RLIP76, an effector of the GTPase Ral, interacts with the AP2 complex: involvement of the Ral pathway in receptor endocytosis
Open accessAbstract
RLIP76 is a modular protein that was identified as a putative effector of Ral, a GTPase activated during Ras signaling. To explore further the contribution of the Ral- RLIP76 pathway to Ras signaling, we have looked for partners of RLIP76. μ2, the medium chain of the AP2 complex is shown to interact with RLIP76. We show also that in vivo endogenous AP2 and RLIP76 form a complex and that this in vivo interaction is independent of cells being stimulated by a growth factor. Furthermore, RLIP76 differentiates AP2 from AP1 in vivo as RLIP76 differentiates μ2 from μ1 in vitro and in two hybrid assays. We show that activated Ral interferes with both tranferrin receptor endocytosis and epidermal growth factor (EGF) receptor endocytosis in HeLa cells. We propose a model where the Ral-RLIP76 pathway connects signal transduction and endocytosis through interaction on one hand between the Ras-Ral pathway and RLIP, on the other hand between RLIP and proteins belonging to the endocytotic machinery.
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Previous studies of Reps1 and Ralbp1 in endocytosis were based on overexpression of dominant-negative mutants in WT cells, precluding direct assessment of their roles in CME.
“Previous studies of Reps1 and Ralbp1 in endocytosis, however, were based on overexpression of dominant-negative mutants in WT cells, precluding direct assessment of their roles in CME (63, 64).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [63]
The sections on transferrin and EGFR-GFP endocytosis describe transfecting HeLa cells with RalB mutants and inferring a possible role for RLIP76/Ralbp1 from their effects, rather than directly testing RLIP76’s role. But the inhibitory mutant in this study was constitutively active RalB; its dominant-negative RalB mutant did not inhibit endocytosis. The copy does not establish that these studies relied on dominant-negative Reps1 or Ralbp1 mutants. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRalBP1 directly interacts with the μ2 subunit of the endocytic AP2 complex.
“Endocytosis occurs when active RalA associates with RalBP1/RLIP76 [31],[32], an endocytic adaptor that directly interacts with the μ2 subunit of the endocytic AP2 complex [33] and EH domain proteins POB1 and Reps1 [34],[35].”
From Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD (2009) · cites this paper as [33]
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Cites
Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator.
Hofer, F., Fields, S., Schneider, C., & Martin, G. S. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.11089 · Cited by 287 · see citing works
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- Sambrook, J., Fritsch, E. F. and Maniatis, T. (1989). Molecular Cloning. A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press.
- Spaargaren, M. and Bischoff, J. R. (1994). Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras and Rap. Proc. Nat. Acad. Sci. USA 91, 12609-12613.
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Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD
Han, K., Kim, M.-H., Seeburg, D., Seo, J., Verpelli, C., Han, S., Chung, H. S., Ko, J., Lee, H. W., Kim, K., et al. (2009) · PLoS Biology · doi:10.1371/journal.pbio.1000187 · Cited by 71 · see citing works
Ral signaling pathway in health and cancer
Moghadam, A. R., Patrad, E., Tafsiri, E., Peng, W., Fangman, B., Pluard, T. J., Accurso, A., Salacz, M., Shah, K., Ricke, B., et al. (2017) · Cancer Medicine · doi:10.1002/cam4.1105 · Cited by 58 · see citing works
Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module
Wang, S., Chen, X., Crisman, L., Dou, X., Winborn, C. S., Wan, C., Puscher, H., Yin, Q., Kennedy, M. J., & Shen, J. (2023) · Science Advances · doi:10.1126/sciadv.ade2540 · Cited by 14 · see citing works
- Authors
- Jullien-Flores, V., Mahé, Y., Mirey, G., Leprince, C., Meunier-Bisceuil, B., Sorkin, A., & Camonis, J. H.
- Affiliations
- Inserm (FR)
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2000-08-15
- Volume
- 113
- Issue
- 16
- Pages
- 2837-2844
- ISSN
- 0021-9533 (ISSN-L)
- 1477-9137
- OpenAlex
- W1943068820
- Cited by
- 186
- References
- 1
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 11 · 2020: 3 · 2019: 9 · 2018: 5 · 2017: 5 · 2016: 9 · 2015: 7 · 2014: 5 · 2013: 11 · 2012: 10
- FWCI
- 3.07
- Type
- journal article
- Language
- en
- Open access
- green
- hal.inrae.fr
- Licence
- Locations
- Journal of Cell Science (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Vlaamse regering
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- RLIP76, Ral GTPase, AP-2, Ras signaling, receptor internalization, epidermal growth factor receptor, transferrin receptor, protein-protein interaction, signal transduction, endocytic machinery
- MeSH terms
- Carrier Proteins, Endocytosis, Epidermal Growth Factor, Epithelial Cells, HeLa Cells, Humans, Indicators and Reagents, Luminescent Proteins, Membrane Proteins, Protein Binding, Receptors, Transferrin, Transfection, Transferrin, Signal Transduction, Mutagenesis, Gene Deletion, Genes, Reporter, ATP-Binding Cassette Transporters, ras Proteins, Evolution, Molecular, GTP Phosphohydrolases, GTPase-Activating Proteins, ral GTP-Binding Proteins, Two-Hybrid System Techniques, Adaptor Proteins, Vesicular Transport, Adaptor Protein Complex 1, Adaptor Protein Complex 2, Adaptor Protein Complex 3, Adaptor Protein Complex alpha Subunits, Adaptor Protein Complex mu Subunits, Green Fluorescent Proteins, ErbB Receptors
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