Ask about this productRelated genes to: MAP4K2 Blocking Peptide
- Gene:
- MAP4K2 NIH gene
- Name:
- mitogen-activated protein kinase kinase kinase kinase 2
- Previous symbol:
- RAB8IP
- Synonyms:
- GCK, BL44
- Chromosome:
- 11q13.1
- Locus Type:
- gene with protein product
- Date approved:
- 1997-08-18
- Date modifiied:
- 2014-11-19
Related products to: MAP4K2 Blocking Peptide
Related articles to: MAP4K2 Blocking Peptide
- Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting and persistent chronic inflammation, yet the multi-lineage cellular drivers of its pathogenesis remain incomplete. In this study, single-cell RNA sequencing (scRNA-seq) identified Atp6ap2 as a profoundly upregulated gene across multiple skeletal muscle cell types-particularly endothelial cells, fibroblasts, and myoblasts-in both mdx and severe mdx mice. Weighted gene co-expression network analysis (WGCNA) linked Atp6ap2 expression to DMD progression, while enrichment analyses revealed that its dysregulation severely impairs vascular homeostasis and extracellular matrix integrity via the PI3K-Akt, focal adhesion, and cell cycle pathways. Utilizing Connectivity Map (CMap) analysis, we identified temozolomide (TMZ) as a top pharmacological candidate capable of reversing the ATP6AP2-associated gene signature. In vivo validation demonstrated that TMZ administration significantly enhanced motor coordination, balance, and grip strength in mdx mice, while markedly preserving dystrophic muscle architecture, reducing myofiber necrosis, and alleviating interstitial fibrosis. Mechanistically, integrated transcriptomic and metabolomic profiling revealed that TMZ induced profound metabolic and signaling shifts, modulating the Notch, MAPK, and Ras pathways, as well as autophagy and glycerophospholipid metabolism. Furthermore, scRNA-seq and cell-cell communication analyses indicated that TMZ dynamically reorganized multicellular networks, decreasing aberrant fibroblast and endothelial interactions. Crucially, immunofluorescence and Western blot validations confirmed that TMZ drastically attenuated the infiltration of F4/80-positive macrophages and suppressed their pro-inflammatory M1 polarization (indicated by reduced co-localization with iNOS and ATP6AP2), while successfully reversing the dysregulation of the ATP6AP2 axis and restoring its downstream targets MAP4K2, DGKE, and EFNA1. Collectively, our findings demonstrate that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD. - Source: PubMed
Publication date: 2026/08/13
Zhou LinZhang YuTan XinxinTao LihongWu Xuan - Abnormal expression of mammalian sterile 20-like kinase 4 (MST4) has been frequently linked to cancer development. This study explores the function of MST4 in non-small cell lung cancer (NSCLC) and delves into its functional mechanism. The expression and clinical indicative values of MST4 in NSCLC were analyzed using tissue microarrays. Gain- and loss-of-function experiments of MST4 were conducted in NSCLC cell lines to identify its effects on cell growth in vitro. Transfected NSCLC cells were co-cultured with natural killer (NK) cells to analyze immune resistance. Mouse NSCLC cells 3LL were transplanted into C57BL/6 mice to generate subcutaneous or orthotopic isograft tumor models. Upstream and downstream factors of MST4 were identified using bioinformatics. MST4 was under-expressed in NSCLC tissue microarrays and human NSCLC cells. MST4 overexpression suppressed growth activity of NSCLC cells in vitro, reduced expression of immune checkpoint genes, and reduced cell resistance to NK cell cytotoxicity. Reverse trends were observed in MST4-silenced cells. In vivo, MST4 overexpression inhibited tumorigenic activity of 3LL cells in mice and reduced immunosuppressive factors in tumor tissues. Regarding the mechanism, MST4 induced phosphorylation and cytoplasmic degradation of YAP1 by influencing the MAP4K2-LATS1/2 cascade. Protein phosphatase 4 catalytic subunit (PPP4C) was found to interact with MST4 and reduce its function, thus promoting growth and immunosuppression in NSCLC by activating YAP1. This study demonstrates that PPP4C-mediated MST4 degradation contributes to growth activity and immunosuppression in NSCLC by restoring YAP1 activity, suggesting PPP4C and MST4 as potential targets for NSCLC management. - Source: PubMed
Publication date: 2026/02/12
Xu ZhengshuiGao JianiYe ChangchunLi YuZhao DanwenLi LiangSun LiangzhangCheng YaoLi WendengJiang JiantaoLiu Shiyuan - Next-generation sequencing (NGS) is increasingly used for diagnosing monogenic forms of diabetes, including maturity-onset diabetes of the young (MODY). We aimed to evaluate the utility of NGS in patients with clinical suspicion of MODY, analyzing genotype-phenotype correlations. A total of 150 unrelated patients from the Region of Murcia (Spain) with suspected MODY were included. Whole-exome sequencing was performed and validated with Sanger and multiplex ligation-dependent probe amplification (MLPA). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) criteria. Relevant clinical data were collected per the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) criteria and analyzed using SPSS v.27.0.2.0. The diagnostic yield was 16.67% (25/150). Pathogenic or likely pathogenic variants were mainly identified in GCK (38.89%) and HNF1A (33.33%). Significant differences were found between patients with and without genetic diagnosis in family history, age of onset, and body mass index (P < 0.05). Variants of uncertain significance (VUS) were identified in 22 families (14.66%). One VUS was reclassified as likely pathogenic, and three were prioritized for further evaluation. NGS is a valuable tool for the genetic diagnosis of MODY. Integration of clinical data and systematic re-evaluation and prioritization of VUS can enhance diagnostic accuracy and inform clinical decision-making. - Source: PubMed
Publication date: 2026/02/25
Expósito García MartaSarabia Meseguer María DesamparadosHernández Martínez Antonio MiguelAragón Alonso AuroraFernández López ManuelaMacanás Botía Gabriel AngelIllán Gómez María FátimaKyriakos GeorgiosHernández López AntonioCerón Moreno Ana MaríaGuirao Blázquez CristinaSánchez Cuenca Juan JoséPascual Gilabert PatriciaAntón Martínez DavidNoguera Velasco José AntonioRuiz Espejo Francisco - Protein phosphorylation has pivotal roles in ABA and dehydration stress signaling in higher plants. However, little is known about MITOGEN-ACTIVATED PROTEIN KINASE KINASE KINASE KINASE (MAP4K) in dehydration tolerance. Here, we report MAP4K1 and MAP4K2 are involved in dehydration tolerance. Mutations in MAP4K1 or MAP4K2 did not show obvious phenotype whereas map4k1 map4k2 double mutant exhibited the dwarf phenotype and low dehydration tolerance with hyposensitivity to exogenous abscisic acid. MAP4K1 and MAP4K2 interacted with SnRK2.2, SnRK2.3, and OST1 in vitro and in vivo. OST1, but not SnRK2.2 or SnRK2.3, phosphorylated MAP4K1 and MAP4K2. Mass spectrometry and phosphorylation activity assay revealed that OST1 phosphorylated MAP4K1 on serine 487 and MAP4K2 on serine 488, respectively. MAP4K1 and MAP4K2 as well as OST1 act in the same dehydration stress pathway, with OST1 acting downstream of MAP4K1 and MAP4K2. Together, we identified MAP4K1 and MAP4K2 as new substrates of OST1, and MAP4K1 and MAP4K2 are redundant in dehydration tolerance. - Source: PubMed
Hu PengchengZheng LipengChen LanZhou YimingWang YuxinHuang TongtongZhang HeDing Yong - MAP kinase kinase kinase kinase (MAP4K) family kinases are key kinases for T cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, scRNA-seq, and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced forkhead box protein P3 (FOXP3) gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and the sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was significantly improved in T-Map4k2 cKO mice, Treg-specific Map4k2-deficient mice, adoptively transferred chimeric mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of patients with pancreatic cancer showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of antitumor immunity. - Source: PubMed
Publication date: 2026/01/29
Chuang Huai-ChiaWang Chia-WenHsueh Chia-HsinXiao Yu-ZhiTsai Ching-YiHsu Pu-MingTan Evelyn LChiu Hsien-YiTan Tse-Hua