ArticleBiochemistry2013
Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome.
Article in Biochemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed.
- Article
- The small GTPase Rap1A expedites the NOX2 oxidative burst by facilitating Rac and NOX2 autoactivations.The FEBS journal · 2025Article
- Distal Covalent Targeting Suppresses Signaling of Oncogenic K-Ras(G13C) in Cancer Cells.ACS chemical biology · 2025Article
- Article
- Impaired MC3T3-E1 osteoblast differentiation triggered by oncogenic HRAS is rescued by the farnesyltransferase inhibitor Tipifarnib.Scientific reports · 2025Article
- Updated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels.Genetics in medicine open · 2025Article
- Systems modeling of oncogenic G-protein and GPCR signaling reveals unexpected differences in downstream pathway activation.NPJ systems biology and applications · 2024Article
- Progress in Targeting KRAS Directly.Methods in molecular biology (Clifton, N.J.) · 2024Article
- Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.Journal of the American Chemical Society · 2023Article
- Article
- Dynamic regulation of RAS and RAS signaling.The Biochemical journal · 2023Article
- Somatic mutations of thymic epithelial tumors with myasthenia gravis.Frontiers in oncology · 2023Article
- Computational Random Mutagenesis to Investigate RAS Mutant Signaling.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S).Nature chemical biology · 2022Article
- Common Patterns of Hydrolysis Initiation in P-loop Fold Nucleoside Triphosphatases.Biomolecules · 2022Article
- Identification of the nucleotide-free state as a therapeutic vulnerability for inhibition of selected oncogenic RAS mutants.Cell reports · 2022Article
- Identification of RAS mutant biomarkers for EGFR inhibitor sensitivity using a systems biochemical approach.Cell reports · 2021Article
- Targeting KRAS(G12C): From Inhibitory Mechanism to Modulation of Antitumor Effects in Patients.Cell · 2020Review
- Development of Noonan syndrome by deregulation of allosteric SOS autoactivation.The Journal of biological chemistry · 2020Article
- Structural impact of GTP binding on downstream KRAS signaling.Chemical science · 2020Article
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5 authors.
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Abstract
Costello syndrome is linked to activating mutations of a residue in the p-loop or the NKCD/SAK motifs of Harvey Ras (HRas). More than 10 HRas mutants that induce Costello syndrome have been identified; G12S HRas is the most prevalent of these. However, certain HRas p-loop mutations also are linked to cancer formation that are exemplified with G12V HRas. Despite these relations, specific links between types of HRas mutations and diseases evade definition because some Costello syndrome HRas p-loop mutations, such as G12S HRas, also often cause cancer. This study established novel kinetic parameter-based equations that estimate the value of the cellular fractions of the GTP-bound active form of HRas mutant proteins. Such calculations differentiate between two basic kinetic mechanisms that populate the GTP-bound form of Ras in cells. (i) The increase in the level of GTP-bound Ras is caused by the HRas mutation-mediated perturbation of the intrinsic kinetic characteristics of Ras. This generates a broad spectrum of the population of the GTP-bound form of HRas that typically causes Costello syndrome. The upper end of this spectrum of HRas mutants, as exemplified by G12S HRas, can also cause cancer. (ii) The increase in the level of GTP-bound Ras occurs because the HRas mutations perturb the action of p120GAP on Ras. This causes production of a significantly high population of the only GTP-bound form of HRas linked merely to cancer formation. HRas mutant G12V belongs to this category.
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