Redox regulation of cell signalling

Lander, Harry M.; Milbank, Aaron J.; Tauras, James M.; Hajjar, David P.; Hempstead, Barbara L.; Schwartz, Gregory D.; Kraemer, Rosemary; Mirza, Urooj A.; Chait, Brian T.; Campbell, Sharon L.; Quilliam, Lawrence A.

doi:10.1038/381380a0

Cited by 285 publications

(208 citation statements)

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“…[1] In addition to its well-characterized regulation by guanine nucleotide exchange factors which release GDP and allow GTP to bind [2,3], and the prenylation of terminal cysteines, which mediates membrane binding [4,5], p21ras activity may be regulated by oxidative post-translational modification of cysteines [6][7][8]. Of the six cysteine residues of p21ras ( Figure 1) four (118, 181, 184 and 186) are surfaceexposed, as shown by structural, chemical and mutational studies [9][10][11]. Although the Cterminal cysteines, Cys 181 , Cys 184 and Cys 186 , are normally adducted by lipid moieties in intact cells, S-nitroso-or S-glutathione thiol adducts of Cys 118 have been implicated as regulating normal and pathological cellular events [6,7,[12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry

Mahadevan

Clavreul

Huang

et al. 2007

Free Radical Biology and Medicine

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Abstractp21ras GTPase is the protein product of the most commonly mutated human oncogene and has been identified as a target for reactive oxygen and nitrogen species (ROS/RNS). Post-translational modification of reactive thiols, by reversible S-glutathiolation and S-nitrosation, and potentially also by irreversible oxidation, may have significant effects on p21ras activity. Here we used an isotopecoded affinity tag (ICAT) and mass spectrometry to quantitate the reversible and irreversible oxidative post-translational thiol modifications of p21ras caused by peroxynitrite (ONOO − ) or glutathione disulfide (GSSG). The activity of p21ras was significantly increased following exposure to GSSG, but not to ONOO − . The results of LC-MS/MS analysis of tryptic peptides of p21ras treated with ONOO − showed that ICAT labeling of Cys 118 was decreased by 47%, whereas Cys 80 was not significantly affected and was thereby shown to be less reactive. The extent of S-glutathiolation of Cys 118 by GSSG was 53%, and that of the terminal cysteines was 85%, as estimated by the decrease in ICAT labeling. The changes in ICAT labeling caused by GSSG were reversible by chemical reduction, but those caused by peroxynitrite were irreversible. The quantitative changes in thiol modification caused by GSSG associated with increased activity demonstrate the potential importance of redox modulation of p21ras.

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Section: Introductionmentioning

confidence: 99%

Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry

Mahadevan

Clavreul

Huang

et al. 2007

Free Radical Biology and Medicine

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“…Likewise, reversible oxidation of the essential Cys residues of Caspase family members, which are implicated in apoptosis, may account for the observed role of H 2 O 2 in apoptosis. Ras is also likely a target of H 2 O 2 : Recently, Cys118 of Ras was shown to be modified by NO, triggering downstream signaling events (Lander et al, 1996).…”

Section: Production Of H 2 O 2 In Response To Receptor Stimulation Inmentioning

confidence: 99%

Redox signaling: hydrogen peroxide as intracellular messenger

1999

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Although superoxide anions (O 2 . -) and H 2 O 2 a r e generally considered to be toxic by-products of respiration, recent evidence suggests that the production of these reactive oxygen species (ROS) might be an integral component of membrane receptor signaling. In mammalian cells, a variety of extracellular stimuli have recently been shown to induce a transient increase in the intracellular concentration of ROS, and specific inhibition of the ROS generation resulted in a complete blockage of stimulant-dependent signaling. In the next few years, therefore, a flurry of research activity is expected in relation to the elucidation of ROS production in response to receptor stimulation, identification of ROS target molecules, and investigation of ROS elimination. The goal of this report is to review our current knowledge of ROSregulated signal trans-duction and propose future directions.

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“…We first demonstrated that ATP induces down-regulation of AT 1 R signaling in rat cardiac fibroblasts. Extracellular ATP in the cardiovascular system may be originated from various cellular sources: perivascular sympathetic nerve endings, myocytes, endothelial cells, and inflammatory cells (14). We found that mechanical stretch-induced ATP release decreases AT 1 R density in mouse hearts with pressure overload (Fig.…”

Section: Discussionmentioning

confidence: 68%

“…Several transmembrane-spanning receptors and their downstream signaling molecules could be modified by NO, including NMDA receptor (11), GPCR kinase 2 (12), β-arrestin (13), and G proteins (14,15). Although exposure of excessive NO has been reported to decrease AT 1 R density (16), the molecular details and its physiological significance are still unknown.…”

mentioning

confidence: 99%

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y ₂ receptor stimulation through S-nitrosylation of NF-κB

Nishida

Mariko

Reiko

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Cross-talk between G protein-coupled receptor (GPCR) signaling pathways serves to fine tune cellular responsiveness by neurohumoral factors. Accumulating evidence has implicated nitric oxide (NO)-based signaling downstream of GPCRs, but the molecular details are unknown. Here, we show that adenosine triphosphate (ATP) decreases angiotensin type 1 receptor (AT 1 R) density through NO-mediated S-nitrosylation of nuclear factor κB (NF-κB) in rat cardiac fibroblasts. Stimulation of purinergic P2Y 2 receptor by ATP increased expression of inducible NO synthase (iNOS) through activation of nuclear factor of activated T cells, NFATc1 and NFATc3. The ATP-induced iNOS interacted with p65 subunit of NF-κB in the cytosol through flavin-binding domain, which was indispensable for the locally generated NO-mediated S-nitrosylation of p65 at Cys38. β-Arrestins anchored the formation of p65/ IκBα/β-arrestins/iNOS quaternary complex. The S-nitrosylated p65 resulted in decreases in NF-κB transcriptional activity and AT 1 R density. In pressure-overloaded mouse hearts, ATP released from cardiomyocytes led to decrease in AT 1 R density through iNOS-mediated S-nitrosylation of p65. These results show a unique regulatory mechanism of heterologous regulation of GPCRs in which cysteine modification of transcriptional factor rather than protein phosphorylation plays essential roles.angiotensin receptor | Ca 2+ signaling | calcineurin | signaling complex | posttranslational modification G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors, which play a critical role in regulating multiple physiological functions (1, 2). Abnormal activation or up-regulation of GPCRs is a major cause of various diseases (3), and about 40% of drugs that are widely used for therapeutic treatment all over the world may directly or indirectly target GPCRs.An important adaptive response of the cell against multiple extracellular stimuli is receptor desensitization, which refers to the reduction of receptor responsiveness despite continuing agonist stimulation. GPCRs have developed elaborate means of turning off signal (4). One mechanism for desensitization is receptor down-regulation, which refers to the net loss of receptors from the cell by a decrease in receptor synthesis, a destabilization of receptor mRNA, or an increase in receptor degradation (4, 5).Two major patterns of down-regulation have been characterized; homologous (or agonist specific) down-regulation and heterologous (or agonist nonspecific) down-regulation (6). The homologous down-regulation indicates that stimulation of one GPCR over time by the agonist reduces expression levels of the same GPCR, without substantial effect on other GPCRs present in the same cell. In contrast, heterologous down-regulation indicates that stimulation of one GPCR reduces expression levels of different GPCR. Although the molecular mechanism of homologous down-regulation has been well analyzed using β-adrenergic receptors (βARs) (4, 5), the mechanism(s) underlying heterologous down-re...

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Redox regulation of cell signalling

Cited by 285 publications

References 5 publications

Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry

Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry

Redox signaling: hydrogen peroxide as intracellular messenger

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y ₂ receptor stimulation through S-nitrosylation of NF-κB

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Redox regulation of cell signalling

Cited by 285 publications

References 5 publications

Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry

Quantification of oxidative posttranslational modifications of cysteine thiols of p21ras associated with redox modulation of activity using isotope-coded affinity tags and mass spectrometry

Redox signaling: hydrogen peroxide as intracellular messenger

Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y 2 receptor stimulation through S-nitrosylation of NF-κB

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Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y ₂ receptor stimulation through S-nitrosylation of NF-κB