Drug Target and Biomarker: MAPK8 (G5599)

NCBI ID: G5599

MAPK8

Drug Target and Biomarker: MAPK8

The JNK pathway, which is synonymous with MAPK8, is involved in various biological processes and diseases. In the context of viral infections, such as DENV2, ZIKV, and CHIKV infections of salivary glands, the JNK pathway is shown to be regulated by these viruses. Furthermore, in cancer cells, the Warburg effect, characterized by increased glucose uptake and glycolysis, desensitizes cells to oxidative stress-induced apoptosis by inhibiting JNK activation.

In the reprogramming of normal adipose tissue macrophages and those in obesity, the JNK pathway is activated to induce proinflammatory gene expression and reprogram macrophages to the M1 phenotype. It is also suggested that the JNK pathway interacts with beta1 integrin signaling, affecting cell cycle regulation and radiation-induced cell cycle modifications.

In the context of myeloproliferative neoplasms (MPN), the JNK pathway is activated in MPN cells in response to chemotherapeutic agents, allowing the cells to escape apoptosis and prolong disease progression.

Overall, the JNK pathway plays a role in viral infections, cancer cell survival, macrophage reprogramming, and MPN cell resistance to chemotherapy.
Based on the provided context information:

JNK1 and JNK2 play differential roles in various skin cancers. In basal cell carcinoma (BCC), JNK1/2 enhances the interaction of Jun/Fos and phosphorylated ATF2, promoting SHH/Gli-induced tumorigenesis. In squamous cell carcinoma (SCC), JNK1 induces apoptosis while JNK2 promotes carcinogenesis in an AP1-dependent manner. SCCA1 inhibits JNK1, promoting SCC, while CYLD inhibits JNK2/AP1 cascade, suppressing SCC.

JNK activation is involved in apoptotic pathways. Upon apoptotic stimuli, JNK is phosphorylated and activated. JNK phosphorylates wild-type p53, leading to the formation of a complex with p73. This complex then drives the transcription of PUMA and Bax genes, ultimately causing apoptosis. However, in the case of mutant p53, phosphorylation by JNK enhances complex formation with p73 but fails to transcribe PUMA and Bax genes, reducing the apoptotic signal and promoting tumor survival.

ws-Lynx1 activates JNK as part of the signaling cascade. The interaction of ws-Lynx1 with alpha7-nAChRs triggers the activation of JAK, JNK, p38alpha, Src, PI3K, and AKT kinases. This subsequently activates transcription factors, including the proapoptotic factor p53, and causes mislocalization of the p27 protein. The overall effects of ws-Lynx1 are mediated by various membrane receptors and regulators.

JNK and p38 are activated by the IL-1 signaling pathway. Upon IL-1 binding to its receptor, the signaling module involving MyD88, IRAK, and TRAF6 is formed. This activates the MAP kinase signaling module, leading to the activation of JNK and p38 via Map kinase kinases (MKKs). The phosphorylation of JNK and p38, along with the expression of their target transcription factors cJun and cFos, results in increased IL-6 gene transcription in immature enterocytes. Later in enterocyte development, JunD replaces cJun/cFos dimers, resulting in lower IL-6 gene transcription. Additionally, a JNK-independent pathway involving JunB represses IL-6 gene transcription in the colon.

The miR-21/PDCD4/JNK/ABCG2 axis is involved in 5-FU-resistant colorectal cancer (CRC) cells. This axis represents a molecular mechanism where miR-21 regulates PDCD4, which then affects JNK signaling and contributes to ABCG2-mediated drug resistance in CRC cells. Treatment with SP600125, a JNK inhibitor, can potentially reverse the resistance in HCT116/FUR cells.

In summary, JNK1 and JNK2 have distinct roles in skin cancers, where JNK1 enhances tumorigenesis in BCC and induces apoptosis in SCC, while JNK2 promotes carcinogenesis in SCC. JNK activation is involved in apoptotic pathways, with its phosphorylation playing different roles in wild-type and mutant p53. ws-Lynx1 activates JNK along with other kinases, leading to various cellular effects. The IL-1 signaling pathway activates JNK and p38, influencing IL-6 gene transcription in immature enterocytes and repressing it in the colon. The miR-21/PDCD4/JNK/ABCG2 axis contributes to drug resistance in CRC cells.

Protein Name: Mitogen-activated Protein Kinase 8

Functions: 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 (PubMed:28943315). 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-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). Phosphorylates NLRP3, promoting assembly of the NLRP3 inflammasome (PubMed:28943315)

The "MAPK8 Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about MAPK8 comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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