ArticleThe Journal of clinical investigation2019
MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling.
Article in The Journal of clinical investigation, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
64 citing papers in PubMed, 101 citations in OpenAlex.
- Multiple organ dysfunction syndrome: molecular mechanisms and therapeutic strategies.Signal transduction and targeted therapy · 2026Review
- Systematic analyses to explore kinase gene set-based signature in glioma, in which WEE1 contributes to tumor progression.Discover oncology · 2026Article
- A novel L-shaped ortho-quinone analog and 2-Deoxy-D-Glucose a synergistic approach to inhibit hepatocellular carcinoma cell proliferation.Scientific reports · 2026Article
- Tumor microbiome-transcriptome crosstalk identifiesTheranostics · 2026Article
- The Impact of Proinflammatory M1 Macrophages on the Proliferation and Expression of Cyclin E2, Mitogen-Activated Protein Kinases 4 and 7 in Hepatocytes Isolated from a Diethylnitrosamine-Induced Hepatocellular Carcinoma Rat Model.Molecules (Basel, Switzerland) · 2025Article
- p53 transcriptionally activates DCP1B to suppress tumor progression and enhance tumor sensitivity to PI3K blockade in non-small cell lung cancer.Cell death and differentiation · 2025Article
- Polystyrene microspheres could inhibit the ferroptosis of prostate cancer cells via USP39/IGF2BP3/MAPK4 axis.Journal of translational medicine · 2025Article
- Investigating Liquid-Liquid Phase Separation in Lung Adenocarcinoma to Improve Prognostic Accuracy and Treatment Efficacy.Journal of cellular and molecular medicine · 2025Article
- Proteomic profiling of plasma extracellular vesicles identifies signatures of innate immunity, coagulation, and endothelial activation in septic patients.Scientific reports · 2025Article
- Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer.Oncogene · 2025Article
- SERPINA1 methylation as a novel diagnostic marker for early-stage papillary thyroid carcinoma via MAPK6-AKT/mTOR pathway.Clinical epigenetics · 2025Article
- A Spermidine Derivative Ameliorates Dextran Sulfate Sodium-Induced Colitis in Mice by Inhibiting the MAPK4/AKT Signaling Pathway.Foods (Basel, Switzerland) · 2025Article
- Clear cell renal carcinoma essentially requires CDKL3 for oncogenesis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- NLRP3 promotes the proliferation and metastasis of colorectal cancer by regulating the S6K1-GLI1 signaling pathway.Journal of Cancer · 2025Article
- Pathogenesis and Management Strategies in Radioiodine-Refractory Differentiated Thyroid Cancer: From Molecular Mechanisms Toward Therapeutic Approaches: A Comprehensive Review.Journal of clinical medicine · 2024Review
- β-elemene promotes miR-127-3p maturation, induces NSCLCs autophagy, and enhances macrophage M1 polarization through exosomal communication.Journal of pharmaceutical analysis · 2024Article
- Combined Inhibition of PI3K and STAT3 signaling effectively inhibits bladder cancer growth.Oncogenesis · 2024Article
- MAPK4 facilitates angiogenesis by inhibiting the ERK pathway in non-small cell lung cancer.Cancer innovation · 2024Article
- MiR-7 deficiency promotes Th1 polarization of CD4Immunologic research · 2024Article
- The mTORC2 signaling network: targets and cross-talks.The Biochemical journal · 2024Review
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 1 institution in 1 country.
Funding
Abstract
MAPK4 is an atypical MAPK. Currently, little is known about its physiological function and involvement in diseases, including cancer. A comprehensive analysis of 8887 gene expression profiles in The Cancer Genome Atlas (TCGA) revealed that MAPK4 overexpression correlates with decreased overall survival, with particularly marked survival effects in patients with lung adenocarcinoma, bladder cancer, low-grade glioma, and thyroid carcinoma. Interestingly, human tumor MAPK4 overexpression also correlated with phosphorylation of AKT, 4E-BP1, and p70S6K, independent of the loss of PTEN or mutation of PIK3CA. This led us to examine whether MAPK4 activates the key metabolic, prosurvival, and proliferative kinase AKT and mTORC1 signaling, independent of the canonical PI3K pathway. We found that MAPK4 activated AKT via a novel, concerted mechanism independent of PI3K. Mechanistically, MAPK4 directly bound and activated AKT by phosphorylation of the activation loop at threonine 308. It also activated mTORC2 to phosphorylate AKT at serine 473 for full activation. MAPK4 overexpression induced oncogenic outcomes, including transforming prostate epithelial cells into anchorage-independent growth, and MAPK4 knockdown inhibited cancer cell proliferation, anchorage-independent growth, and xenograft growth. We concluded that MAPK4 can promote cancer by activating the AKT/mTOR signaling pathway and that targeting MAPK4 may provide a novel therapeutic approach for cancer.
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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.