Editors' ChoicePhosphatases

Phosphatases Feel the Oxidative Stress

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Science's STKE  26 Feb 2002:
Vol. 2002, Issue 121, pp. tw82
DOI: 10.1126/stke.2002.121.tw82

H2O2 inhibits protein tyrosine phosphatase (PTP) activity in vitro because of the oxidation of a critical cysteine residue in the catalytic domain. However, it has not been clear whether this is a physiologically relevant regulatory mechanism. Meng et al. now show that when Rat-1 cells were exposed to H2O2, several PTPs were oxidized and inactivated in vivo. These were quickly reduced once exogenous H2O2 was removed. Treatment of cells with platelet-derived growth factor (PDGF), a mitogen that stimulates intracellular reactive oxygen species (ROS) production, also caused PTP oxidation, including SHP-2. Recruitment of cytoplasmic SHP-2 to activated PDGF receptors was required for SHP-2 oxidation. Receptor association may induce a conformational change in SHP-2 that facilitates oxidation of the cysteine residue and inactivates the enzyme. This would allow recruitment of downstream signaling to phosphorylated receptors.

Blanchetot et al. also show that receptor-type PTPs (RPTPs) are inhibited by oxidative stress. Most RPTPs contain two intracellular enzymatic domains (D1 and D2). By expressing various deletion mutants of RPTPα in cultured cells, the authors show that a region in the cytoplasmic domain containing D2 is in a closed conformation and is unable to bind to RPTPα monomers. However, treatment of cells with H2O2 induced a conformational change in the cytoplasmic region in vivo that was dependent on a cysteine residue in D2. The conformational change correlated with increased RPTPα dimerization and inactivation of phosphatase activity. Inactivation by oxidation and subsequent dimer stabilization may be a general regulatory mechanism for RPTP activity.

C. Blanchetot, L. G. J. Tertoolen, J. den Hertog, Regulation of receptor protein-tyrosine phosphatase a by oxidative stress. EMBO J. 21, 493-503 (2002). [Abstract] [Full Text]

T.-C. Meng, T. Fukuda, N. K. Tonks, Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Molec. Cell 9, 387-399 (2002). [Online Journal]

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