Ras-dependent activation of the small GTPase Ral
Open accessAbstract
The small GTPase Ral is a Ras-like GTPase [1] that has been implicated in growth-factor-induced and Ras-induced DNA synthesis [2-4], and Ras-induced oncogenic transformation [3,5]. Recently, we and others found that three different Ral guanine nucleotide exchange factors (Ral GEFs) - Ral GDS, Rgl and Rlf - bind specifically to the GTP-bound form of several Ras-like GTPases [6-9]. Although oncogenic Ras is able to activate these Ral GEFs [2,5,10], it is unknown whether growth factors can induce the activation of Ral and, if so, which small GTPase is involved in this process. Here, we show that stimulation of various growth factor receptors, including receptor tyrosine kinases and serpentine receptors, results in rapid activation of Ral. This activation correlates with the activation of Ras, and dominant-negative Ras completely inhibits Ral activation induced by insulin and epidermal growth factor (EGF). From these results, we conclude that Ral activation is a direct downstream effect of growth-factor-induced Ras activation.
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RAS recruits RalGEFs to promote Ral activation.
“Although hepatic RalGEF levels were not changed by HCD, these proteins can drive Ral activation through a GTPase cascade downstream of RAS, in which RAS recruits RalGEFs to promote Ral activation 20 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [20]
RAS functions upstream of Ral GTPases by recruiting RalGEFs, which catalyse the exchange of GDP for GTP on Ral proteins, thus triggering their activation.
“Once activated, RAS functions upstream of Ral GTPases by recruiting RalGEFs, which catalyse the exchange of GDP for GTP on Ral proteins, thus triggering their activation 20 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [20]
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Tracy, K., Velentzas, P. D., & Baehrecke, E. H. (2016) · The EMBO Reports · doi:10.15252/embr.201541283 · Cited by 22 · 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
- Wolthuis, R. M. F., Zwartkruis, F., Moen, T. C., & Bos, J. L.
- Affiliations
- Utrecht University (NL)
- Corresponding author
- Bos, Johannes L.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 1998-04
- Volume
- 8
- Issue
- 8
- Pages
- 471-474
- ISSN
- 0960-9822 (ISSN-L)
- OpenAlex
- W2070992726
- Cited by
- 111
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2022: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 3 · 2014: 2 · 2013: 6
- FWCI
- 5.00
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion)
- 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 › Protein Tyrosine Phosphatases
- Keywords
- Ral GTPase, Ras-related GTPases, growth factor signaling, receptor tyrosine kinase, serpentine receptors, Ras activation, insulin, epidermal growth factor, oncogenic transformation, dominant negative Ras
- MeSH terms
- Animals, Cell Line, Enzyme Activation, Epidermal Growth Factor, Fibroblasts, Insulin, Lysophospholipids, Mutation, Genes, ras, Recombinant Fusion Proteins, 3T3 Cells, Receptors, Endothelin, Receptors, Platelet-Derived Growth Factor, GTP-Binding Proteins, GTP Phosphohydrolases, ral GTP-Binding Proteins, Mice, Rats
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