Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction

Chiarugi, Paola; Cirri, Paolo

doi:10.1016/s0968-0004(03)00174-9

Cited by 308 publications

(246 citation statements)

References 70 publications

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“…We have demonstrated that NS, which contains nine cysteine residues, forms oligomers in response to oxidative stress. Oxidative modifications of cysteines have been shown to result in changes in protein conformation, activity, localization, stability, or interactions (15,18,20,(42)(43)(44). Our data have demonstrated that ROS, generated endogenously in transformed cells or induced exogenously by oxidizing agents, result in NS oligomerization, impaired protein degradation and, under more pronounced oxidative conditions, reduced solubility and immobilization of NS in the nucleolus.…”

Section: Discussionmentioning

confidence: 61%

“…), hydroxyl radicals (OH ⅐ ), nitric oxide (NO), and monoxide radical (NO ⅐ ), play crucial roles in modulating many physiologic and pathologic processes. ROS act as mitogenic signals to promote cellular proliferation at lower concentrations and as inducers of apoptosis or necrotic cell death at higher concentrations (15)(16)(17). Reduced GSH is a major antioxidant and intracellular free radical scavenger of ROS, whereas N-acetyl-L-cysteine (NAC) is a cell-permeable precursor of GSH (18).…”

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confidence: 99%

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Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

Huang¹,

Whang²,

Chodaparambil

et al. 2011

Journal of Biological Chemistry

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Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H 2 O 2 ) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H 2 O 2 impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation of NS by ROS was validated in a murine lymphoma tumor model in which c-Myc is overexpressed and in CD34؉ cells from patients with chronic myelogenous leukemia in blast crisis. In both instances, increased ROS levels were associated with markedly increased expression of NS protein and thiol-reversible oligomerization. Site-directed mutagenesis of critical cysteinecontaining regions of nucleostemin altered both its intracellular localization and its stability. MG132, a potent proteasome inhibitor and activator of ROS, markedly decreased degradation and increased nucleolar retention of NS mutants, whereas N-acetyl-L-cysteine largely prevented the effects of MG132. These results indicate that NS is a highly redox-sensitive protein. Increased intracellular ROS levels, such as those that result from oncogenic transformation in hematopoietic malignancies, regulate the ability of NS to oligomerize, prevent its degradation, and may alter its ability to regulate cell proliferation.Nucleostemin (NS) is a GTP-binding nucleolar protein that has been implicated in a variety of cellular processes, including cell cycle progression involving the G 1 -S (1, 2) and G 2 -M transitions (3), pre-rRNA processing (4), stress responses involving nucleoplasmic translocation (5, 6), cellular senescence (7), and inhibition of cell proliferation (8). NS shuttles from the nucleolus to the nucleoplasm in response to a variety of cellular stressors, including inhibition of RNA synthesis (5). We have recently demonstrated that reduction of intracellular GTP levels results not only in the nuclear translocation of NS, as had been observed previously (6), but also its rapid proteasomal degradation in an apparent Mdm2-dependent manner (9). A number of nuclear proteins interact with nucleostemin (10), including p53 (1, 8), Mdm2 (2, 3), ribosomal L1 domain-containing 1 (RSL1D1) (11), and telomeric repeat binding factor 1 (TRF-1) (7, 12). The regulation of these diverse proteins through their interactions with NS results in functional alterations in cell cycle control and telomere maintenance (10), although the precise mechanisms of regulation remain to be elucidated. Complete loss of NS, either through siRNA knockdown experiments (1, 2, 13, 14) or through it...

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Section: Discussionmentioning

confidence: 61%

mentioning

confidence: 99%

Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

Huang¹,

Whang²,

Chodaparambil

et al. 2011

Journal of Biological Chemistry

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“…Work from several laboratories has now established that multiple members of the PTP family are susceptible to reversible oxidation, both in vitro and in cell culture (9,25). In the classical PTPs, such as PTP1B, oxidation of this cysteine to sulfenic acid, with subsequent conversion into a sulfenamide species (38), abrogates the nucleophilic properties of this residue, thereby inhibiting PTP activity.…”

Section: Discussionmentioning

confidence: 99%

“…The low pK a promotes the function of this Cys residue as a nucleophile in catalysis but renders it highly susceptible to oxidation with concomitant inhibition of PTP activity (15)(16)(17). It is now known that multiple PTPs are transiently oxidized by H 2 O 2 (18 -20) and also in response to certain cellular stimuli (17,(21)(22)(23)(24), illustrating that this mode of regulation may apply broadly across the enzyme family (25).…”

mentioning

confidence: 99%

Regulation of Insulin Signaling through Reversible Oxidation of the Protein-tyrosine Phosphatases TC45 and PTP1B

Meng

Buckley

Galić

et al. 2004

Journal of Biological Chemistry

250

220

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Many studies have illustrated that the production of reactive oxygen species (ROS) is important for optimal tyrosine phosphorylation and signaling in response to diverse stimuli. Protein-tyrosine phosphatases (PTPs), which are important regulators of signal transduction, are exquisitely sensitive to inhibition after generation of ROS, and reversible oxidation is becoming recognized as a general physiological mechanism for regulation of PTP function. Thus, production of ROS facilitates a tyrosine phosphorylation-dependent cellular signaling response by transiently inactivating those PTPs that normally suppress the signal. In this study, we have explored the importance of reversible PTP oxidation in the signaling response to insulin. Using a modified ingel PTP assay, we show that stimulation of cells with insulin resulted in the rapid and transient oxidation and inhibition of two distinct PTPs, which we have identified as PTP1B and TC45, the 45-kDa spliced variant of the T cell protein-tyrosine phosphatase. We investigated further the role of TC45 as a regulator of insulin signaling by combining RNA interference and the use of substrate-trapping mutants. We have shown that TC45 is an inhibitor of insulin signaling, recognizing the ␤-subunit of the insulin receptor as a substrate. The data also suggest that this strategy, using ligand-induced oxidation to tag specific PTPs and using interference RNA and substrate-trapping mutants to illustrate their role as regulators of particular signal transduction pathways, may be applied broadly across the PTP family to explore function.The reversible phosphorylation of tyrosyl residues in proteins, catalyzed by the coordinated actions of protein tyrosine kinases and protein-tyrosine phosphatases (PTPs), 1 is of paramount importance to the control of such fundamental physiological functions as cell proliferation, differentiation, survival, metabolism, and motility (1, 2). The phosphorylation of a target protein alters its function, including changes in enzymatic activity or its ability to associate with other proteins. In response to a stimulus, such as a growth factor or hormone, multiple phosphorylation and dephosphorylation reactions are coordinated in signal transduction cascades that culminate in the physiological response (3, 4). A characterization of the enzymes responsible for the regulation of protein tyrosine phosphorylation in vivo will be essential for an understanding of the control of signal transduction under normal and pathophysiological conditions and would be expected to identify important new targets for therapeutic intervention in human disease. We are focusing on this process from the perspective of the PTP family of enzymes.A substantial body of information has been accumulated to describe the role of protein tyrosine kinases in the regulation of signal transduction. In contrast, we are only now beginning to appreciate in mechanistic detail the role of some members of the PTP family in fine-tuning the signaling response to extracellular stimuli. Analysis ...

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“…It has been directly associated with heart failure, and is generally associated with a poor prognosis [13]; the mortality rate of cardiac cachexia is 50% at 18 months following diagnosis [14]. Proteolysis, the dissociation of proteins into smaller peptides, has been liked with the cachexia process, thereby promoting loss of organ function [15,16]. Although the skeletal and heart muscle tissues have much in common, in general, the heart mass loss profile differs from that of the skeletal muscle [17,18].…”

Section: Introductionmentioning

confidence: 99%

Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia

et al. 2014

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Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction

Cited by 308 publications

References 70 publications

Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

Reactive Oxygen Species Regulate Nucleostemin Oligomerization and Protein Degradation

Regulation of Insulin Signaling through Reversible Oxidation of the Protein-tyrosine Phosphatases TC45 and PTP1B

Oxidative and proteolytic profiles of the right and left heart in a model of cancer-induced cardiac cachexia

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