Identification and Characterization of Ral-Binding Protein 1, a Potential Downstream Target of Ral GTPases
Open accessAbstract
Ral proteins constitute a distinct family of Ras-related GTPases. Although similar to Ras in amino acid sequence, Ral proteins are activated by a unique nucleotide exchange factor and inactivated by a distinct GTPase-activating protein. Unlike Ras, they fail to promote transformed foci when activated versions are expressed in cells. To identify downstream targets that might mediate a Ral-specific function, we used a Saccharomyces cerevisiae-based interaction assay to clone a novel cDNA that encodes a Ral-binding protein (RalBP1). RalBP1 binds specifically to the active GTP-bound form of RalA and not to a mutant Ral with a point mutation in its putative effector domain. In addition to a Ral-binding domain, RalBP1 also contains a Rho-GTPase-activating protein domain that interacts preferentially with Rho family member CDC42. Since CDC42 has been implicated in bud site selection in S. cerevisiae and filopodium formation in mammalian cells, Ral may function to modulate the actin cytoskeleton through its interactions with RalBP1.
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RalA and RalB are Ras effectors which also regulate Rlip.
“RalA and RalB are Ras effectors [101] which also regulate Rlip [8,9].”
From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [9]
The ‘Binding of RalBP1 to Ral in vitro’ section shows that active Ral binds RalBP1, the protein referred to here as Rlip. But the Discussion proposes rather than demonstrates that Ral binding regulates RalBP1 activity, and the reported binding experiments do not separately establish this for RalB. The Ras-effector clause has a different citation and is not the part attributed to this paper. (LLM, conf=0.85)
Experimental — accuracy not yet measuredActive RalA associates with RalBP1/RLIP76 to promote endocytosis.
“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 [32]
The Abstract and “Binding of RalBP1 to Ral in vitro” section report that RalBP1 binds active, GTP-bound RalA. The Discussion notes Ral’s presence in clathrin-coated vesicles and speculates about where it might recruit RalBP1, but does not show that their association promotes endocytosis. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRal proteins bind RalBP1 specifically in their active GTP-bound state.
“Ral proteins bind RalBP1 specifically in their active GTP-bound state 29 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [29]
Ralbp1 selectively binds to the active GTP-bound form of Ral GTPases.
“Ralbp1 selectively binds to the active GTP-bound form of Ral GTPases, offering a reliable approach to quantify active RalA proteins (37, 45, 46).”
From Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module (2023) · cites this paper as [37]
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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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Research works printed but not linked: 4
- In J. C. Lacal and F. McCormick (ed.), The ras superfamily of GTPases. CRC Press, Inc., Boca Raton, Fla.
- Feig, L. A., B. T. Pan, T. M. Roberts, and G. M. Cooper. 1986. Isolation of ras GTP-binding mutants using an in situ colony-binding assay. Proc. Natl. Acad. Sci. USA 83:4607-4611.
- Spaargaren, M., and J. R. Bischoff. 1994. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-Ras, N-Ras, K-Ras and Rap. Proc. Natl. Acad. Sci. USA 91:12609-12613.
- Swick, A. G., M. Janicot, T. Cheneval-Kastelic, J. C. McLenithan, and M. D. Lane. 1992. Promoter-cDNA-directed heterologous protein expression in Xenopus laevis oocytes. Proc. Natl. Acad. Sci. USA 89:1812-1816.
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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
Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease?
Hindle, A., Singh, S. P., Pradeepkiran, J. A., Bose, C., Vijayan, M., Kshirsagar, S., Sawant, N. A., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116098 · Cited by 14 · see citing works
Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Feng, X., Zhang, S., Wang, Y., Kurlagunda, T., Sit, A., Jaishankar, P., Yang, P., Sakane, S., Park, S. Y., Wisessaowapak, C., et al. (2026) · Nature · doi:10.1038/s41586-026-10697-z · Cited by 2 · see citing works
- Authors
- Cantor, S. B., Urano, T., & Feig, L. A.
- Affiliations
- Tufts University (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1995-08-01
- Volume
- 15
- Issue
- 8
- Pages
- 4578-4584
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC230698
- OpenAlex
- W2153604383
- Cited by
- 310
- References
- 1
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 9 · 2016: 8 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 22
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- National Institute of General Medical Sciences (GM47717)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Ral GTPase, RalA, downstream effectors, Cdc42, actin cytoskeleton, bud site selection, Ras-related GTPases
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, Cells, Cultured, Fungal Proteins, Molecular Sequence Data, Protein Binding, Recombinant Proteins, Saccharomyces cerevisiae, Immunoblotting, Blotting, Northern, Signal Transduction, Gene Library, Sequence Homology, Amino Acid, Sequence Analysis, DNA, DNA, Complementary, Cell Cycle Proteins, GTP-Binding Proteins, GTP Phosphohydrolases, GTPase-Activating Proteins, ral GTP-Binding Proteins, cdc42 GTP-Binding Protein, Saccharomyces cerevisiae, Rats
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