ArticleeLife2016
The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids.
Article in eLife, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 38 citations in OpenAlex.
- Review
- Lysosomal quality control Review.Autophagy · 2025Review
- The Emerging Roles of Vacuolar-Type ATPase-Dependent Lysosomal Acidification in Cardiovascular Disease.Biomolecules · 2025Review
- Novel determinants of NOTCH1 trafficking and signaling in breast epithelial cells.Life science alliance · 2025Article
- ZNRF2 is essential for gliomagenesis through orchestrating glycolysis and acts as a promising therapeutic target in glioma.Journal of translational medicine · 2025Article
- Review
- The Drosophila ZNRF1/2 homologue, detour, interacts with HOPS complex and regulates autophagy.Communications biology · 2024Article
- A pancancer analysis of the oncogenic role of ZNRF2 in human tumours.Journal of cellular and molecular medicine · 2023Review
- The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to limit lung barrier damage.The Journal of experimental medicine · 2023Article
- ZNRF2 as an oncogene is transcriptionally regulated by CREB1 in breast cancer models.Human cell · 2023Article
- Comparative Ubiquitination Proteomics Revealed the Salt Tolerance Mechanism in Sugar Beet Monomeric Additional Line M14.International journal of molecular sciences · 2022Article
- Purine nucleotide depletion prompts cell migration by stimulating the serine synthesis pathway.Nature communications · 2022Article
- Role of hsa‑miR‑105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer.Oncology reports · 2021Observational
- A semi-supervised Bayesian approach for simultaneous protein sub-cellular localisation assignment and novelty detection.PLoS computational biology · 2020Article
- DNA methylation-based prognostic biomarkers of acute myeloid leukemia patients.Annals of translational medicine · 2019Article
- ANKRD44 Gene Silencing: A Putative Role in Trastuzumab Resistance in Her2-Like Breast Cancer.Frontiers in oncology · 2019Article
- MicroRNA-100 suppresses human osteosarcoma cell proliferation and chemo-resistance via ZNRF2.Oncotarget · 2017Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.
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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.