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Redox-based probes for protein tyrosine phosphatases.

Over the past two decades, it has been established that growth factors, cytokines, and a host of other ligands trigger the production of hydrogen peroxide (H2O2) in nonphagocytic cells through their corresponding membrane receptors. Such H2O2 generation has been demonstrated to regulate many basic cellular processes including growth, differentiation, adhesion, migration, senescence, and autophagy. Once formed, H2O2 promotes autophosphorylation of the membrane receptor and induction of the signaling cascade. Landmark publications from the Finkel and Rhee laboratories were the first to demonstrate an essential role for reactive oxygen species (ROS) growth factor receptor-mediated signal transduction. As illustrated in Figure 1, ligand stimulation leads to a transient burst of H2O2 and a net increase in tyrosine phosphorylation of numerous proteins, including the growth factor receptor itself. Likewise, application of peroxide scavengers such as N-acetyl cysteine or catalase inhibits ligand-induced tyrosine phosphorylation. In large part, these effects are believed to arise from oxidative inhibition of protein tyrosine phosphatases (PTPs), which function as antagonists of protein tyrosine kinases and return membrane receptors to their resting state. There are about 80 members of the PTP superfamily, including the tyrosine (Tyr)-specific enzymes and dualspecificity phosphatases (DSPs), which also recognize serine (Ser) and threonine (Thr). The catalytic activity of PTPs depends upon an invariant active site cysteine (Cys) within the conserved signature motif [His-Cys-(X)5-Arg-(Ser/Thr)] (His = histidine, Arg = arginine; X = any residue) located at the bottom of the active site pocket. Owing to the environment of the active site, the catalytic Cys residue exhibits a remarkably low pKa (4.5 to 5.5) and is present as the thiolate anion at physiological pH. The low pKa serves to enhance the nucleophilicity of this residue, but also renders it susceptible to oxidation and enzymatic inactivation. Consequently, oxidative inhibition of PTPs promotes phosphorylationdependent signaling cascades. Biochemical evidence indicates that upon exposure to H2O2, the catalytic Cys residue is converted into the sulfenic acid form and results in PTP inactivation (Figure 1). This oxo form can react with a backbone amide to form a cyclic sulfenyl amide for classical PTPs or an adjacent thiol in DSPs to form an intramolecular disulfide. The activity of PTPs can be restored through the action of cellular antioxidants, such as the thioredoxin and glutaredoxin reducing systems. Thus, oxidation of the catalytic Cys is reversible and represents a dynamic mechanism of PTP regulation. Although the model presented in Figure 1 is supported by a number of elegant studies, it is also well-known that the rate of reaction of a PTP with H2O2 is about 10 5 times slower than the equivalent reaction with peroxiredoxin, an antioxidant enzyme. 10] This raises the question of whether a nonenzymatic reaction can account for the formation of the sulfenic acid in PTPs. This apparent discrepancy may reflect the possibility that enzymatic H2O2 generation needs to occur in close proximity to PTPs so that the concentration of the Figure 1. Proposed model for redox-dependent signal transduction. After ligand stimulation the H2O2 level increases through cytosolic proteins and subsequent activation of membrane-bound NADPH oxidase (Nox). Increased H2O2 production can lead to oxidation of specific reactive Cys residues within proteins, with concomitant modulation of the protein function. In PTPs, oxidation results in inactivation (and unopposed kinase action) until the H2O2 level declines and phosphatase activity is restored by reduction of the Cys residue. Trx = thioredoxin, TR = thioredoxin reductase, Grx= glutaredoxin, GR = glutaredoxin reductase.