Ask about this productRelated genes to: MAP4K4 antibody
- Gene:
- MAP4K4 NIH gene
- Name:
- mitogen-activated protein kinase kinase kinase kinase 4
- Previous symbol:
- -
- Synonyms:
- HGK, NIK, FLH21957
- Chromosome:
- 2q11.2
- Locus Type:
- gene with protein product
- Date approved:
- 1999-09-07
- Date modifiied:
- 2016-10-05
Related products to: MAP4K4 antibody
Related articles to: MAP4K4 antibody
- The incidence of obesity and male infertility continues to rise, and a complex pathophysiological association exists between the two. However, the comorbid molecular mechanisms remain incompletely elucidated. In this study, bioinformatics and machine learning methods were integrated to systematically explore the shared mechanisms of obesity and male infertility, and to predict natural compounds and TCMs with therapeutic potential based on multi-omics data. Datasets of male infertility and obesity were obtained from the GEO database, and 43 intersecting genes were identified through differential expression analysis. Using three machine learning algorithms, including random forest, least absolute shrinkage and selection operator(LASSO) regression, and support vector machine(SVM), five Hub genes(MAP4K4, GPT2, ADSSL1, PAIP2, and GINS3) were screened. The combined diagnostic model achieved an area under the curve(AUC) greater than 0.8, indicating good diagnostic performance. Functional enrichment analysis revealed that these genes are mainly involved in key biological processes such as amino acid metabolism, cell migration, and DNA replication. Immune infiltration analysis showed a significant upregulation of central memory CD4~+ T cells in both diseases, suggesting that chronic immune activation is an important basis for their comorbidity. Single-cell sequencing and pseudotime analyses demonstrated disordered cell differentiation trajectories in the adipose tissue of obese patients and the testicular tissue of infertile patients. Based on the connectivity map(CMap) database, ten natural compounds, including berberine, curcumin, and ginsenosides, were predicted and further validated by molecular docking to have strong binding affinities with the Hub genes. Integration with the traditional Chinese medicine systems pharmacology(TCMSP) platform enabled the construction of a "target-natural compound-herbal medicine" interaction network, identifying 38 corresponding herbal medicines. Property and meridian analysis indicated a predominance of warm nature, sweet flavor, and liver meridian tropism, consistent with the TCM therapeutic principles of "resolving phlegm and dampness, strengthening the spleen, and tonifying the kidney". This study reveals, at the molecular level, the comorbid mechanisms of obesity and male infertility in immune-inflammatory regulation and cell differentiation dysfunction, providing a theoretical basis and potential drug targets for precise TCM intervention in obesity-related male infertility. - Source: PubMed
Gong Zhuo-ZhiFeng Qiu-JianGao Qing-HeWang FuGuo JunLiu Sheng-Jing - Alternative splicing (AS) is increasingly recognized as a hallmark of cancer, contributing to tumor progression and therapeutic resistance. Zinc finger MYND-type containing 11 (ZMYND11), a critical reader of the histone modification H3.3K36me3, is frequently downregulated in various cancers. However, its specific role in regulating AS in prostate cancer (PCa) remains unclear. This study aimed to elucidate the mechanisms by which ZMYND11 modulates AS in PCa and evaluate its potential as a therapeutic target. - Source: PubMed
Publication date: 2025/02/14
Lian ChengWang ZixianGao XuWei Gong-Hong - The c-Jun N-terminal kinase (JNK) pathway is a central driver of fibrosis, inflammation, and neurodegeneration. While direct JNK inhibitors have shown therapeutic promise, achieving high isoform selectivity remains a significant medicinal chemistry challenge. Furthermore, targeting the upstream 'gatekeepers' MKK4 and MKK7 offers a distinct mechanism to modulate pathway output with greater precision. Consequently, medicinal chemistry efforts have shifted upstream to the dual-specificity kinases MKK4 and MKK7. This review critically evaluates the structural biology and pharmacological evolution of small-molecule inhibitors targeting these nodes. We contrast the distinct therapeutic landscapes of the two kinases: while MKK4 inhibition has emerged as a breakthrough strategy for unlocking liver regeneration (exemplified by the first-in-class clinical candidate HRX215), MKK7 inhibition is primarily pursued for its anti-fibrotic and anti-inflammatory potential. Special attention is given to structure-based design strategies, including the exploitation of the unique hinge-region cysteine (Cys218) for MKK7-specific covalent targeting and the optimization of scaffold selectivity against off-targets like BRAF. Finally, we discuss emerging modalities, such as PROTACs and dual inhibitors, outlining a roadmap for the next generation of precision therapeutics targeting the MKK-JNK axis. - Source: PubMed
Publication date: 2026/02/15
Zhao MinLi BaojianGao YingLiang YanShao NanqiShi XinboLi Jie - Hippo is the namesake component of a conserved transduction cascade/regulator of tissue homeostasis and development across metazoans. The Ste20 family kinase Hippo/MST activates the NDR family kinase Warts/LATS to inhibit the transcriptional coactivator Yorkie/YAP/TAZ and its transcription factor partner Scalloped/TEAD. In Caenorhabditis elegans, cell lineages and organ sizes are largely invariant, and classical Hippo phenotypes such as tissue overgrowth are absent. Nevertheless, WTS-1, YAP-1, and the TEAD-like transcription factor EGL-44 form a conserved core module required for larval development past the L2 stage. Crucially, a direct role for Hippo signaling remains unestablished. To address this question, we generated a fluorescently tagged endogenous YAP-1 as a live biomarker of pathway activity. Upon WTS-1 loss, endogenous YAP-1 translocated from cytosol to nucleus in epithelium and intestine. Tissue-specific depletion revealed that intestinal but not epithelial WTS-1 is essential for progression past L2. The duplicated Hippo-related kinases CST-1 and CST-2 repressed YAP-1 nuclear localization in the epithelium but not intestine, indicating that intestinal WTS-1 functions without CST-1/2. The Ste20 kinase MIG-15, orthologous to Drosophila Misshapen and mammalian MAP4K4/6/7, was redundant with CST-1/2 for larval progression. Yet deficient MIG-15 uniquely increased YAP-1 abundance without driving nuclear localization. By contrast, the Ste20 kinase GCK-2, orthologous to Drosophila Happyhour and mammalian MAP4K1/2/3/5, had no detectable role. Our findings establish C. elegans as a model for Hippo signaling, with Hippo-dependent and -independent cascades controlling WTS-1 in epithelia and intestine, respectively. In this context, YAP-1/EGL-44 outputs are repurposed from the conventional association with growth control to non-proliferative developmental functions. - Source: PubMed
Publication date: 2026/02/26
Huynh LinhFakieh Razan AHendrix C'BrionnePowell ReidReiner David J - Bt Cry toxins remain the cornerstone of transgenic crop protection against Lepidopteran pests, yet field-evolved resistance, particularly in invasive species such as and , can threaten their long-term efficacy. This review presents a comprehensive and unified mechanistic framework that synthesizes current understanding of Bt Cry toxin modes of action and the complex, multilayered regulatory mechanisms of field-evolved resistance. Beyond the classical pore-formation model, emerging evidence highlights signal transduction cascades, immune evasion via suppression of Toll/IMD pathways, and tripartite toxin-host-microbiota interactions that can dynamically modulate protoxin activation and receptor accessibility. Resistance arises from target-site alterations (e.g., , mutations), altered midgut protease profiles, enhanced immune regeneration, and microbiota-mediated detoxification, orchestrated by transcription factor networks (GATA, FoxA, FTZ-F1), constitutive MAPK hyperactivation (especially MAP4K4-driven cascades), along with preliminary emerging findings on non-coding RNA involvement. Countermeasures now integrate synergistic Cry/Vip pyramiding, CRISPR/Cas9-validated receptor knockouts revealing functional redundancy, Domain III chimerization (e.g., Cry1A.105), phage-assisted continuous evolution (PACE), and the emerging application of AlphaFold3 for structure-guided rational redesign of resistance-breaking variants. Future sustainability hinges on system-level integration of single-cell transcriptomics, midgut-specific CRISPR screens, microbiome engineering, and AI-accelerated protein design to preempt resistance trajectories and secure Bt biotechnology within integrated resistance and pest management frameworks. - Source: PubMed
Publication date: 2026/01/25
Xie JunfeiHe WenfengQiu MinLin JiaxinShu HaoranWang JintaoLiu Leilei