Redox regulation of protein-tyrosine phosphatases

Hertog, Jeroen den; Groen, Arnoud; Wijk, Thea van der

doi:10.1016/j.abb.2004.05.024

Cited by 144 publications

(116 citation statements)

References 33 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…or no phosphatase catalytic activity (4). Structural features of the phosphatase catalytic site are conserved in D2s to create the microenvironment necessary for the reduced pK a of the catalytic Cys residue essential for its role as a redox sensor.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Reversible Oxidation of the Membrane Distal Domain of Receptor PTPα Is Mediated by a Cyclic Sulfenamide

et al. 2006

Self Cite

View full text Add to dashboard Cite

Protein tyrosine phosphatases (PTPs) are fundamental to the regulation of cellular signalling cascades triggered by protein tyrosine kinases. Most receptor-like PTPs (RPTPs) comprise two tandem PTP domains, with only the membrane proximal domains (D1) having significant phosphatase activity; the membrane distal domains (D2) display little to no catalytic activity. Intriguingly, however, many RPTP D2s share the catalytically essential Cys and Arg residues of D1s. D2 of RPTPR may function as a redox sensor that mediates regulation of D1 via reactive oxygen species. Oxidation of Cys723 of RPTPR D2 (equivalent to PTP catalytic Cys residues) stabilizes RPTPR dimers, induces rotational coupling, and is required for inactivation of D1 phosphatase activity. Here, we investigated the structural consequences of RPTPR D2 oxidation. Exposure of RPTPR D2 to oxidants promotes formation of a cyclic sulfenamide species, a reversibly oxidized state of Cys723, accompanied by conformational changes of the D2 catalytic site. The cyclic sulfenamide is highly resistant to terminal oxidation to sulfinic and sulfonic acids. Conformational changes associated with RPTPR D2 oxidation have implications for RPTPR quaternary structure and allosteric regulation of D1 phosphatase activity.The reversible tyrosine phosphorylation of proteins, reciprocally controlled by tyrosine kinases and phosphatases, is crucial to the regulation of diverse cellular processes, including growth, proliferation, and differentiation (1). Redox reactions, mediated by reactive oxygen species (ROS), 1 control PTP activity in response to a variety of hormones and growth factors (2-6). Generation of ROS accompanies PTK activation (7,8), with oxidation-induced inhibition of PTP activity amplifying PTK-dependent signaling (9-11).PTP-catalyzed protein dephosphorylation proceeds via a nucleophilic displacement reaction utilizing an essential cysteine residue conserved within the PTP signature motif Cys(X) 5 Arg (12-15). The low pK a of the catalytic cysteine necessary for its function (16) renders PTPs susceptible to inactivation by ROS-induced cysteine oxidation. However, the reversibility of redox-mediated inactivation of PTPs requires that a reversibly oxidized state of the cysteine residue be stabilized at the PTP catalytic site and that formation of SO 2 and SO 3 , two irreversibly oxidized species of cysteine, be suppressed (17). Crystallographic studies of the tyrosine specific cytosolic PTP1B revealed that the reversibly oxidized form of the enzyme was not the expected sulfenic acid or disulfide bond, but an oxidation state of cysteine termed a cyclic sulfenamide, a species not previously observed in proteins (18,19). Generation of the cyclic sulfenamide inhibits catalytic activity by blocking the nucleophilic cysteine residue through a covalent bond of its thiol group with the neighboring main chain amide, a linkage that is accompanied by profound conformational transitions of the catalytic site PTP and pTyr loops. The oxidation properties of the catalyt...

show abstract

Section: Discussionmentioning

confidence: 99%

“…Redox reactions, mediated by reactive oxygen species (ROS), 1 control PTP activity in response to a variety of hormones and growth factors (2)(3)(4)(5)(6). Generation of ROS accompanies PTK activation (7,8), with oxidation-induced inhibition of PTP activity amplifying PTK-dependent signaling (9)(10)(11).…”

mentioning

confidence: 99%

Reversible Oxidation of the Membrane Distal Domain of Receptor PTPα Is Mediated by a Cyclic Sulfenamide

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…Enzymes with activesite Cys include caspases, kinases, phosphatases, and proteases. Reversible oxidation of the active site of protein tyrosine phosphatase-1B has been associated with control of biological function in redox signaling (39). Oxidation of Cys by S-glutathionylation (GS-ylation) regulates glyceraldehyde 3-phosphate dehydrogenase (125) and caspase-3 (173).…”

Section: The Redox Hypothesismentioning

confidence: 99%

“…PTP-1B and glyceraldehyde 3-phosphate dehydrogenase are inactivated by GS-ylation (39,125). GS-ylation controls activity of H-Ras at the same C118 residue as S-nitrosylation (3,120,121).…”

Section: Gsh and Trxs As Common Control Nodes For Protein Thiol Redoxmentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

995

823

View full text Add to dashboard Cite

Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

show abstract

“…Therefore, the activity of PRLs might be regulated by redox status. Oxidation as an important regulatory mechanism for the PTP family of enzymes has been reviewed elsewhere (13).…”

Section: Prl Genes and Protein Productsmentioning

confidence: 99%

PRL phosphatases as potential molecular targets in cancer

Stephens¹,

Han

Gokhale

et al. 2005

Molecular Cancer Therapeutics

129

154

View full text Add to dashboard Cite

The phosphatase of regenerating liver (PRL) family of phosphatases, consisting of PRL-1, PRL-2, and PRL-3, represents an intriguing group of proteins being validated as biomarkers and therapeutic targets in cancer. Individual PRLs are overexpressed in a variety of cancer cell lines and tissues when compared with their normal counterparts. More importantly, several recent studies have shown that PRL-3 is expressed at higher levels and at a greater frequency in colorectal cancer metastases compared with primary colorectal tumors and normal colon tissue. Ectopic expression of PRLs in nontumorigenic cells can influence proliferation and the migratory and invasive properties of cells, while knockdown of endogenous PRL-3 or PRL-1 in cancerous cells using small interfering RNA can abrogate cell motility and ability to metastasize in a mouse model. However, the exact biological function and cellular substrates of the PRLs remain unclear. This review will discuss what is known about the PRLs, what makes the PRLs possible attractive targets for therapeutic intervention, and the possible future directions in PRL biology and inhibitor identification. [Mol Cancer Ther 2005;4(11):1653 -61]

show abstract

Redox regulation of protein-tyrosine phosphatases

Cited by 144 publications

References 33 publications

Reversible Oxidation of the Membrane Distal Domain of Receptor PTPα Is Mediated by a Cyclic Sulfenamide

Reversible Oxidation of the Membrane Distal Domain of Receptor PTPα Is Mediated by a Cyclic Sulfenamide

Radical-free biology of oxidative stress

PRL phosphatases as potential molecular targets in cancer

Contact Info

Product

Resources

About