Bridging Ral GTPase to Rho Pathways
Open accessAbstract
Ra1A and Ra1B are GTPases of unknown function and are activated by proteins, Ra1GDS, that interact with the active form of another GTPase, Ras. To elucidate Ral function, we have searched for proteins interacting with an activated form of Ra1A using the two-hybrid method and a Jurkat cell library. We have identified a partial cDNA encoding a protein, RLIP1, which binds to activated Ra1A and this binding requires an intact effector domain of Ra1A. Biochemical data with purified Ra1A confirm the genetic results. This protein also bears a region of homology with GTPase-activating protein (GAP) domains that are involved in the regulation of GTPases of the Rho family and, indeed, RLIP1 displays a GAP activity acting upon Rac1 and CDC42, but not RhoA. This GAP region is not required for RLIP1 binding to Ra1. The whole cDNA was cloned, and it encodes a 76-kDa polypeptide, RLIP76, which also binds RalA. The Rho pathway is involved in membrane and cytoskeleton modifications after mitogenic stimulation and acts in parallel to and synergistically with the Ras pathway. We propose that these pathways are linked through a cascade composed of Ras --> Ra1GDS --> Ra1 --> RLIP76 --> CDC42/Rac1/Rho, allowing modulation of the Rho pathway by the Ras pathway.
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Active 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 [31]
The Results show that RLIP1 binds GTP-bound RalA, and the Abstract identifies the full-length protein as RLIP76. The paper does not report that this association promotes endocytosis; its Discussion instead examines a possible role in Rho-pathway signaling. The indexed passages provide section labels but no page numbers. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRalbp1 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 [46]
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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: 2
- [1]1. Chardin, P. ∙ Tavitian, A. EMBO J. 1986; 5:2203-2208 Crossref Scopus (202) PubMed Google Scholar
- [2]2. Frech, M. ∙ Schlichting, I. ∙ Wittinghofer, A. ... J. Biol. Chem. 1990; 265:6353-6359
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Mitogen-activated protein kinase cascades and regulation of gene expression
Su, B., & Karin, M. (1996) · Current Opinion in Immunology · doi:10.1016/s0952-7915(96)80131-2 · Cited by 747 · see citing works
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
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
- Authors
- Jullien-Flores, V., Dorseuil, O., Romero, F., Letourneur, F., Saragosti, S., Berger, R., Tavitian, A., Gacon, G., & Camonis, J. H.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Camonis, Jacques H.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1995-09
- Volume
- 270
- Issue
- 38
- Pages
- 22473-22477
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2078948761
- Cited by
- 338
- References
- 1
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 7 · 2018: 4 · 2017: 7 · 2016: 10 · 2015: 8 · 2014: 9 · 2013: 8 · 2012: 24
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Receptor Mechanisms and Signaling
- Keywords
- Ral GTPase, RalA, RalB, RalGDS, RLIP76, GTPase-activating protein, Rac1, Cdc42, RhoA, Rho pathway, Ras signaling, effector domain, protein-protein interaction, cytoskeleton regulation, mitogenic signaling, signaling pathways
- MeSH terms
- Amino Acid Sequence, Base Sequence, Carrier Proteins, Enzyme Activation, Humans, Molecular Sequence Data, Protein Binding, Proteins, Consensus Sequence, DNA Primers, ATP-Binding Cassette Transporters, Cell Cycle Proteins, GTP-Binding Proteins, GTP Phosphohydrolases, GTPase-Activating Proteins, ras GTPase-Activating Proteins, ral GTP-Binding Proteins, rho GTP-Binding Proteins, rac GTP-Binding Proteins, cdc42 GTP-Binding Protein, In Vitro Techniques
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