ArticleeLife2023
Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
5 citing papers in PubMed, 6 citations in OpenAlex.
- A catalogue of missense and nonsense mutation abundances for the U.S. cancer patient population.medRxiv : the preprint server for health sciences · 2026Article
- Analysis of the Modulation of RAF Signaling by 14-3-3 Proteins.Bulletin of mathematical biology · 2026Article
- Review
- Mathematical modeling suggests 14-3-3 proteins modulate RAF paradoxical activation.PLoS computational biology · 2025Article
- Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
RAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as 'paradoxical activation' (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA and derive rigorous analytical expressions that illuminate the underlying mechanism of this complex phenomenon. We find that conformational autoinhibition modulation by a RAF inhibitor could be sufficient to create PA. We find that experimental RAF inhibitor drug dose-response data that characterize PA across different types of RAF inhibitors are best explained by a model that includes RAF inhibitor modulation of three properties: conformational autoinhibition, dimer affinity, and drug binding within the dimer (i.e., negative cooperativity). Overall, this work establishes conformational autoinhibition as a robust mechanism for RAF inhibitor-driven PA based solely on equilibrium dynamics of canonical interactions that comprise RAF signaling and inhibition.
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Registered trials
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