EEA1 links PI(3)K function to Rab5 regulation of endosome fusion
Abstract
GTPases and lipid kinases regulate membrane traffic along the endocytic pathway by mechanisms that are not completely understood. Fusion between early endosomes requires phosphatidylinositol-3-OH kinase (PI(3)K) activity as well as the small GTPase Rab5. Excess Rab5-GTP complex restores endosome fusion when PI(3)K is inhibited. Here we identify the early-endosomal autoantigen EEA1 which binds the PI(3)K product phosphatidylinositol-3-phosphate, as a new Rab5 effector that is required for endosome fusion. The association of EEA1 with the endosomal membrane requires Rab5-GTP and PI(3)K activity, and excess Rab5-GTP stabilizes the membrane association of EEA1 even when PI(3)K is inhibited. The identification of EEA1 as a direct Rab5 effector provides a molecular link between PI(3)K and Rab5, and its restricted distribution to early endosomes indicates that EEA1 may confer directionality to Rab5-dependent endocytic transport.
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PI(3)P contributes to the recruitment of proteins containing PX or FYVE motifs including EEA1 and the NADPH-oxidase subunits p40phox and p47phox.
“PI(3)P also contributes to the recruitment of proteins containing PX or FYVE motifs including EEA1 and the NADPH-oxidase subunits p40phox and p47phox (25–27).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [25]
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- Authors
- Simonsen, A., Lippe, R., Christoforidis, S., Gaullier, J.-M., Brech, A., Callaghan, J., Toh, B.-H., Murphy, C., Zerial, M., & Stenmark, H.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Stenmark, Harald
- Venue
- Nature
- Published
- 1998-07-30
- Volume
- 394
- Issue
- 6692
- Pages
- 494-498
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1614056212
- Cited by
- 1,133
- References
- 27
- Citations by year
- 2026: 16 · 2025: 27 · 2024: 13 · 2023: 33 · 2022: 22 · 2021: 37 · 2020: 33 · 2019: 36 · 2018: 29 · 2017: 41 · 2016: 44 · 2015: 23 · 2014: 37 · 2013: 39 · 2012: 44
- FWCI
- 27.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- EEA1, phosphatidylinositol 3-phosphate, phosphatidylinositol 3-kinase, Rab5, endocytic transport, membrane trafficking, GTPase signaling
- MeSH terms
- Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Autoantigens, Cattle, Cell Line, Cloning, Molecular, Enzyme Inhibitors, Guanosine Triphosphate, Cricetinae, HeLa Cells, Humans, Intracellular Membranes, Membrane Fusion, Membrane Proteins, Endosomes, Recombinant Fusion Proteins, Mutagenesis, GTP-Binding Proteins, Phosphatidylinositol 3-Kinases, rab5 GTP-Binding Proteins, Vesicular Transport Proteins
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