JNK2 (MAPK9)

Mitogen-activated protein kinase 9 (MAPK9), also well known as c-Jun N-terminal kinase (JNK2), is a member of MAP kinase subfamily belonging to the protein kinase superfamily. MAPK9 responds to activation by environmental stress and pro-inflammatory cytokines by phosphorylating a number of transcription factors, such as c-Jun and ATF2. The crystal structure of human JNK2 complexed with an indazole inhibitor by applying a high-throughput protein engineering and surface-site mutagenesis approach. A novel conformation of the activation loop is observed, which is not compatible with its phosphorylation by upstream kinases. This activation inhibitory conformation of JNK2 is stabilized by the MAP kinase insert that interacts with the activation loop in an induced-fit manner. It suggest that the MAP kinase insert of JNK2 plays a role in the regulation of JNK2 activation, possibly by interacting with intracellular binding partners. JNK2 deficiency leads to reduced c-Jun degradation, thereby augmenting c-Jun levels and cellular proliferation, and suggests that JNK2 is a negative regulator of cellular proliferation in multiple cell types. JNK2 prevents replicative stress by coordinating cell cycle progression and DNA damage repair mechanisms. JNK2 blocks the ubiquitination of tumor suppressor p53, and thus increases the stability of p53 in nonstressed cells. JNK2 negatively regulates antigen-specific CD8+ T cell expansion and effector function, and thus selectively blocking JNK2 in CD8+ T cells may potentially enhance anti-tumor immune response. Lack of JNK2 expression was associated with higher tumor aneuploidy and reduced DNA damage response. Additionally,the JNK2 protein could be a novel therapeutic target in dry eye disease, and may provide a novel target for prevention of vascular disease and atherosclerosis.

JNK2 (MAPK9) Related Areas

Enzyme>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>JNK2/MAPK9

Neuroscience>>Axon Guidance>>Wnt Signaling Pathway>>JNK2/MAPK9

Signal Transduction>>Protein Kinase>>Intracellular Kinase>>Mitogen-Activated Protein Kinase (MAPK)>>JNK2/MAPK9

Signal Transduction>>Wnt Signaling Pathway>>Non-Canonical Wnt Pathway>>JNK2/MAPK9

Stem Cell>>Wnt Signaling Pathway>>Non-Canonical Wnt Pathway>>JNK2/MAPK9

JNK2 (MAPK9) Alternative Names

JNK2, MAPK9, JNK2A, JNK2ALPHA, JNK2B, JNK2BETA, PRKM9, p54aSAPK, SAPK, stress-activated protein kinase JNK2, p54a, NK-55 [Homo sapiens]

JNK2, Mapk9, Prkm9, p54aSAPK, JNK/SAPK alpha, stress-activated protein kinase JNK2, RP23-10G21.6, AI851083 [Mus musculus]

Summaries for JNK2 (MAPK9)

Entrez Gene summary for MAPK9:

The protein encoded by this MAPK9 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. JNK2 targets specific transcription factors, and thus mediates immediate-early gene expression in response to various cell stimuli. JNK2 is most closely related to MAPK8, both of which are involved in UV radiation induced apoptosis, thought to be related to the cytochrome c-mediated cell death pathway. This MAPK9 gene and MAPK8 are also known as c-Jun N-terminal kinases. JNK2 blocks the ubiquitination of tumor suppressor p53, and thus it increases the stability of p53 in nonstressed cells. Studies of this gene's mouse counterpart suggest a key role in T-cell differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Sep 2008]

Wikipedia summary for JNK2:

Mitogen-activated protein kinase 9 is an enzyme that in humans is encoded by the MAPK9 gene.

Human JNK2 (MAPK9) Protein General Information

 

• Protein names: Mitogen-activated protein kinase 9, Short name=MAPK 9
• Sequence length: 424 AA.
• Domain: The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.
• Catalytic activity: ATP + a protein = ADP + a phosphoprotein.
• Cofactor: Magnesium.
• Enzyme regulation: JNK2 is activated by threonine and tyrosine phosphorylation by either of two dual specificity kinases, MAP2K4 and MAP2K7. MAP2K4 shows a strong preference for Tyr-185 while MAP2K7 phosphorylates Tyr-183 preferentially. JNK2 is inhibited by dual specificity phosphatases, such as DUSP1.
• Sequence similarities: JNK2 belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. JNK2 contains 1 protein kinase domain.
• Post-translational modification: Dually phosphorylated on Thr-183 and Tyr-185 by MAP2K7 and MAP2K4, which activates the enzyme. Autophosphorylated in vitro.
• Subunit structure: JNK2 interacts with MECOM and DCLK2. JNK2 binds to at least four scaffolding proteins, MAPK8IP1/JIP-1, MAPK8IP2/JIP-2, MAPK8IP3/JIP-3/JSAP1 and SPAG9/MAPK8IP4/JIP-4. These proteins also bind other components of the JNK signaling pathway. JNK2 interacts with NFATC4. JNK2 interacts with ATF7; the interaction does not phosphorylate ATF7 but acts as a docking site for ATF7-associated partners such as JUN. JNK2 interacts with BCL10. JNK2 interacts with CTNNB1 and GSK3B.
• Subcellular location: Cytoplasm. Nucleus

General information above from UniProt

Function for JNK2 (MAPK9) Protein

UniProtKB:

JNK2 is Serine/threonine-protein kinase involved in various processes such as cell proliferation, differentiation, migration, transformation and programmed cell death. Extracellular stimuli such as proinflammatory 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 MAPK9/JNK2. In turn, MAPK9/JNK2 phosphorylates a number of transcription factors, primarily components of AP-1 such as JUN and ATF2 and thus regulates AP-1 transcriptional activity. In response to oxidative or ribotoxic stresses, inhibits rRNA synthesis by phosphorylating and inactivating the RNA polymerase I-specific transcription initiation factor RRN3. JNK2 promotes stressed cell apoptosis by phosphorylating key regulatory factors including TP53 and Yes-associates protein YAP1. In T-cells, MAPK8 and JNK2 are required for polarized differentiation of T-helper cells into Th1 cells. Upon T-cell receptor (TCR) stimulation, is activated by CARMA1, BCL10, MAP2K7 and MAP3K7/TAK1 to regulate JUN protein levels. Plays an important role in the osmotic stress-induced epithelial tight-junctions disruption. When activated, JNK2 promotes beta-catenin/CTNNB1 degradation and inhibits the canonical Wnt signaling pathway. JNK2 participates also in neurite growth in spiral ganglion neurons.

Genatlas:

• JNK2 plays a role in the signal transduction pathway initiated by proinflammatory cytokines and UV radiation
• JNK2 plays a necessary role for epithelial morphogenesis and essential regulator of signal transduction by the EGF receptor in the epidermis
• MAP3K1-MAPK8/9 axis governs the JNK activation levels to control downstream transcriptional events and eyelid morphogenesis and reduction of upstream MAP3K1 signals uncovers analogous but differential roles of MAPK8 and JNK2 in a biological process
• both MAPK8 and JNK2, have cytotoxic potential, however JNK2 is the primary signal transducer (Pubmed 19864026)
• JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor CDKN1B and the activation of NF-kappaB (Pubmed 20354187)
• role of JNK2 in the mechanism of osmotic stress-induced tight junction disruption in the intestinal epithelium (Pubmed 20595622)
• JNK2 is critically involved in stress-induced deficit of contextual fear (Pubmed 20926661)
• JNK2 plays a key role in Ras-induced tumorigenesis (Pubmed 21282468)
• critical role for JNK2 and EPS8 in receptor tyrosine kinase signaling and trafficking to convey distinctly different effects on cell migration (Pubmed 21357683)
• JNK2 enhances growth factor-induced cell migration by regulating RTK trafficking and modulating EPS8 levels (Pubmed 21357683)

Homology for human JNK2 (MAPK9)

• homolog to C.elegans B0478.1