ArticleThe Journal of clinical investigation2017
Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 48 citations in OpenAlex.
- Epac1 deletion attenuates Müller glial pathological activation and mitigates retinal neurodegeneration in ischemia-induced retinopathy.Journal of advanced research · 2026Article
- Rapid activation of ARF6 after RAF inhibition augments BRAFOncogene · 2026Article
- EHD4 and ASAP2 are critical negative regulators of the claudin-5-based endothelial barrier.The FEBS journal · 2026Article
- Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.Neural regeneration research · 2026Article
- Rapid activation of ARF6 after RAF inhibition augments BRAFV600E and promotes therapy resistance.Research square · 2025Article
- Robo4 inhibits neovascularization in oxygen-induced retinopathy by regulating ARF6 and VEGF.Human cell · 2025Article
- Tumour-intrinsic endomembrane trafficking by ARF6 shapes an immunosuppressive microenvironment that drives melanomagenesis and response to checkpoint blockade therapy.Nature communications · 2024Article
- A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed/refractory B-cell lymphomas.Investigational new drugs · 2024Article
- Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Endomucin selectively regulates vascular endothelial growth factor receptor-2 endocytosis through its interaction with AP2.Cell communication and signaling : CCS · 2024Article
- Arf6 is required for endocytosis and filamentous actin assembly during angiogenesis in vitro.Microcirculation (New York, N.Y. : 1994) · 2023Article
- ADP-Ribosylation Factor 6 Pathway Acts as a Key Executor of Mesenchymal Tumor Plasticity.International journal of molecular sciences · 2023Review
- ARF6-dependent endocytic trafficking of the Interferon-γ receptor drives adaptive immune resistance in cancer.bioRxiv : the preprint server for biology · 2023Article
- Arf6 as a therapeutic target: Structure, mechanism, and inhibitors.Acta pharmaceutica Sinica. B · 2023Review
- KIF13B mediates VEGFR2 recycling to modulate vascular permeability.Cellular and molecular life sciences : CMLS · 2023Article
- Arf6 Regulates Endocytosis and Angiogenesis by Promoting Filamentous Actin Assembly.bioRxiv : the preprint server for biology · 2023Article
- SENP6-Mediated deSUMOylation of VEGFR2 Enhances Its Cell Membrane Transport in Angiogenesis.International journal of molecular sciences · 2023Article
- Heterozygosity for ADP-ribosylation factor 6 suppresses the burden and severity of atherosclerosis.PloS one · 2023Article
- V-ATPase modulates exocytosis in neuroendocrine cells through the activation of the ARNO-Arf6-PLD pathway and the synthesis of phosphatidic acid.Frontiers in molecular biosciences · 2023Article
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Authors and funding
24 authors at 4 institutions in 4 countries.
Funding
Abstract
The devastating sequelae of diabetes mellitus include microvascular permeability, which results in retinopathy. Despite clinical and scientific advances, there remains a need for new approaches to treat retinopathy. Here, we have presented a possible treatment strategy, whereby targeting the small GTPase ARF6 alters VEGFR2 trafficking and reverses signs of pathology in 4 animal models that represent features of diabetic retinopathy and in a fifth model of ocular pathological angiogenesis. Specifically, we determined that the same signaling pathway utilizes distinct GEFs to sequentially activate ARF6, and these GEFs exert distinct but complementary effects on VEGFR2 trafficking and signal transduction. ARF6 activation was independently regulated by 2 different ARF GEFs - ARNO and GEP100. Interaction between VEGFR2 and ARNO activated ARF6 and stimulated VEGFR2 internalization, whereas a VEGFR2 interaction with GEP100 activated ARF6 to promote VEGFR2 recycling via coreceptor binding. Intervening in either pathway inhibited VEGFR2 signal output. Finally, using a combination of in vitro, cellular, genetic, and pharmacologic techniques, we demonstrated that ARF6 is pivotal in VEGFR2 trafficking and that targeting ARF6-mediated VEGFR2 trafficking has potential as a therapeutic approach for retinal vascular diseases such as diabetic retinopathy.
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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.