ArticleNature communications2025
The small GTPase MRAS is a broken switch.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
5 citing papers in PubMed.
- Novel Exploratory Transcriptomic Candidates as Biomarkers and Cancer Hallmark Fingerprints for Ovarian Endometroid and Clear Cell Carcinomas in Women.Antioxidants (Basel, Switzerland) · 2026Article
- Structure of SHOC2-KRAS-PP1C complex reveals RAS isoform-specific determinants and insights into targeting complex assembly by RAS inhibitors.Nature communications · 2026Article
- Targeting the ARL4C/RAP1/PI3K-Akt-mTOR signaling loop promotes ARL4C ubiquitination and reverses oxaliplatin resistance in colorectal cancer.Theranostics · 2026Article
- M-Ras distinct activation scenarios: A mechanistic outlook and targeting.Computational and structural biotechnology journal · 2025Article
- Unfolding ARF and ARL GTPases: from biophysics to systems-level insights.Frontiers in molecular biosciences · 2025Review
Corrections and comments
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Authors and funding
6 authors.
Funding
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Abstract
Intense research on founding members of the RAS superfamily has defined our understanding of these critical signalling proteins, leading to the premise that small GTPases function as molecular switches dependent on differential nucleotide loading. The closest homologs of H/K/NRAS are the three-member RRAS family, and interest in the MRAS GTPase as a regulator of MAPK activity has recently intensified. We show here that MRAS does not function as a classical switch and is unable to exchange GDP-to-GTP in solution or when tethered to a lipid bilayer. The exchange defect is unaffected by inclusion of the GEF SOS1 and is conserved in a distal ortholog from nematodes. Synthetic activating mutations widely used to study the function of MRAS in a presumed GTP-loaded state do not increase exchange, but instead drive effector binding due to sampling of an activated conformation in the GDP-loaded state. This includes nucleation of the SHOC2-PP1Cα holophosphatase complex. Acquisition of NMR spectra from isotopically labeled MRAS in live cells validated the GTPase remains fully GDP-loaded, even a supposed activated mutant. These data show that RAS GTPases, including those most similar to KRAS, have disparate biochemical activities and challenge current dogma on MRAS, suggesting previous data may need reinterpretation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.