Two vicinal cysteines confer a peculiar redox regulation to low molecular weight protein tyrosine phosphatase in response to platelet-derived growth factor receptor stimulation

Low molecular weight protein tyrosine phosphatase (LMW-PTP) is an enzyme in volved in platelet-derived growth factor (PDGF)-induced mitogenesis and cyt oskeleton rearrangement because it is able to bind and dephosphorylate the activated receptor. LMW-PTP presents two cysteines in positions 12 and 17, both belonging to the catalytic pocket; this is a unique feature of LMW-PTP among all protein tyrosine phosphatases. Our previous results demonstrated that in vitro LMW-PTP is oxidized by either H2O2 or nitric oxide with the formation of a disulfide bond between Cys-12 and Cys-17. This oxidation lea ds to reversible enzyme inactivation because treatment with reductants perm its catalytic activity rescue. In the present study we investigated the in vivo inactivation of LMW-PTP by either extracellularly or intracellularly g enerated H2O2, evaluating its action directly on its natural substrate, PDG F receptor. LMW-PTP is oxidized and inactivated by exogenous oxidative stre ss and recovers its activity after oxidant removal. LMW-PTP is oxidized als o during PDGF signaling, very likely upon PDGF-induced H2O2 production, and recovers its activity within 40 min. Our results strongly suggest that rev ersibility of in vivo LMW-PTP oxidation is glutathione-dependent. In additi on, we propose an intriguing and peculiar role of Cys-17 in the formation o f a S-S intramolecular bond, which protects the catalytic Cys-12 from furth er and irreversible, oxidation. On the basis of our results we propose that the presence of an additional cysteine near the catalytic cysteine could c onfer to LMW-PTP the ability to rapidly recover its activity and finely reg ulate PDGF receptor activation during both extracellularly and intracellula rly generated oxidative stress.