Sensing electrons: protein phosphatase redox regulation

Abstract

Regulation of signal transduction is a multifaceted process involving ligands, receptors, second messengers, protein kinases and phosphatases, transcription factors, and target enzymes and genes. Here we consider how oxidative stress and cellular redox can provide additional mechanisms for gating signal transduction. The activities of both protein serine/threonine and tyrosine phosphatases are affected by the oxidation state of redox-sensitive functional groups. For the phosphatases calcineurin and purple acid phosphatase, activity depends upon the oxidation state of an active-site Fe ion. 1. Yu L. et al. Evidence that calcineurin accommodates an active site binuclear metal center. J. Am. Chem. Soc. 1995; 117: 10147-10148 Crossref Scopus (59) Google Scholar , 2. Yu L. et al. Spectroscopic and enzymatic characterization of the active site dinuclear metal center of calcineurin: implications for a mechanistic role. Biochemistry. 1997; 36: 10727-10734 Crossref PubMed Scopus (55) Google Scholar , 3. Merkx M. et al. The activity of oxidized bovine spleen purple acid phosphatase is due to an Fe(III)Zn(II) ‘impurity’. Biochemistry. 1998; 37: 11223-11231 Crossref PubMed Scopus (40) Google Scholar In the tyrosine phosphatases, oxidation of an active-site cysteine residue leads to inactivation. 4. Denu J.M. et al. Protein tyrosine phosphatases: mechanisms of catalysis and regulation. Curr. Opin. Chem. Biol. 1998; 2: 633-641 Crossref PubMed Scopus (334) Google Scholar , 5. Denu J.M. et al. Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry. 1998; 37: 5633-5642 Crossref PubMed Scopus (816) Google Scholar Redox reactions involving these functional groups and cellular oxidants and reductants could provide a direct link between phosphatase activity and cellular redox perturbations. We propose that protein phosphatases could be key mediators for the regulation of signal transduction by oxidative stress or cytoplasmic redox, or both.