The redox regulation of LMW-PTP during cell proliferation or growth inhibition.
Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) is an enzyme involved in platelet derived growth factor (PDGF)-induced mitogenesis and cytoskeleton rearrangement, because it is able to bind and dephosphorylate the activated receptor. LMW-PTP contains two cysteines located in position 12 and 17, both inside the catalytic pocket: this is a unique feature of LMW-PTP among all protein tyrosine phosphatases. LMW-PTP is oxidized and inactivated both in vitro and in vivo by exogenous oxidative stress and by endogenously generated oxidative burst produced during PDGF signaling, and recovers its activity within 40 min. The reversibility of in vivo LMW-PTP oxidation is glutathione dependent. The additional catalytic pocket cysteine, in position 17, retains an intriguing and peculiar role in the formation of a S-S intramolecular bond, which protects the catalytic Cys12 from further and irreversible oxidation. The presence of an additional cysteine near the catalytic one, confers to LMW-PTP the ability to rapidly recover its activity and finely regulate PDGF receptor activation during both extracellularly and intracellularly generated oxidative stress. In addition, redox up-regulation of LMW-PTP is involved in intracellular delivery of antiproliferative signals, as the arrest of growth induced by cell confluence and differentiation are associated with a decrease in the steady-state levels of intracellular ROS. The studies of the redox state of LMW-PTP in contact-inhibited cells and in mature myoblasts demonstrate that the protein is reduced and activated in both these conditions, thus leading to the hypothesis that LMW-PTP is a modulator of growth inhibition.
Chiarugi
P
P
Dipartimento di Scienze Biochimiche, Universita' di Firenze, Italy. paola.chiarugi@.unifi.it
D000818:Animals; D002455:Cell Division; D015536:Down-Regulation; D004790:Enzyme Induction; D006801:Humans; D008970:Molecular Weight; D010084:Oxidation-Reduction; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction
D010982:Platelet-Derived Growth Factor; D017027:Protein Tyrosine Phosphatases