ArticleProceedings of the National Academy of Sciences of the United States of America2014
EFA6 controls Arf1 and Arf6 activation through a negative feedback loop.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 38 citations in OpenAlex.
- The cytokinesis regulator RacGAP1 is a Rac1-specific GAP on membranes.Protein science : a publication of the Protein Society · 2026Article
- Arf6 is required for endocytosis and filamentous actin assembly during angiogenesis in vitro.Microcirculation (New York, N.Y. : 1994) · 2023Article
- Arf6 as a therapeutic target: Structure, mechanism, and inhibitors.Acta pharmaceutica Sinica. B · 2023Review
- The ARF GTPase regulatory network in collective invasion and metastasis.Biochemical Society transactions · 2023Review
- The small GTPase ARF3 controls invasion modality and metastasis by regulating N-cadherin levels.The Journal of cell biology · 2023Article
- Structural basis for the initiation of COPII vesicle biogenesis.Structure (London, England : 1993) · 2021Article
- EFA6 in Axon Regeneration, as a Microtubule Regulator and as a Guanine Nucleotide Exchange Factor.Cells · 2021Review
- PI 3-kinase delta enhances axonal PIPEMBO molecular medicine · 2020Article
- Extensive GTPase crosstalk regulates Golgi trafficking and maturation.Current opinion in cell biology · 2020Review
- NMT1 and NMT2 are lysine myristoyltransferases regulating the ARF6 GTPase cycle.Nature communications · 2020Article
- Ancient complement and lineage-specific evolution of the Sec7 ARF GEF proteins in eukaryotes.Molecular biology of the cell · 2019Article
- ARF GTPases and their GEFs and GAPs: concepts and challenges.Molecular biology of the cell · 2019Review
- PH-domain-binding inhibitors of nucleotide exchange factor BRAG2 disrupt Arf GTPase signaling.Nature chemical biology · 2019Article
- A NUMB-EFA6B-ARF6 recycling route controls apically restricted cell protrusions and mesenchymal motility.The Journal of cell biology · 2018Article
- EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment.Journal of cell science · 2017Article
- Allosteric inhibition of the guanine nucleotide exchange factor DOCK5 by a small molecule.Scientific reports · 2017Article
- Multiple interactions between an Arf/GEF complex and charged lipids determine activation kinetics on the membrane.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Allosteric regulation of Arf GTPases and their GEFs at the membrane interface.Small GTPases · 2016Review
- β-Arrestin-mediated Angiotensin II Signaling Controls the Activation of ARF6 Protein and Endocytosis in Migration of Vascular Smooth Muscle Cells.The Journal of biological chemistry · 2016Article
- Endothelial Barrier and Its Abnormalities in Cardiovascular Disease.Frontiers in physiology · 2015Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Guanine nucleotide exchange factors (GEFs) of the exchange factor for Arf6 (EFA6), brefeldin A-resistant Arf guanine nucleotide exchange factor (BRAG), and cytohesin subfamilies activate small GTPases of the Arf family in endocytic events. These ArfGEFs carry a pleckstrin homology (PH) domain in tandem with their catalytic Sec7 domain, which is autoinhibitory and supports a positive feedback loop in cytohesins but not in BRAGs, and has an as-yet unknown role in EFA6 regulation. In this study, we analyzed how EFA6A is regulated by its PH and C terminus (Ct) domains by reconstituting its GDP/GTP exchange activity on membranes. We found that EFA6 has a previously unappreciated high efficiency toward Arf1 on membranes and that, similar to BRAGs, its PH domain is not autoinhibitory and strongly potentiates nucleotide exchange on anionic liposomes. However, in striking contrast to both cytohesins and BRAGs, EFA6 is regulated by a negative feedback loop, which is mediated by an allosteric interaction of Arf6-GTP with the PH-Ct domain of EFA6 and monitors the activation of Arf1 and Arf6 differentially. These observations reveal that EFA6, BRAG, and cytohesins have unanticipated commonalities associated with divergent regulatory regimes. An important implication is that EFA6 and cytohesins may combine in a mixed negative-positive feedback loop. By allowing EFA6 to sustain a pool of dormant Arf6-GTP, such a circuit would fulfill the absolute requirement of cytohesins for activation by Arf-GTP before amplification of their GEF activity by their positive feedback loop.
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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.