ArticleOncogene2021
MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3.
Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 33 citations in OpenAlex.
- Article
- TNIK as a molecular switch regulating platelet function in hemostasis and hyperlipidemia-associated thrombosis.Blood advances · 2026Article
- Defining treatment-resistant brain cancer: Genetic screening to identify oncogene-driven immunomodulation and therapy resistance.Cancer gene therapy · 2026Review
- Long-term cytokine exposure remodels the methylome and transcriptome of recessive dystrophic epidermolysis bullosa keratinocytes - a bioinformatic analysis.Frontiers in cell and developmental biology · 2026Article
- Post-Translational Modifications: Key "Regulators" of Pancreatic Cancer Malignant Phenotype-Advances in Mechanisms and Targeted Therapies.Biomedicines · 2025Review
- MAP4K signaling pathways in cancer: roles, mechanisms and therapeutic opportunities.Experimental & molecular medicine · 2025Review
- In silico screening and in vitro biological evaluation reveal Queuine as a promising MAP4K4 inhibitor for treating pancreatic cancer.BMC biotechnology · 2025Article
- Transcriptome-Based Survival Analysis IdentifiesCancers · 2025Article
- Article
- Peptide Transporter 1-Mediated Dipeptide Transport Promotes Hepatocellular Carcinoma Metastasis by Activating MAP4K4/G3BP2 Signaling Axis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- A single-cell strategy for the identification of intronic variants related to mis-splicing in pancreatic cancer.NAR genomics and bioinformatics · 2024Article
- MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer.Molecular oncology · 2024Article
- Myeloid cells interact with a subset of thyrocytes to promote their migration and follicle formation through NF-κB.Nature communications · 2023Article
- In silico identification and biological evaluation of a selective MAP4K4 inhibitor against pancreatic cancer.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- MLK3 localizes mainly to the cytoplasm and promotes oxidative stress injury via a positive feedback loop.Cell biochemistry and biophysics · 2023Article
- MAP4K4 promotes ovarian cancer metastasis through diminishing ADAM10-dependent N-cadherin cleavage.Oncogene · 2023Article
- Review
- MAP4K4 and cancer: ready for the main stage?Frontiers in oncology · 2023Review
- Bioinformatics and Experimental Analyses Reveal MAP4K4 as a Potential Marker for Gastric Cancer.Genes · 2022Article
- Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma.Cell death & disease · 2022Article
Corrections and comments
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
MAP4K4 is a Ste20 member and reported to play important roles in various pathologies, including in cancer. However, the mechanism by which MAP4K4 promotes pancreatic cancer is not fully understood. It is suggested that MAP4K4 might function as a cancer promoter via specific downstream target(s) in an organ-specific manner. Here we identified MLK3 as a direct downstream target of MAP4K4. The MAP4K4 and MLK3 associates with each other, and MAP4K4 phosphorylates MLK3 on Thr738 and increases MLK3 kinase activity and downstream signaling. The phosphorylation of MLK3 by MAP4K4 promotes pancreatic cancer cell proliferation, migration, and colony formation. Moreover, MAP4K4 is overexpressed in human pancreatic tumors and directly correlates with the disease progression. The MAP4K4-specific pharmacological inhibitor, GNE-495, impedes pancreatic cancer cell growth, migration, induces cell death, and arrests cell cycle progression. Additionally, the GNE-495 reduced the tumor burden and extended survival of the KPC mice with pancreatic cancer. The MAP4K4 inhibitor also reduced MAP4K4 protein expression, tumor stroma, and induced cell death in murine pancreatic tumors. These findings collectively suggest that MLK3 phosphorylation by MAP4K4 promotes pancreatic cancer, and therefore therapies targeting MAP4K4 might alleviate the pancreatic cancer tumor burden in patients.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.