Protein Tyrosine Phosphorylation and Reversible Oxidation: Two Cross-Talking Posttranslation Modifications

Abstract

In addition to protein phosphorylation, redox-dependent posttranslational modification of proteins is emerging as a key signaling system, conserved throughout evolution, and influencing many aspects of cellular homeostasis. Recent data have provided new insight about the interplay between phosphorylation- and redox-dependent signaling, and reactive oxygen species have been included among intracellular signal transducers of growth factor and extracellular matrix receptors. Both tyrosine phosphorylation and thiol oxidation are reversible and dynamic, and this review will particularly focus on the cross-talk between these posttranslational protein regulatory means. Although these modifications share their reversibility, their effects on enzymatic activity of protein tyrosine phosphatases (PTPs) and protein tyrosine kinases (PTKs) may be even opposite. Indeed, while tyrosine phosphorylation is frequently correlated to enzyme activation, thiol oxidation leads to inactivation of PTPs and to superactivation of PTKs. Several papers describe that both these modifications occur during the same input, (i.e., cell proliferation and motility induced by numerous growth factors and cytokines). The review will discuss several aspects of phosphorylation\oxidation interplay, describing both convergent and divergent features of the integrated and coordinated function of PTPs and PTKs during signaling.

Convergent signaling pathways—interaction between methionine oxidation and serine/threonine/tyrosine O-phosphorylation

“…The interplay between O-phosphorylation and redoxdependent signaling based on Cys oxidation is well established (Chiarugi and Buricchi 2007). While both modifications are reversible, their effects on protein Tyr-kinase and phosphatase activities are often in opposition.…”

Constitutive Activation of Epidermal Growth Factor Receptor Promotes Tumorigenesis of Cr(VI)-transformed Cells through Decreased Reactive Oxygen Species and Apoptosis Resistance Development

“…Previous study has documented that several agents such as radiation, oxidants, and alkylating agents induce ligand-independent activation of the EGFR (31). ROS play an essential role in EGFR signaling as an intracellular signal transducer (10). Several studies have reported that NADPH oxidase 1 (NOX1) enhances the expression of EGFR signaling components and confers autocrine growth (32,33).…”

“…Another mechanism of EGFR transactivation is related to reactive oxygen species (ROS) (10). ROS regulate numerous intracellular signal transduction pathways as well as the activities of various transcription factors.…”

Redox signaling mediated by the gut microbiota

“…Mass spectrometry analysis has revealed that redox-sensitive thiolates are present in a limited subset of enzymes. Examples include protein tyrosine phosphatases (PTP) [65], the lipid phosphatase (PTEN) [62,66], MAP kinase phosphatases (MAPKP) such as DUSP3 [63], and lowmolecular-weight protein tyrosine phosphatases (LMW-PTP) [67], in enzymes involved in the sumoylation and neddylation reactions, and well as in oxidant sensors such as Keap1, which control of overall redox balance of the cell. (Figure 1).…”

“…Evidence from the Drosophila model point to the notion that ROS generation in the gut epithelia may represent an evolutionary conserved response to microbes [55]. In mice, ROS generated in epithelial cells in response to lactobacilli undoubtedly functions in a signaling cell signaling events through reversible redox inactivation of regulatory proteins [52,65]. Importantly, leading edge proteomic methodology can be employed as a screening system to identify microbial-specific, oxidantsensitive regulatory proteins [104].…”