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J. Biol. Chem., Vol. 280, Issue 11, 10298-10304, March 18, 2005

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Differential Oxidation of Protein-tyrosine Phosphatases^*

Arnoud Groen, Simone Lemeer, Thea van der Wijk, John Overvoorde, Albert J. R. Heck, Arne Ostman¶, David Barford||, Monique Slijper, and Jeroen den Hertog**

From the Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands, Utrecht University, Department of Biomolecular Mass Spectrometry, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands, the ^¶Karolinska Institute, Cancer Center Karolinska, Dept. of Pathology-Oncology, SE-171 76 Stockholm, Sweden, and the ^||Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, United Kingdom

Oxidation is emerging as an important regulatory mechanism of protein-tyrosine phosphatases (PTPs). Here we report that PTPs are differentially oxidized, and we provide evidence for the underlying mechanism. The membrane-proximal RPTP-D1 was catalytically active but not readily oxidized as assessed by immunoprobing with an antibody that recognized oxidized catalytic site cysteines in PTPs (oxPTPs). In contrast, the membrane-distal RPTP-D2, a poor PTP, was readily oxidized. Oxidized catalytic site cysteines in PTP immunoprobing and mass spectrometry demonstrated that mutation of two residues in the Tyr(P) loop and the WPD loop that reverse catalytic activity of RPTP-D1 and RPTP-D2 also reversed oxidizability, suggesting that oxidizability and catalytic activity are coupled. However, catalytically active PTP1B and LAR-D1 were readily oxidized. Oxidizability was strongly dependent on pH, indicating that the microenvironment of the catalytic cysteine has an important role. Crystal structures of PTP domains demonstrated that the orientation of the absolutely conserved PTP loop arginine correlates with oxidizability of PTPs, and consistently, RPTPµ-D1, with a similar conformation as RPTP-D1, was not readily oxidized. In conclusion, PTPs are differentially oxidized at physiological pH and H₂O₂ concentrations, and the PTP loop arginine is an important determinant for susceptibility to oxidation.

Received for publication, November 3, 2004 , and in revised form, December 8, 2004.

^* This work was supported in part by the Netherlands Proteomics Centre and grants from the Research Council for Earth and Life Sciences (Aarden Levenswetenschappen) and Aspasia with financial aid from the Netherlands Organisation for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) and the Dutch Cancer Society/Koningin Wilhelmina Fonds. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 31-30-2121800; Fax: 31-30-2516464; E-mail: hertog{at}niob.knaw.nl.

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