Oxidation and tyrosine phosphorylation: synergistic or antagonistic cues in protein tyrosine phosphatase.
Protein tyrosine phosphatases (PTPs) have been generally recognised as key modulators of cell proliferation, differentiation, adhesion and motility. During signalling, several PTPs undergo two posttranslational modifications that greatly affect their enzymatic activity: tyrosine phosphorylation and cysteine oxidation. Although these modifications share their reversibility depending on the intracellular environment, their effects on enzymatic activity are opposite, tyrosine phosphorylation being correlated to enzyme activation and thiol oxidation to complete inactivation. Several papers have suggested that both these modifications occur in response to the same stimuli i.e. cell proliferation induced by numerous growth factors and cytokines. Conversely, the possibility that these two regulation mechanisms act simultaneously on PTPs has not been established and very few reports investigated this dual regulation of PTPs. To underline the relevance of the question, we discuss several possibilities: (i) that tyrosine phosphorylation and cysteine oxidation of PTPs may share the same target molecules but with different kinetics; (ii) that PTP phosphorylation and oxidation may take place on different subcellular pools of the same protein and (iii) that these two modifications, although having divergent effects on enzyme activity, cooperate in the integrated and coordinated function of PTPs during receptor tyrosine kinase signalling. We believe that our perspective will open new perspectives on an ancient problem--the apparent contradiction of opposing enzymatic regulation of many PTPs--thus clarifying their role as positive or negative transducers (or both) of many extracellular stimuli.
Chiarugi
P
P
Department of Biochemical Sciences, University of Florence, 50134, Firenze, Italy. paola.chiarugi@unifi.it
Taddei
M L
ML
Ramponi
G
G
D003545:Cysteine / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008954:Models, Biological; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism*
D017382:Reactive Oxygen Species; D014443:Tyrosine; D017027:Protein Tyrosine Phosphatases; D003545:Cysteine