ArticleProceedings of the National Academy of Sciences of the United States of America2019
Canonical Wnt is inhibited by targeting one-carbon metabolism through methotrexate or methionine deprivation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 57 citations in OpenAlex.
- Non-Covalent Active Mixing as a Viable Alternative to Covalent Conjugation for the Intracellular Delivery of Biologics: The Case of Glucarpidase.Applied biochemistry and biotechnology · 2026Article
- Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis.Signal transduction and targeted therapy · 2026Article
- Article
- Methionine induced placental angiogenesis through activating WNT3A/CTNNB1-PIGF-VEGFR1 pathway.Cell communication and signaling : CCS · 2025Article
- Deep-Red Cyanine-Based Fluorescent Probes with 6-Quinolinium Acceptors for Mitochondrial NAD(P)H Imaging in Live Cells and Human Diseased Kidney Tissues.ACS applied bio materials · 2025Article
- Mechanisms and rationales of SAM homeostasis.Trends in biochemical sciences · 2025Review
- Methionine Modulates the Growth and Development of Heat-Stressed Dermal Papilla Cells via the Wnt/β-Catenin Signaling Pathway.International journal of molecular sciences · 2025Article
- Steroids and One-Carbon Metabolism: Clinical Implications in Endocrine Disorders.Neuroendocrinology · 2025Review
- Methionine ameliorates intestinal injury in senescence-accelerated mouse prone-8 mice by reducing sulfate-reducing bacteria and enhancing barrier function.Frontiers in nutrition · 2025Article
- DGDRP: drug-specific gene selection for drug response prediction via re-ranking through propagating and learning biological network.Frontiers in genetics · 2024Article
- The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy.Frontiers in pharmacology · 2024Review
- The WNT/β-catenin system in chronic kidney disease-mineral bone disorder syndrome.International urology and nephrology · 2023Review
- The Functional Roles of Methionine and Arginine in Intestinal and Bone Health of Poultry: Review.Animals : an open access journal from MDPI · 2023Review
- Vitamin BScience advances · 2023Article
- Article
- The emerging mechanisms and functions of microautophagy.Nature reviews. Molecular cell biology · 2023Review
- Asymmetric and symmetric protein arginine methylation in methionine-addicted human cancer cells.PloS one · 2023Article
- Arginine methylation in the epithelial-to-mesenchymal transition.The FEBS journal · 2022Review
- Simplifying the B Complex: How Vitamins B6 and B9 Modulate One Carbon Metabolism in Cancer and Beyond.Metabolites · 2022Review
- Ribosome-Directed Therapies in Cancer.Biomedicines · 2022Review
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The nutrient-sensing metabolite S-adenosylmethionine (SAM) controls one-carbon metabolism by donating methyl groups to biochemical building blocks, DNA, RNA, and protein. Our recent work uncovered a requirement for cytoplasmic arginine methylation during Wnt signaling through the activity of protein arginine methyltransferase 1 (PRMT1), which transfers one-carbon groups from SAM to many protein substrates. Here, we report that treatments that decrease levels of the universal methyl donor SAM were potent inhibitors of Wnt signaling and of Wnt-induced digestion of extracellular proteins in endolysosomes. Thus, arginine methylation provides the canonical Wnt pathway with metabolic sensing properties through SAM. The rapid accumulation of Wnt-induced endolysosomes within 30 minutes was inhibited by the depletion of methionine, an essential amino acid that serves as the direct substrate for SAM production. We also found that methionine is required for GSK3 sequestration into multivesicular bodies through microautophagy, an essential step in Wnt signaling activity. Methionine starvation greatly reduced Wnt-induced endolysosomal degradation of extracellular serum proteins. Similar results were observed by addition of nicotinamide (vitamin B3), which serves as a methyl group sink. Methotrexate, a pillar in the treatment of cancer since 1948, decreases SAM levels. We show here that methotrexate blocked Wnt-induced endocytic lysosomal activity and reduced canonical Wnt signaling. Importantly, the addition of SAM during methionine depletion or methotrexate treatment was sufficient to rescue endolysosomal function and Wnt signaling. Inhibiting the Wnt signaling pathway by decreasing one-carbon metabolism provides a platform for designing interventions in Wnt-driven disease.
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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.