PDBsum entry 1oem

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Hydrolase PDB id
Protein chain
281 a.a. *
Waters ×181
* Residue conservation analysis
PDB id:
Name: Hydrolase
Title: Ptp1b with the catalytic cysteine oxidized to a sulfenyl-amide bond
Structure: Protein-tyrosine phosphatase, non-receptor type 1. Chain: x. Fragment: catalytic domain, residues 1-321. Synonym: protein-tyrosine phosphatase 1b, ptp-1b. Engineered: yes. Other_details: sulfenyl-amide bond between cys215 sg and ser216 n
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
1.80Å     R-factor:   0.204     R-free:   0.227
Authors: A.Salmeen,J.N.Andersen,M.P.Myers,T.C.Meng,J.A.Hinks, N.K.Tonks,D.Barford
Key ref:
A.Salmeen et al. (2003). Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature, 423, 769-773. PubMed id: 12802338 DOI: 10.1038/nature01680
28-Mar-03     Release date:   12-Jun-03    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P18031  (PTN1_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 1
435 a.a.
281 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
+ H(2)O
= protein tyrosine
+ phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     dephosphorylation   2 terms 
  Biochemical function     phosphatase activity     2 terms  


DOI no: 10.1038/nature01680 Nature 423:769-773 (2003)
PubMed id: 12802338  
Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate.
A.Salmeen, J.N.Andersen, M.P.Myers, T.C.Meng, J.A.Hinks, N.K.Tonks, D.Barford.
The second messenger hydrogen peroxide is required for optimal activation of numerous signal transduction pathways, particularly those mediated by protein tyrosine kinases. One mechanism by which hydrogen peroxide regulates cellular processes is the transient inhibition of protein tyrosine phosphatases through the reversible oxidization of their catalytic cysteine, which suppresses protein dephosphorylation. Here we describe a structural analysis of the redox-dependent regulation of protein tyrosine phosphatase 1B (PTP1B), which is reversibly inhibited by oxidation after cells are stimulated with insulin and epidermal growth factor. The sulphenic acid intermediate produced in response to PTP1B oxidation is rapidly converted into a previously unknown sulphenyl-amide species, in which the sulphur atom of the catalytic cysteine is covalently linked to the main chain nitrogen of an adjacent residue. Oxidation of PTP1B to the sulphenyl-amide form is accompanied by large conformational changes in the catalytic site that inhibit substrate binding. We propose that this unusual protein modification both protects the active-site cysteine residue of PTP1B from irreversible oxidation to sulphonic acid and permits redox regulation of the enzyme by promoting its reversible reduction by thiols.
  Selected figure(s)  
Figure 1.
Figure 1: Oxidation of PTP1B results in formation of a sulphenyl-amide bond between Cys 215 and Ser 216. a, The PTP loop in the sulphenyl-amide structure. Cyan, red and yellow correspond to 2F[o] - F[c] and positive and negative F[o] - F[c] electron density maps, respectively. The F[o] - F[c] density indicates that there are no oxygen atoms attached to the Cys 215 S atom, although a small amount of the enzyme is still reduced. b, Time course of PTP1B oxidation. Electron density maps (2F[o] - F[c]) show the time-dependent changes at the catalytic Cys 215 of PTP1B over a 16-h period. At 40 and 75 min, there is a mixture of reduced and oxidized states. H[2]O[2] was in 100- to 1,000-fold molar excess over PTP1B. red, reduced; ox, sulphenyl-amide structures. All figures were drawn with PYMOL (see fence fence ).
Figure 2.
Figure 2: Conformational changes accompanying the oxidation of PTP1B. a, Ribbon diagram showing catalytic site of reduced PTP1B. The PTP loop is shown in red. b, Sulphenyl-amide species of PTP1B in the same orientation as in a. c, Chemical mechanism for generating the sulphenyl-amide bond. 'X:' denotes a nucleophile. d, Superimposition of reduced (red) and sulphenyl-amide (ox) states of PTP1B. Gly 218 is shown in yellow. For clarity, the view has been rotated relative to a and b.
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2003, 423, 769-773) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

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PDB code: 3h2x
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Supreme EnLIGHTenment: damage recognition and signaling in the mammalian UV response.
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PDB codes: 2psz 2pt0 3d1h 3d1o 3d1q
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PDB codes: 2e2g 2e2m 2nvl 2zct
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PDB code: 3eu0
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PDB code: 2oz5
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Hydrogen peroxide sensing and signaling.
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PDB codes: 2j16 2j17
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A complex thiolate switch regulates the Bacillus subtilis organic peroxide sensor OhrR.
  Proc Natl Acad Sci U S A, 104, 8743-8748.  
17854705 J.Ying, N.Clavreul, M.Sethuraman, T.Adachi, and R.A.Cohen (2007).
Thiol oxidation in signaling and response to stress: detection and quantification of physiological and pathophysiological thiol modifications.
  Free Radic Biol Med, 43, 1099-1108.  
17473844 K.L.Jeffrey, M.Camps, C.Rommel, and C.R.Mackay (2007).
Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses.
  Nat Rev Drug Discov, 6, 391-403.  
17280484 L.C.Hool, and B.Corry (2007).
Redox control of calcium channels: from mechanisms to therapeutic opportunities.
  Antioxid Redox Signal, 9, 409-435.  
17673310 L.Yu, U.Kelly, J.N.Ebright, G.Malek, P.Saloupis, D.W.Rickman, B.S.McKay, V.Y.Arshavsky, and C.Bowes Rickman (2007).
Oxidative stress-induced expression and modulation of Phosphatase of Regenerating Liver-1 (PRL-1) in mammalian retina.
  Biochim Biophys Acta, 1773, 1473-1482.  
17546004 M.B.Tierno, P.A.Johnston, C.Foster, J.J.Skoko, S.N.Shinde, T.Y.Shun, and J.S.Lazo (2007).
Development and optimization of high-throughput in vitro protein phosphatase screening assays.
  Nat Protoc, 2, 1134-1144.  
17638532 P.A.Johnston, C.A.Foster, T.Y.Shun, J.J.Skoko, S.Shinde, P.Wipf, and J.S.Lazo (2007).
Development and implementation of a 384-well homogeneous fluorescence intensity high-throughput screening assay to identify mitogen-activated protein kinase phosphatase-1 dual-specificity protein phosphatase inhibitors.
  Assay Drug Dev Technol, 5, 319-332.  
17115885 P.Chiarugi, and F.Buricchi (2007).
Protein tyrosine phosphorylation and reversible oxidation: two cross-talking posttranslation modifications.
  Antioxid Redox Signal, 9, 1.  
17061035 S.Carballal, B.Alvarez, L.Turell, H.Botti, B.A.Freeman, and R.Radi (2007).
Sulfenic acid in human serum albumin.
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17115887 S.W.Ryter, H.P.Kim, A.Hoetzel, J.W.Park, K.Nakahira, X.Wang, and A.M.Choi (2007).
Mechanisms of cell death in oxidative stress.
  Antioxid Redox Signal, 9, 49-89.  
17525152 T.R.Hurd, T.A.Prime, M.E.Harbour, K.S.Lilley, and M.P.Murphy (2007).
Detection of reactive oxygen species-sensitive thiol proteins by redox difference gel electrophoresis: implications for mitochondrial redox signaling.
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17655326 T.Wymore, D.W.Deerfield, and J.Hempel (2007).
Mechanistic implications of the cysteine-nicotinamide adduct in aldehyde dehydrogenase based on quantum mechanical/molecular mechanical simulations.
  Biochemistry, 46, 9495-9506.  
17604642 V.Shetty, D.S.Spellman, and T.A.Neubert (2007).
Characterization by tandem mass spectrometry of stable cysteine sulfenic acid in a cysteine switch peptide of matrix metalloproteinases.
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16557282 A.Ostman, C.Hellberg, and F.D.Böhmer (2006).
Protein-tyrosine phosphatases and cancer.
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16781456 A.Rinna, M.Torres, and H.J.Forman (2006).
Stimulation of the alveolar macrophage respiratory burst by ADP causes selective glutathionylation of protein tyrosine phosphatase 1B.
  Free Radic Biol Med, 41, 86-91.  
17043136 B.Szöor, J.Wilson, H.McElhinney, L.Tabernero, and K.R.Matthews (2006).
Protein tyrosine phosphatase TbPTP1: A molecular switch controlling life cycle differentiation in trypanosomes.
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16261333 C.Cheng-Hsien, H.Yung-Ho, S.Yuh-Mou, H.Chun-Cheng, L.Horng-Mo, H.Huei-Mei, and C.Tso-Hsiao (2006).
Src homology 2-containing phosphotyrosine phosphatase regulates endothelin-1-induced epidermal growth factor receptor transactivation in rat renal tubular cell NRK-52E.
  Pflugers Arch, 452, 16-24.  
17081111 C.Jacob, I.Knight, and P.G.Winyard (2006).
Aspects of the biological redox chemistry of cysteine: from simple redox responses to sophisticated signalling pathways.
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17081112 C.von Montfort, V.S.Sharov, S.Metzger, C.Schöneich, H.Sies, and L.O.Klotz (2006).
Singlet oxygen inactivates protein tyrosine phosphatase-1B by oxidation of the active site cysteine.
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16485024 D.Bennett, R.J.Matthews, and J.G.Sathish (2006).
The whys and wherefores of phosphate removal. Meeting on The Biology of Phosphatases.
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16541109 F.V.Rao, H.C.Dorfmueller, F.Villa, M.Allwood, I.M.Eggleston, and D.M.van Aalten (2006).
Structural insights into the mechanism and inhibition of eukaryotic O-GlcNAc hydrolysis.
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PDB codes: 2cbi 2cbj
16775014 J.Li, M.Stouffs, L.Serrander, B.Banfi, E.Bettiol, Y.Charnay, K.Steger, K.H.Krause, and M.E.Jaconi (2006).
The NADPH oxidase NOX4 drives cardiac differentiation: Role in regulating cardiac transcription factors and MAP kinase activation.
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16677071 J.R.Stone, and S.Yang (2006).
Hydrogen peroxide: a signaling messenger.
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16987034 J.V.Cross, and D.J.Templeton (2006).
Regulation of signal transduction through protein cysteine oxidation.
  Antioxid Redox Signal, 8, 1819-1827.  
16567803 K.Kaiserova, S.Srivastava, J.D.Hoetker, S.O.Awe, X.L.Tang, J.Cai, and A.Bhatnagar (2006).
Redox activation of aldose reductase in the ischemic heart.
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16445714 L.C.Hool (2006).
Reactive oxygen species in cardiac signalling: from mitochondria to plasma membrane ion channels.
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16893901 M.Kanda, Y.Ihara, H.Murata, Y.Urata, T.Kono, J.Yodoi, S.Seto, K.Yano, and T.Kondo (2006).
Glutaredoxin modulates platelet-derived growth factor-dependent cell signaling by regulating the redox status of low molecular weight protein-tyrosine phosphatase.
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17057753 N.K.Tonks (2006).
Protein tyrosine phosphatases: from genes, to function, to disease.
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16369939 N.W.Blackstone (2006).
Multicellular redox regulation: integrating organismal biology and redox chemistry.
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16716890 P.Eaton (2006).
Protein thiol oxidation in health and disease: techniques for measuring disulfides and related modifications in complex protein mixtures.
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16278309 R.Gupta, S.Karpatkin, and R.S.Basch (2006).
Hematopoiesis and stem cell renewal in long-term bone marrow cultures containing catalase.
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16987038 T.Finkel (2006).
Intracellular redox regulation by the family of small GTPases.
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16607115 W.Dröge (2006).
Redox regulation in anabolic and catabolic processes.
  Curr Opin Clin Nutr Metab Care, 9, 190-195.  
16987000 W.Maret (2006).
Zinc coordination environments in proteins as redox sensors and signal transducers.
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16797630 Y.Chen, M.Yu, D.P.Jones, J.T.Greenamyre, and J.Cai (2006).
Protection against oxidant-induced apoptosis by mitochondrial thioredoxin in SH-SY5Y neuroblastoma cells.
  Toxicol Appl Pharmacol, 216, 256-262.  
16944453 Y.Shinozaki, S.Koizumi, Y.Ohno, T.Nagao, and K.Inoue (2006).
Extracellular ATP counteracts the ERK1/2-mediated death-promoting signaling cascades in astrocytes.
  Glia, 54, 606-618.  
16549430 Y.Urata, Y.Ihara, H.Murata, S.Goto, T.Koji, J.Yodoi, S.Inoue, and T.Kondo (2006).
17Beta-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells.
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15843166 A.Barthel, and L.O.Klotz (2005).
Phosphoinositide 3-kinase signaling in the cellular response to oxidative stress.
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15623519 A.Groen, S.Lemeer, T.van der Wijk, J.Overvoorde, A.J.Heck, A.Ostman, D.Barford, M.Slijper, and J.den Hertog (2005).
Differential oxidation of protein-tyrosine phosphatases.
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15787978 A.S.Müller, E.Most, and J.Pallauf (2005).
Effects of a supranutritional dose of selenate compared with selenite on insulin sensitivity in type II diabetic dbdb mice.
  J Anim Physiol Anim Nutr (Berl), 89, 94.  
15890001 A.Salmeen, and D.Barford (2005).
Functions and mechanisms of redox regulation of cysteine-based phosphatases.
  Antioxid Redox Signal, 7, 560-577.  
15677487 B.J.Goldstein, K.Mahadev, M.Kalyankar, and X.Wu (2005).
Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets.
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15998257 B.J.Goldstein, K.Mahadev, X.Wu, L.Zhu, and H.Motoshima (2005).
Role of insulin-induced reactive oxygen species in the insulin signaling pathway.
  Antioxid Redox Signal, 7, 1021-1031.  
16306267 C.E.McCartney, H.McClafferty, J.M.Huibant, E.G.Rowan, M.J.Shipston, and I.C.Rowe (2005).
A cysteine-rich motif confers hypoxia sensitivity to mammalian large conductance voltage- and Ca-activated K (BK) channel alpha-subunits.
  Proc Natl Acad Sci U S A, 102, 17870-17876.  
16271885 C.Grundner, H.L.Ng, and T.Alber (2005).
Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site.
  Structure, 13, 1625-1634.
PDB code: 1ywf
15579467 D.J.Levinthal, and D.B.Defranco (2005).
Reversible oxidation of ERK-directed protein phosphatases drives oxidative toxicity in neurons.
  J Biol Chem, 280, 5875-5883.  
16158225 H.Haase, and W.Maret (2005).
Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants.
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15766528 H.Kamata, S.Honda, S.Maeda, L.Chang, H.Hirata, and M.Karin (2005).
Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.
  Cell, 120, 649-661.  
15650395 I.Rahman, S.K.Biswas, L.A.Jimenez, M.Torres, and H.J.Forman (2005).
Glutathione, stress responses, and redox signaling in lung inflammation.
  Antioxid Redox Signal, 7, 42-59.  
16055727 J.Alblas, H.Honing, Lavalette, M.H.Brown, C.D.Dijkstra, and T.K.van den Berg (2005).
Signal regulatory protein alpha ligation induces macrophage nitric oxide production through JAK/STAT- and phosphatidylinositol 3-kinase/Rac1/NAPDH oxidase/H2O2-dependent pathways.
  Mol Cell Biol, 25, 7181-7192.  
15933714 J.Kwon, C.K.Qu, J.S.Maeng, R.Falahati, C.Lee, and M.S.Williams (2005).
Receptor-stimulated oxidation of SHP-2 promotes T-cell adhesion through SLP-76-ADAP.
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15998259 J.L.Evans, B.A.Maddux, and I.D.Goldfine (2005).
The molecular basis for oxidative stress-induced insulin resistance.
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16200195 J.L.Luo, H.Kamata, and M.Karin (2005).
IKK/NF-kappaB signaling: balancing life and death--a new approach to cancer therapy.
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16380818 J.L.Luo, H.Kamata, and M.Karin (2005).
The anti-death machinery in IKK/NF-kappaB signaling.
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15890022 J.Rudolph (2005).
Redox regulation of the Cdc25 phosphatases.
  Antioxid Redox Signal, 7, 761-767.  
15917192 M.E.Handley, M.Thakker, G.Pollara, B.M.Chain, and D.R.Katz (2005).
JNK activation limits dendritic cell maturation in response to reactive oxygen species by the induction of apoptosis.
  Free Radic Biol Med, 38, 1637-1652.  
16234241 M.Noguchi, T.Takata, Y.Kimura, A.Manno, K.Murakami, M.Koike, H.Ohizumi, S.Hori, and A.Kakizuka (2005).
ATPase activity of p97/valosin-containing protein is regulated by oxidative modification of the evolutionally conserved cysteine 522 residue in Walker A motif.
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15890002 P.Chiarugi, and E.Giannoni (2005).
Anchorage-dependent cell growth: tyrosine kinases and phosphatases meet redox regulation.
  Antioxid Redox Signal, 7, 578-592.  
15780595 S.G.Rhee, S.W.Kang, W.Jeong, T.S.Chang, K.S.Yang, and H.A.Woo (2005).
Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins.
  Curr Opin Cell Biol, 17, 183-189.  
15998263 S.J.Salsman, K.Hensley, and R.A.Floyd (2005).
Sensitivity of protein tyrosine phosphatase activity to the redox environment, cytochrome C, and microperoxidase.
  Antioxid Redox Signal, 7, 1078-1088.  
16148011 S.Kang, H.Li, A.Rao, and P.G.Hogan (2005).
Inhibition of the calcineurin-NFAT interaction by small organic molecules reflects binding at an allosteric site.
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15563471 T.L.Schmitt, A.Hotz-Wagenblatt, H.Klein, and W.Dröge (2005).
Interdependent regulation of insulin receptor kinase activity by ADP and hydrogen peroxide.
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15630428 T.Mustelin, T.Vang, and N.Bottini (2005).
Protein tyrosine phosphatases and the immune response.
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16321806 W.Dröge (2005).
Oxidative stress and ageing: is ageing a cysteine deficiency syndrome?
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15998262 W.Dröge (2005).
Oxidative enhancement of insulin receptor signaling: experimental findings and clinical implications.
  Antioxid Redox Signal, 7, 1071-1077.  
15604151 A.T.Saurin, H.Neubert, J.P.Brennan, and P.Eaton (2004).
Widespread sulfenic acid formation in tissues in response to hydrogen peroxide.
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14762163 C.Persson, T.Sjöblom, A.Groen, K.Kappert, U.Engström, U.Hellman, C.H.Heldin, J.den Hertog, and A.Ostman (2004).
Preferential oxidation of the second phosphatase domain of receptor-like PTP-alpha revealed by an antibody against oxidized protein tyrosine phosphatases.
  Proc Natl Acad Sci U S A, 101, 1886-1891.  
14704153 G.Kozlov, J.Cheng, E.Ziomek, D.Banville, K.Gehring, and I.Ekiel (2004).
Structural insights into molecular function of the metastasis-associated phosphatase PRL-3.
  J Biol Chem, 279, 11882-11889.
PDB code: 1r6h
14581479 J.A.Rosado, P.C.Redondo, G.M.Salido, E.Gómez-Arteta, S.O.Sage, and J.A.Pariente (2004).
Hydrogen peroxide generation induces pp60src activation in human platelets: evidence for the involvement of this pathway in store-mediated calcium entry.
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15534200 J.Kwon, S.R.Lee, K.S.Yang, Y.Ahn, Y.J.Kim, E.R.Stadtman, and S.G.Rhee (2004).
Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors.
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15292244 J.P.Brennan, R.Wait, S.Begum, J.R.Bell, M.J.Dunn, and P.Eaton (2004).
Detection and mapping of widespread intermolecular protein disulfide formation during cardiac oxidative stress using proteomics with diagonal electrophoresis.
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15352167 J.V.Cross, and D.J.Templeton (2004).
Thiol oxidation of cell signaling proteins: Controlling an apoptotic equilibrium.
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15180991 K.Chen, S.R.Thomas, A.Albano, M.P.Murphy, and J.F.Keaney (2004).
Mitochondrial function is required for hydrogen peroxide-induced growth factor receptor transactivation and downstream signaling.
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14744249 L.B.Poole, P.A.Karplus, and A.Claiborne (2004).
Protein sulfenic acids in redox signaling.
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15280876 M.A.Lemmon, and S.J.Smerdon (2004).
Signaling by the sea.
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15110387 O.Augusto, M.G.Bonini, and D.Trindade (2004).
Spin trapping of glutathiyl and protein radicals produced from nitric oxide-derived oxidants.
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15247926 P.Gulati, B.Markova, M.Göttlicher, F.D.Böhmer, and P.A.Herrlich (2004).
UVA inactivates protein tyrosine phosphatases by calpain-mediated degradation.
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15192089 T.C.Meng, D.A.Buckley, S.Galic, T.Tiganis, and N.K.Tonks (2004).
Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B.
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15294898 T.van der Wijk, J.Overvoorde, and J.den Hertog (2004).
H2O2-induced intermolecular disulfide bond formation between receptor protein-tyrosine phosphatases.
  J Biol Chem, 279, 44355-44361.  
14670964 X.Fu, J.L.Kao, C.Bergt, S.Y.Kassim, N.P.Huq, A.d'Avignon, W.C.Parks, R.P.Mecham, and J.W.Heinecke (2004).
Oxidative cross-linking of tryptophan to glycine restrains matrix metalloproteinase activity: specific structural motifs control protein oxidation.
  J Biol Chem, 279, 6209-6212.  
15382121 Y.Fang, S.I.Han, C.Mitchell, S.Gupta, E.Studer, S.Grant, P.B.Hylemon, and P.Dent (2004).
Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes.
  Hepatology, 40, 961-971.  
14504278 Q.Wang, G.R.Pfeiffer, and W.A.Gaarde (2003).
Activation of SRC tyrosine kinases in response to ICAM-1 ligation in pulmonary microvascular endothelial cells.
  J Biol Chem, 278, 47731-47743.  
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