ArticleProceedings of the National Academy of Sciences of the United States of America2020
Analysis of RAS protein interactions in living cells reveals a mechanism for pan-RAS depletion by membrane-targeted RAS binders.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 22 citations in OpenAlex.
- Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.PLoS computational biology · 2025Article
- Statins inhibit onco-dimerization of the 4Ig isoform of B7-H3.bioRxiv : the preprint server for biology · 2024Article
- Computationally designed sensors detect endogenous Ras activity and signaling effectors at subcellular resolution.Nature biotechnology · 2024Article
- KRAS is vulnerable to reversible switch-II pocket engagement in cells.Nature chemical biology · 2022Article
- Protease-controlled secretion and display of intercellular signals.Nature communications · 2022Article
- Equilibria between conformational states of the Ras oncogene protein revealed by high pressure crystallography.Chemical science · 2022Article
- Engineered variants of the Ras effector protein RASSF5 (NORE1A) promote anticancer activities in lung adenocarcinoma.The Journal of biological chemistry · 2021Article
- Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery.International journal of molecular sciences · 2021Review
- Ras isoform-specific expression, chromatin accessibility, and signaling.Biophysical reviews · 2021Review
- RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention.Biomolecules · 2021Review
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
HRAS, NRAS, and KRAS4A/KRAS4B comprise the RAS family of small GTPases that regulate signaling pathways controlling cell proliferation, differentiation, and survival. RAS pathway abnormalities cause developmental disorders and cancers. We found that KRAS4B colocalizes on the cell membrane with other RAS isoforms and a subset of prenylated small GTPase family members using a live-cell quantitative split luciferase complementation assay. RAS protein coclustering is mainly mediated by membrane association-facilitated interactions (MAFIs). Using the RAS-RBD (CRAF RAS binding domain) interaction as a model system, we showed that MAFI alone is not sufficient to induce RBD-mediated RAS inhibition. Surprisingly, we discovered that high-affinity membrane-targeted RAS binding proteins inhibit RAS activity and deplete RAS proteins through an autophagosome-lysosome-mediated degradation pathway. Our results provide a mechanism for regulating RAS activity and protein levels, a more detailed understanding of which should lead to therapeutic strategies for inhibiting and depleting oncogenic RAS proteins.
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