ArticleFree radical biology & medicine2015
Redox regulation of Rac1 by thiol oxidation.
Article in Free radical biology & medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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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
22 citing papers in PubMed, 39 citations in OpenAlex.
- Non-canonical and constitutive activation of small GTPases: more than an exception to the rule?The Biochemical journal · 2026Review
- Redox Control in Platelet Activity and Therapy.Antioxidants (Basel, Switzerland) · 2025Review
- Covalent Fragment Inhibits RhoA Activation by Guanine Exchange Factors.ACS chemical neuroscience · 2023Article
- A Role for Second Messengers in Axodendritic Neuronal Polarity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Review
- Stimulation of RAS-dependent ROS signaling extends longevity by modulating a developmental program of global gene expression.Science advances · 2022Article
- Nitric Oxide and Electrophilic Cyclopentenone Prostaglandins in Redox signaling, Regulation of Cytoskeleton Dynamics and Intercellular Communication.Frontiers in cell and developmental biology · 2021Review
- Phosphorylated cofilin-2 is more prone to oxidative modifications on Cys39 and favors amyloid fibril formation.Redox biology · 2020Article
- The molecular basis for immune dysregulation by the hyperactivated E62K mutant of the GTPase RAC2.The Journal of biological chemistry · 2020Article
- ROS regulation of RAS and vulva development in Caenorhabditis elegans.PLoS genetics · 2020Article
- Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation.Cell death and differentiation · 2019Article
- Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity.Cell reports · 2019Article
- Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.Blood · 2019Article
- Reactive oxygen species in haematopoiesis: leukaemic cells take a walk on the wild side.Journal of experimental & clinical cancer research : CR · 2018Review
- ROLE OF THIOLS IN OXIDATIVE STRESS.Current opinion in toxicology · 2018Article
- RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes.American journal of human genetics · 2017Article
- Redox regulation of the actin cytoskeleton and its role in the vascular system.Free radical biology & medicine · 2017Review
- Metabolic rewiring in melanoma.Oncogene · 2017Review
- The redox mechanism for vascular barrier dysfunction associated with metabolic disorders: Glutathionylation of Rac1 in endothelial cells.Redox biology · 2016Article
- Thiyl radicals and induction of protein degradation.Free radical research · 2016Review
- Protein thiyl radical reactions and product formation: a kinetic simulation.Free radical biology & medicine · 2015Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The Rac1 GTPase is an essential and ubiquitous protein that signals through numerous pathways to control critical cellular processes, including cell growth, morphology, and motility. Rac1 deletion is embryonic lethal, and its dysregulation or mutation can promote cancer, arthritis, cardiovascular disease, and neurological disorders. Rac1 activity is highly regulated by modulatory proteins and posttranslational modifications. Whereas much attention has been devoted to guanine nucleotide exchange factors that act on Rac1 to promote GTP loading and Rac1 activation, cellular oxidants may also regulate Rac1 activation by promoting guanine nucleotide exchange. Herein, we show that Rac1 contains a redox-sensitive cysteine (Cys(18)) that can be selectively oxidized at physiological pH because of its lowered pKa. Consistent with these observations, we show that Rac1 is glutathiolated in primary chondrocytes. Oxidation of Cys(18) by glutathione greatly perturbs Rac1 guanine nucleotide binding and promotes nucleotide exchange. As aspartate substitutions have been previously used to mimic cysteine oxidation, we characterized the biochemical properties of Rac1(C18D). We also evaluated Rac1(C18S) as a redox-insensitive variant and found that it retains structural and biochemical properties similar to those of Rac1(WT) but is resistant to thiol oxidation. In addition, Rac1(C18D), but not Rac1(C18S), shows greatly enhanced nucleotide exchange, similar to that observed for Rac1 oxidation by glutathione. We employed Rac1(C18D) in cell-based studies to assess whether this fast-cycling variant, which mimics Rac1 oxidation by glutathione, affects Rac1 activity and function. Expression of Rac1(C18D) in Swiss 3T3 cells showed greatly enhanced GTP-bound Rac1 relative to Rac1(WT) and the redox-insensitive Rac1(C18S) variant. Moreover, expression of Rac1(C18D) in HEK-293T cells greatly promoted lamellipodia formation. Our results suggest that Rac1 oxidation at Cys(18) is a novel posttranslational modification that upregulates Rac1 activity.
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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.