunoprecipitation-mass spectrometry; JIP-4 or JNK2 knockdown enhances cetuximab efficacy and tumor cell radiosensitivity. Phosphoproteome arrays, immunoprecipitation-mass spectrometry, siRNA knockdown, 3D cell culture, xenograft model Cancer research Medium 23074283
2014 MAVS specifically activates JNK2 (but not other MAP kinases) during viral infection; MAVS recruits MKK7 to mitochondria via its 3D domain, which phosphorylates JNK2 to activate the apoptosis pathway; Jnk2-/- but not Jnk1-/- cells fail to initiate virus-induced apoptosis. Mkk7-/- and Jnk2-/- knockout cells, co-immunoprecipitation, mitochondrial recruitment assays, Sendai virus infection model PLoS pathogens High 24651600
2015 JNK2 phosphorylates GRASP65 at Ser277 during G2 to promote Golgi stack separation; inhibition of JNK2 by RNAi or pharmacological inhibitors causes persistent G2 cell cycle block and prevents Golgi tubule cleavage; JNK activity is dispensable for mitotic entry if the Golgi is disassembled by brefeldin A or GRASP65 depletion. RNAi, pharmacological inhibition, cell cycle analysis, FRAP, epistasis with brefeldin A/GRASP65 depletion Journal of cell science High 25948586
2015 The Ca2+/Ask1/MKK7/JNK2/c-Src signaling cascade mediates DSS-induced intestinal epithelial tight junction disruption; recombinant JNK2 induces threonine phosphorylation and autophosphorylation of c-Src; JNK2 knockdown or inhibition attenuates DSS-induced barrier dysfunction. siRNA knockdown, pharmacological inhibition, in vitro kinase assay with recombinant JNK2, mouse colitis model The Biochemical journal Medium 25377781
2015 JNK1 and JNK2 have combined hepatoprotective effects; combined hepatocyte-specific deletion of Jnk1 and Jnk2 (Jnk-Δhepa) results in greater liver injury from acetaminophen and CCl4 than deletion of Jnk1 alone, with increased oxidative stress, decreased AMPK activation, reduced pJunD, and necrosis. Hepatocyte-specific conditional double KO mice, gene expression microarray, phosphoproteomics, histology Gastroenterology High 26708719
2018 JNK2 activates CaMKII (CaMKIIδ) in aged atria, leading to diastolic SR Ca2+ leak via RyR2 and enhanced atrial fibrillation propensity; JNK2 ablation or CaMKII inhibition eliminates this proarrhythmic mechanism; JNK2 upregulates CaMKIIδ expression at the transcriptional level through c-Jun binding to the CaMKIIδ promoter. Transgenic/KO mouse models, electrophysiology, chromatin immunoprecipitation (XChIP), promoter reporter assays, dominant-negative JNK2, human donor hearts Circulation research High 29352041 29360953
2005 During glucose deprivation, JNK2 is phosphorylated by SEK1 on Tyr-185 (via ASK1-JIP3 complex), then JNK2 binds to JIP1 and is phosphorylated on Thr-183; JNK2 then phosphorylates JIP1 on Thr-103, releasing Akt1 which inhibits upstream kinases via feedback phosphorylation of SEK1-Ser80 and ASK1-Ser83. Co-immunoprecipitation, phosphosite mapping, site-directed mutagenesis, kinase assays The Journal of biological chemistry Medium 15911620
2004 Inhibition of JNK2 (but not JNK1) by dominant-negative mutant, pharmacological inhibitor, or RNAi causes G2 accumulation, defects in central spindle formation, and chromosome segregation errors during anaphase, resulting in polyploidy; cyclin B1/CDK1 turnover remains intact, defining a novel JNK2-specific role in anaphase progression. Dominant-negative mutant, pharmacological inhibition, RNAi, cell cycle analysis, immunofluorescence The Journal of biological chemistry Medium 15262983
1999 In adult mouse brain, JNK2 (SAPKbeta) is localized in both nucleus and cytoplasm of neurons, whereas JNK1 (SAPKgamma) is detected mainly in cytoplasm and dendrites; all SAPK isoforms show extraordinarily high basal kinase activities in brain compared to peripheral organs. Immunohistochemistry, subcellular fractionation, biochemical kinase activity assay Brain research. Molecular brain research Medium 10381549
2001 MKP-7, a novel dual-specificity phosphatase, binds to and inactivates JNK/SAPK (as well as p38α and p38β but not ERK or p38γ/δ); MKP-7 is predominantly cytoplasmic, distinguishing it from related MKPs. Molecular cloning, co-immunoprecipitation, in vitro phosphatase assay, subcellular localization The Journal of biological chemistry Medium 11359773
2002 PAK1 phosphorylates MEKK1 on serine 67 within a D-domain that binds JNK/SAPK; constitutive Ser67 phosphorylation inhibits JNK/SAPK binding to MEKK1, and dephosphorylation upon stress (UV, anisomycin) relieves this inhibition, providing a mechanism for negative regulation of the JNK pathway by PAK. In vitro kinase assay, co-immunoprecipitation, phosphosite mutagenesis, stress stimulus experiments The Journal of biological chemistry Medium 12228228
1999 ATFa serves as a JNK2-docking site enabling phosphorylation of ATFa-associated partners such as JunD by the bound JNK2; the N-terminal domain of ATFa stably binds JNK2 but is not itself a JNK2 substrate in vivo. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis Oncogene Low 10376527

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 1680 8598911
1995 The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 1581 7600581
1994 Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature 966 7997269
1999 The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron 759 10230788
1994 JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes & development 588 8001819
1999 Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 502 10367887
1997 Activation of SAPK/JNK by TNF receptor 1 through a noncytotoxic TRAF2-dependent pathway. Science (New York, N.Y.) 407 8985011
2000 Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage. The Journal of biological chemistry 374 10617621
2006 JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology (Baltimore, Md.) 313 16374858
2001 IFN-gamma + LPS induction of iNOS is modulated by ERK, JNK/SAPK, and p38(mapk) in a mouse macrophage cell line. American journal of physiology. Cell physiology 297 11171562
1999 Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mechanisms of development 295 10559486
1996 MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. The EMBO journal 281 9003778
2006 Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America 278 16818881
1998 Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway. The Journal of biological chemistry 278 9452508
1999 JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Current biology : CB 249 10021384
2000 Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain research. Molecular brain research 236 10814833
2004 Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science (New York, N.Y.) 234 15567863
1997 A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses. The EMBO journal 232 9384583
1996 Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes & development 220 8824585
1995 Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature 210 7477268
2009 Differential effects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology (Baltimore, Md.) 188 19053047
1996 Differential activation of ERK, JNK/SAPK and P38/CSBP/RK map kinase family members during the cellular response to arsenite. Free radical biology & medicine 185 8902523
2006 Tumor necrosis factor-induced toxic liver injury results from JNK2-dependent activation of caspase-8 and the mitochondrial death pathway. The Journal of biological chemistry 178 16571730
2005 The nucleolus as a stress sensor: JNK2 inactivates the transcription factor TIF-IA and down-regulates rRNA synthesis. Genes & development 175 15805466
1999 Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis. Cancer research 151 10344758
2001 A Novel MAPK phosphatase MKP-7 acts preferentially on JNK/SAPK and p38 alpha and beta MAPKs. The Journal of biological chemistry 136 11359773
1997 Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-p38 pathways independent of CPP32-like proteases. The Journal of cell biology 136 9362518
2012 JNK2 and JNK3 are major regulators of axonal injury-induced retinal ganglion cell death. Neurobiology of disease 123 22353563
2007 Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway. Oncogene 115 17525747
1999 Sending signals from the synapse to the nucleus: possible roles for CaMK, Ras/ERK, and SAPK pathways in the regulation of synaptic plasticity and neuronal growth. Journal of neuroscience research 114 10491574
2004 Physiological roles of SAPK/JNK signaling pathway. Journal of biochemistry 111 15496581
1997 JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases. Oncogene 111 9393873
2008 JNK2-dependent regulation of SIRT1 protein stability. Cell cycle (Georgetown, Tex.) 109 18838864
2001 The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation. Experimental cell research 98 11716547
1998 Activation of RhoA and SAPK/JNK signalling pathways by the RhoA-specific exchange factor mNET1. The EMBO journal 98 9670022
2002 Differential effects of JNK1 and JNK2 on signal specific induction of apoptosis. Oncogene 91 11948429
2015 Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium. The Biochemical journal 88 25377781
2016 Gallic acid prevents isoproterenol-induced cardiac hypertrophy and fibrosis through regulation of JNK2 signaling and Smad3 binding activity. Scientific reports 84 27703224
1999 Quinone reductase inhibitors block SAPK/JNK and NFkappaB pathways and potentiate apoptosis. The Journal of biological chemistry 82 10531305
2015 Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterology 79 26708719
1998 Potential role of the JNK/SAPK signal transduction pathway in the induction of iNOS by TNF-alpha. Biochemical and biophysical research communications 79 9918806
2012 EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated radiosensitization of squamous cell carcinoma cells. Cancer research 74 23074283
2018 Stress Signaling JNK2 Crosstalk With CaMKII Underlies Enhanced Atrial Arrhythmogenesis. Circulation research 71 29352041
2012 Coordinated control of replication and transcription by a SAPK protects genomic integrity. Nature 71 23178807
2014 miR200c attenuates P-gp-mediated MDR and metastasis by targeting JNK2/c-Jun signaling pathway in colorectal cancer. Molecular cancer therapeutics 70 25205654
2001 Induction of the SAPK activator MIG-6 by the alkylating agent methyl methanesulfonate. Molecular carcinogenesis 68 11429782
2014 Sirtuin 7 promotes cellular survival following genomic stress by attenuation of DNA damage, SAPK activation and p53 response. Experimental cell research 67 25445786
2014 Palmitic acid induces autophagy in hepatocytes via JNK2 activation. Acta pharmacologica Sinica 63 24608675
2002 Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases. Progress in medicinal chemistry 63 12516522
2013 SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress. Nature communications 62 23653187
1997 A role for JNK/SAPK in proliferation, but not apoptosis, of IL-3-dependent cells. Current biology : CB 61 9382802
2012 JNK2 is activated during ER stress and promotes cell survival. Cell death & disease 59 23171849
2008 Pro-inflammatory cytokine-induced SAPK/MAPK and JAK/STAT in rheumatoid arthritis and the new anti-depression drugs. Expert opinion on therapeutic targets 58 18208366
2005 JNK1 and JNK2 oppositely regulate p53 in signaling linked to apoptosis triggered by an altered fibronectin matrix: JNK links FAK and p53. The Journal of biological chemistry 57 15778501
2003 Oxidative stress and neuronal adaptation in Alzheimer disease: the role of SAPK pathways. Antioxidants & redox signaling 57 14580312
2008 Mechanism of copper-activated transcription: activation of AP-1, and the JNK/SAPK and p38 signal transduction pathways. Journal of molecular biology 56 18793645
2006 Release of RASSF1C from the nucleus by Daxx degradation links DNA damage and SAPK/JNK activation. The EMBO journal 56 16810318
2001 The p38-MAPK/SAPK pathway is required for human keratinocyte migration on dermal collagen. The Journal of investigative dermatology 55 11886529
2015 JNK2 controls fragmentation of the Golgi complex and the G2/M transition through phosphorylation of GRASP65. Journal of cell science 54 25948586
2014 RITA can induce cell death in p53-defective cells independently of p53 function via activation of JNK/SAPK and p38. Cell death & disease 52 25010984
2004 JNK2 mediates TNF-induced cell death in mouse embryonic fibroblasts via regulation of both caspase and cathepsin protease pathways. Cell death and differentiation 52 14685158
2008 Inhibition of MITF and tyrosinase by paeonol-stimulated JNK/SAPK to reduction of phosphorylated CREB. The American journal of Chinese medicine 51 18457359
1999 Distinct localization of SAPK isoforms in neurons of adult mouse brain implies multiple signaling modes of SAPK pathway. Brain research. Molecular brain research 49 10381549
2008 The crystal structure of JNK2 reveals conformational flexibility in the MAP kinase insert and indicates its involvement in the regulation of catalytic activity. Journal of molecular biology 48 18801372
2012 Fucoxanthin induces GADD45A expression and G1 arrest with SAPK/JNK activation in LNCap human prostate cancer cells. Anticancer research 47 22399598
2003 Induction of apoptosis through the activation of SAPK/JNK followed by the expression of death receptor Fas in X-irradiated cells. Journal of radiation research 46 14646222
2019 Overexpressed miR-200a promotes bladder cancer invasion through direct regulating Dicer/miR-16/JNK2/MMP-2 axis. Oncogene 45 31772330
2017 Moscatilin induces apoptosis of pancreatic cancer cells via reactive oxygen species and the JNK/SAPK pathway. Molecular medicine reports 45 28138710
2003 Aluminum-induced apoptosis in cultured cortical neurons and its effect on SAPK/JNK signal transduction pathway. Brain research 45 12865155
1998 IL-16 activates the SAPK signaling pathway in CD4+ macrophages. Journal of immunology (Baltimore, Md. : 1950) 45 9637499
2014 MAVS-MKK7-JNK2 defines a novel apoptotic signaling pathway during viral infection. PLoS pathogens 43 24651600
2001 Adaptive concentrations of hydrogen peroxide suppress cell death by blocking the activation of SAPK/JNK pathway. Journal of cell science 43 11739664
2016 Inhibition of EZH2 via activation of SAPK/JNK and reduction of p65 and DNMT1 as a novel mechanism in inhibition of human lung cancer cells by polyphyllin I. Journal of experimental & clinical cancer research : CR 39 27421653
2019 TNF-α Drives the CCL4 Expression in Human Monocytic Cells: Involvement of the SAPK/JNK and NF-κB Signaling Pathways. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 38 30964608
2010 Jnk2 effects on tumor development, genetic instability and replicative stress in an oncogene-driven mouse mammary tumor model. PloS one 38 20454618
2002 Binding of JNK/SAPK to MEKK1 is regulated by phosphorylation. The Journal of biological chemistry 38 12228228
2011 Development of JNK2-selective peptide inhibitors that inhibit breast cancer cell migration. ACS chemical biology 37 21438496
2010 The p38 SAPK is recruited to chromatin via its interaction with transcription factors. The Journal of biological chemistry 37 20682780
2003 SAPK/JNK regulates cdc2/cyclin B kinase through phosphorylation and inhibition of cdc25c. Cellular signalling 37 12742231
2000 Hypoosmotic stress activates p38, ERK 1 and 2, and SAPK/JNK in rat hepatocytes. The Journal of surgical research 36 10781376
2013 A novel JNK2/SREBP-1c pathway involved in insulin-induced fatty acid synthesis in human adipocytes. Journal of lipid research 35 23515281
2009 Murine 12/15-lipoxygenase regulates ATP-binding cassette transporter G1 protein degradation through p38- and JNK2-dependent pathways. The Journal of biological chemistry 35 19713213
2003 Src-CrkII-C3G-dependent activation of Rap1 switches growth hormone-stimulated p44/42 MAP kinase and JNK/SAPK activities. The Journal of biological chemistry 35 12734187
2000 Activation of SAPK/JNK by camptothecin sensitizes androgen-independent prostate cancer cells to Fas-induced apoptosis. British journal of cancer 35 10839298
2018 Transcriptional regulation of stress kinase JNK2 in pro-arrhythmic CaMKIIδ expression in the aged atrium. Cardiovascular research 34 29360953
2018 TGF-β downregulation-induced cancer cell death is finely regulated by the SAPK signaling cascade. Experimental & molecular medicine 34 30523245
2009 NAG7 promotes human nasopharyngeal carcinoma invasion through inhibition of estrogen receptor alpha and up-regulation of JNK2/AP-1/MMP1 pathways. Journal of cellular physiology 33 19591174
2005 Cross-talk between JIP3 and JIP1 during glucose deprivation: SEK1-JNK2 and Akt1 act as mediators. The Journal of biological chemistry 33 15911620
2010 p27 suppresses arsenite-induced Hsp27/Hsp70 expression through inhibiting JNK2/c-Jun- and HSF-1-dependent pathways. The Journal of biological chemistry 32 20566634
2009 GSK3beta is involved in JNK2-mediated beta-catenin inhibition. PloS one 32 19675674
2009 Basal cancer cell survival involves JNK2 suppression of a novel JNK1/c-Jun/Bcl-3 apoptotic network. PloS one 32 19806201
2013 JNK1 and JNK2 regulate α-SMA in hepatic stellate cells during CCl4 -induced fibrosis in the rat liver. Pathology international 31 24134609
2015 Gardenia jasminoides extracts and gallic acid inhibit lipopolysaccharide-induced inflammation by suppression of JNK2/1 signaling pathways in BV-2 cells. Iranian journal of basic medical sciences 30 26221479
2007 Anti endothelial cell autoantibodies selectively activate SAPK/JNK signalling in Wegener's granulomatosis. Journal of the American Society of Nephrology : JASN 29 17699811
2004 Inhibition of JNK2 disrupts anaphase and produces aneuploidy in mammalian cells. The Journal of biological chemistry 29 15262983
1999 Role of the ATFa/JNK2 complex in Jun activation. Oncogene 29 10376527
2018 Anti-JNK2 peptide-siRNA nanostructures improve plaque endothelium and reduce thrombotic risk in atherosclerotic mice. International journal of nanomedicine 28 30233180
2012 Increased hepatic fibrosis and JNK2-dependent liver injury in mice exhibiting hepatocyte-specific deletion of cFLIP. American journal of physiology. Gastrointestinal and liver physiology 27 22700824
2016 Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways. Oncotarget 26 26918455
2011 c-Jun N-terminal kinase 2 (JNK2) enhances cell migration through epidermal growth factor substrate 8 (EPS8). The Journal of biological chemistry 26 21357683