Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

Abstract

Significance: Redox modifications of thiols serve as a molecular code enabling precise and complex regulation of protein tyrosine phosphatases (PTPs) and other proteins. Particular gasotransmitters and even the redox modifications themselves affect each other, of which a typical example is S-nitrosylation-mediated protection against the further oxidation of protein thiols. Recent Advances: For a long time, PTPs were considered constitutively active housekeeping enzymes. This view has changed substantially over the last two decades, and the PTP family is now recognized as a group of tightly and flexibly regulated fundamental enzymes. In addition to the conventional ways in which they are regulated, including noncovalent interactions, phosphorylation, and oxidation, the evidence that has accumulated during the past two decades suggests that many of these enzymes are also modulated by gasotransmitters, namely by nitric oxide (NO) and hydrogen sulfide (H 2 S). Critical Issues: The specificity and selectivity of the methods used to detect nitrosylation and sulfhydration remains to be corroborated, because several researchers raised the issue of false-positive results, particularly when using the most widespread biotin switch method. Further development of robust and straightforward proteomic methods is needed to further improve our knowledge of the full extent of the gasotransmitters-mediated changes in PTP activity, selectivity, and specificity. Further Directions: Results of the hitherto performed studies on gasotransmitter-mediated PTP signaling await translation into clinical medicine and pharmacotherapeutics. In addition to directly affecting the activity of particular PTPs, the use of reversible S-nitrosylation as a protective mechanism against oxidative stress should be of high interest. Antioxid. Redox Signal. 20, 2191-2209.

Hydrogen Sulfide as Potential Regulatory Gasotransmitter in Arthritic Diseases

“…Furthermore, H 2 S can have an inhibitory effect on some phosphodiesterase (PDE) enzymes and, consequently, a positive effect on inflammation [92,93]. PDE inhibitors can have beneficial effects in inflammation by increasing cAMP level, as well as inhibiting the production of ROS and cytokines such as TNF-α and IL-1.…”

The PTEN/NRF2 Axis Promotes Human Carcinogenesis

“…It is both a lipid phosphatase that eliminates phosphatidylinositol 3,4,5-trisphosphate generated by PI3K and a protein phosphatase which self-dephosphorylates at Thr 366 , and both activities appear to be relevant in invasion (57). A multitude of posttranslational modifications such as phosphorylation, ubiquitination, acetylation, and redox modifications fine tune its catalytic activity (10,49). Thus, PTEN is inhibited by oxidation (17) or S-sulfhydration (8) of the redox-sensitive cysteine Cys 124 located at the catalytic center and by S-nitrosylation of the alosteric Cys 83 residue (28).…”

Hydrogen sulfide promotes cell proliferation of oral cancer through activation of the COX2/AKT/ERK1/2 axis

“…To date, H 2 S is considered as the third gaseotransmitter along with nitric oxide and carbon monoxide, and exerts important physiological and pathological functions in the entire body. For example, H 2 S is involved in the process of oxidative stress-induced cytotoxicity (4)(5)(6), cardioprotection (7)(8)(9), inflammation (10)(11)(12) and cancer development (13,14). However, the underlying mechanisms regulating the multiple functions of H 2 S in many tissues and organs remain unknown.…”