Trends in Biochemical Sciences
Redox regulation of protein tyrosine phosphatases during receptor tyrosine kinase signal transduction
Section snippets
Reactive oxygen species in receptor-mediated signal transduction
During the past decade, reactive oxygen species (ROS), namely H2O2, O2− and OH−, have been identified as important mediators of cell growth, differentiation and apoptosis (Fig. 1). Mitochondria are the predominant source of ROS in all cell types, 1–5% of electrons from the respiratory chain being typically diverted to the formation of O2− by ubiquinone-dependent reduction [3] (Fig. 1a). Recent evidence supports the hypothesis that mitochondrial ROS production is not only related to apoptotic
PTPs as intracellular targets of ROS
Recent evidence has claimed a role for H2O2 as an intracellular messenger that regulates protein phosphorylation of tyrosine residues 15, 16. Unlike other known second messengers, H2O2 is not directly recognized by a sensor protein, instead it modulates intracellular protein phosphorylation by the reversible modification of downstream effectors. H2O2 is a mild oxidant and might oxidize cysteine residues in proteins to cysteine sulfenic acid or disulfide, both of which are readily re-reduced to
RTK activation via redox regulation of PTPs
It is well established that ligand binding to RTKs increases their intrinsic tyrosine kinase activity [37]. The tyrosine phosphorylation level of an RTK is given by the ratio between its intrinsic tyrosine kinase activity and the coordinated activity of PTPs (see Table 1 for an outlook of PTPs identified as negative regulators of RTKs). Growing evidence suggests that inhibition of PTP activity, as well as reduced sensitivity of RTKs to dephosphorylation [38], occurs after RTK dimerization and,
The role of redox regulation of PTPs in the ligand-independent activation of RTKs
A large body of experimental evidence suggests that, in addition to endogenous ROS formation, extracellular oxidants affect RTK signaling. Adverse agents such as radiation, exposure to metals, alkylating agents and environmental oxidants have been found to activate RTKs in a ligand-independent manner, which is referred to as RTK trans-activation [49]. Again, oxidation and subsequent inactivation of PTPs seems responsible for RTK trans-activation by extracellular oxidants. For instance, cysteine
Concluding remarks
Mounting evidence indicates PTP redox regulation as pivotal in RTK signaling. Indeed, although growth-factor-induced oxidative PTP inactivation enables correct duration and amplitude of RTK signal transduction, the transient nature of oxidation-dependent PTP inhibition warrants RTK dephosphorylation and signal downregulation. Hence, given the remarkable importance of PTP in cell proliferation and related pathophysiology, further studies are needed to define the complete set of redox-regulated
Acknowledgements
We thank G. Ramponi and G. Camici for helpful suggestions regarding cellular redox regulation, and A. Chiarugi for critical reading of the article. Work in authors' laboratories has been supported by grants from the Italian Association for Cancer Research, Ministero della Università e Ricerca Scientifica e Tecnologica and Cassa di Risparmio di Firenze.
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