Differential Oxidation of Protein-tyrosine Phosphatases

Groen, Arnoud; Lemeer, Simone; Wijk, Thea van der; Overvoorde, John; Heck, Albert J. R.; Östman, Arne; Barford, David; Slijper, Monique; Hertog, Jeroen den

doi:10.1074/jbc.m412424200

Cited by 122 publications

(99 citation statements)

References 44 publications

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“…For this purpose an antibody-based PTP oxidation assay, previously used to monitor PTP oxidation in vitro, was applied (13). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…As a consequence of the microenvironment of the conserved active site of PTPs, the catalytic cysteine of PTPs usually exists as thiolate anion, which is highly susceptible to oxidation. Studies in cellular models, as well as in vitro studies, indicate that PTPs display intrinsic differences in oxidation susceptibility (13)(14)(15). PTP oxidation has been shown after activation of reactive oxygen species (ROS)-inducing cell-surface receptors, such as RTKs, G proteincoupled receptors (GPCRs), integrins, B cell receptors, and T cell receptors (6,(16)(17)(18)(19)(20).…”

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confidence: 99%

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12/15-lipoxygenase–derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases

Conrad

Sandin

Förster

et al. 2010

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

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Protein tyrosine phosphatases (PTPs) are regulated through reversible oxidation of the active-site cysteine. Previous studies have implied soluble reactive oxygen species (ROS), like H 2 O 2 , as the mediators of PTP oxidation. The potential role(s) of peroxidized lipids in PTP oxidation have not been described. This study demonstrates that increases in cellular lipid peroxides, induced by disruption of glutathione peroxidase 4, induce cellular PTP oxidation and reduce the activity of PDGF receptor targeting PTPs. These effects were accompanied by site-selective increased PDGF β-receptor phosphorylation, sensitive to 12/15-lipoxygenase (12/15-LOX) inhibitors, and increased PDGF-induced cytoskeletal rearrangements. Importantly, the 12/15-LOX-derived 15-OOH-eicosatetraenoic acid lipid peroxide was much more effective than H 2 O 2 in induction of in vitro PTP oxidation. Our study thus establishes that lipid peroxides are previously unrecognized inducers of oxidation of PTPs. This identifies a pathway for control of receptor tyrosine kinase signaling, which might also be involved in the etiology of diseases associated with increased lipid peroxidation.phospholipid hydroperoxide glutathione peroxidase | PDGF | redox regulation | reversible oxidation S ignaling through receptor tyrosine kinases (RTKs), such as the PDGF β-receptor, is subjected to negative control by protein tyrosine phosphatases (PTPs) (1-3). Consequently, alterations in expression levels or the specific activity of PTPs will affect the cellular response to ligands of RTKs. With regard to the PDGF β-receptor, a series of PTPs, including T cell protein tyrosine phosphatase (TC-PTP), density enhanced phosphatase-1 (DEP-1), SHP-2, and PTP-1B, have been found to modulate receptor signaling (4-7). Detailed analyses of the consequences of deletion of individual PTPs have shown that individual PDGF receptorantagonizing PTPs preferentially dephosphorylate particular phospho-tyrosine residues of the receptor and thereby are able to modulate the signaling output (4,(8)(9)(10).Inhibitory and reversible oxidation of the active-site cysteine has emerged as a general mechanism for PTP regulation (11,12). As a consequence of the microenvironment of the conserved active site of PTPs, the catalytic cysteine of PTPs usually exists as thiolate anion, which is highly susceptible to oxidation. Studies in cellular models, as well as in vitro studies, indicate that PTPs display intrinsic differences in oxidation susceptibility (13-15). PTP oxidation has been shown after activation of reactive oxygen species (ROS)-inducing cell-surface

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“…For this purpose an antibody-based PTP oxidation assay, previously used to monitor PTP oxidation in vitro, was applied (13). Fig.…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

12/15-lipoxygenase–derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases

Conrad

Sandin

Förster

et al. 2010

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

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“…However, in a separate step, these PTPs are then terminally oxidized to the sulfonic acid form by treatment with pervanadate and identified by immunoblotting with the oxPTP antibodies (25). This approach has been used successfully to distinguish the susceptibility of different PTPs to oxidation (26), in particular demonstrating that the second, membrane-distal PTP domain of RPTP␣ is more sensitive to oxidation than the membrane-proximal catalytic domain and may serve as a redox sensor (26). A problem with this approach is that it would measure not only those PTPs that were subject to regulation by reversible oxidation, but also register any PTPs that were already present in the cell in a terminally oxidized state.…”

Section: Discussionmentioning

confidence: 99%

“…Other potential challenges include the specificity and sensitivity of the antibody. Most of the studies to date that have used this approach have examined the oxidation of ectopically expressed classical PTPs (25,26). It remains to be established whether this antibody is able to recognize all members of the PTP superfamily, in particular the DSPs, and to what extent it has the sensitivity to measure oxidation of PTPs at physiological levels of expression.…”

Section: Discussionmentioning

confidence: 99%

A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells

Boivin

Zhang

Arbiser

et al. 2008

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

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The production of reactive oxygen species (ROS) exerts an additional tier of control over tyrosine phosphorylation-dependent signal transduction by transiently inhibiting the catalytic activity of specific protein tyrosine phosphatases (PTPs). Hence, the ability to detect reversible oxidation of PTPs in vivo is critical to understanding the complex biological role of ROS in the control of cellular signaling. Here, we describe an assay for identifying those PTPs that are reversibly oxidized in vivo, which utilizes the unique chemistry of the invariant catalytic Cys residue in labeling the active site with biotinylated small molecules under mildly acidic conditions. We have applied this cysteinyl-labeling assay to the study of platelet-derived growth factor (PDGF) receptor signaling in an angiomyolipoma cell model. Doing so has allowed us to detect reversible oxidation of several proteins in response to sustained PDGF stimulation. As in other cell systems, we have observed the reversible oxidation of the classical PTP SHP2 and the tumor suppressor phosphatase PTEN in response to PDGF stimulation. Furthermore, we detected reversible oxidation of members of two other subclasses of PTPs, the receptor PTP LAR and the dual-specificity phosphatase MKP1. These data demonstrate the broad selectivity of the assay, allowing us to detect representatives of all of the major subgroups of the PTP superfamily. We anticipate that this cysteinyl-labeling enrichment strategy can be applied broadly to study reversible oxidation as a mechanism of harnessing PTP catalytic activity in a variety of signaling pathways.reactive oxygen species ͉ signal transduction ͉ tyrosine phosphorylation ͉ dual specificity phosphatases ͉ cancer R egulated and localized generation of reactive oxygen species (ROS) creates an oxidative microenvironment important for optimal tyrosine phosphorylation-dependent signal transduction. Previous studies have shown that ROS-mediated transient inhibition of the catalytic activity of members of the protein tyrosine phosphatase (PTP) superfamily plays a crucial role in facilitating signal transduction (1-3). The PTP superfamily consists of Ϸ100 genes encoding structurally diverse enzymes, which are characterized by a conserved catalytic domain and which all perform phosphoryl hydrolysis by using a cysteinylbased nucleophilic core within a conserved signature motif. The PTP signature motif, HC(X) 5 R(S/T), creates a unique environment for the catalytic Cys residue. In this setting, the pK a of the Cys residue, located at the base of a cleft formed by the extremity of ␤-sheet 12 and ␣-helix 4 [features named for the structure of PTP1B (4)], is lowered by the presence of the conserved Arg residue, in addition to the helix dipole of ␣-4 and microdipoles generated by backbone atoms in the signature motif (4, 5). Hence, the Cys residue of the signature motif displays an unusually low pK a , making it both a good nucleophile at neutral pH in addition to being highly susceptible to oxidation (6). The sensitivity of PTPs to i...

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“…Because of the presence of an invariant catalytic cysteine residue within PTPs, which possesses an unusually low pK a due to the presence of vicinal basic residues, these enzymes are uniquely susceptible to oxidative inactivation, and a number of PTPs or other cysteine-containing phosphatases have been shown to be similarly subjected to oxidative inactivation in relation to cytokine and/or growth factor signaling due to the activation of NOX/DUOX enzymes, including PTP1B, low molecular weight (LMW-) PTP, SHP-1 and SHP-2, and PTEN (3,(41)(42)(43)(44)(45)(46)(47) (Fig. 3).…”

Section: Targets For Nox-derived Ros: Protein Cysteine Residuesmentioning

confidence: 99%

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

Vliet

2008

Free Radical Biology and Medicine

187

192

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The deliberate production of reactive oxygen species (ROS) by phagocyte NADPH oxidase is widely appreciated as a critical component of antimicrobial host defense. Recently, additional homologs of NADPH oxidase (NOX) have been discovered throughout the animal and plant kingdoms, which appear to possess diverse functions in addition to host defense, including cell proliferation, differentiation, and regulation of gene expression. Several of these NOX homologs are also expressed within the respiratory tract, where they participate in innate host defense as well as in epithelial and inflammatory cell signaling and gene expression, and fibroblast and smooth muscle cell proliferation, in response to bacterial or viral infection and environmental stress. Inappropriate expression or activation of NOX/DUOX during various lung pathologies suggests their specific involvement in respiratory disease. This review summarizes the current state of knowledge regarding the general functional properties of mammalian NOX enzymes, and their specific importance in respiratory tract physiology and pathology.

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Differential Oxidation of Protein-tyrosine Phosphatases

Cited by 122 publications

References 44 publications

12/15-lipoxygenase–derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases

12/15-lipoxygenase–derived lipid peroxides control receptor tyrosine kinase signaling through oxidation of protein tyrosine phosphatases

A modified cysteinyl-labeling assay reveals reversible oxidation of protein tyrosine phosphatases in angiomyolipoma cells

NADPH oxidases in lung biology and pathology: Host defense enzymes, and more

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