Abstract
PRL family constitutes a unique class of phosphatases associated with metastasis. The phosphatase activity of PRL has been reported to be important for promoting metastasis, and it is inactivated by reversible oxidation of its catalytic cysteine. Here, we show that TRP32 specifically reduces PRL. Reduction of oxidized PRL in cells is inhibited by 2,4-dinitro-1-chlorobenzene, an inhibitor of TRX reductase. In vitro assays for the reduction of PRL show that only TRP32 can potently reduce oxidized PRL, whereas other TRX-related proteins linked to TRX reductase show little or no reducing activity. Indeed, TRP32 knockdown significantly prolongs the H2O2-induced oxidation of PRL. Binding analyses reveal that the unique C-terminal domain of TRP32 is required and sufficient for its direct interaction with PRL. These results suggest that TRP32 maintains the reduced state of PRL and thus regulates the biological function of PRL.
Highlights
Phosphatase of regenerating liver (PRL) is a metastasis-associated protein that is susceptible to inactivation by oxidation
We showed that Thioredoxin-related protein 32 (TRP32), a TRX-related protein of unknown function, binds to and reduces PRL
Previous studies have shown that the phosphatase activity of PRL is inactivated by the oxidation of its catalytic cysteine [11] and that the catalytically inactive mutant of PRL lacks the ability to promote metastasis [6]
Summary
Phosphatase of regenerating liver (PRL) is a metastasis-associated protein that is susceptible to inactivation by oxidation. Results: Thioredoxin-related protein 32 (TRP32) binds and reduces oxidized PRL. The phosphatase activity of PRL has been reported to be important for promoting metastasis, and it is inactivated by reversible oxidation of its catalytic cysteine. Binding analyses reveal that the unique C-terminal domain of TRP32 is required and sufficient for its direct interaction with PRL These results suggest that TRP32 maintains the reduced state of PRL and regulates the biological function of PRL. The active site cysteine residues in phosphatase with sequence homology to tensin (PTEN) and protein-tyrosine phosphatase 1B (PTP1B) are oxidized to form a disulfide bond and a sulfenyl amide bond, respectively, in response to physiological stimuli [8, 9]. We found that this specific interaction is mediated through the DUF1000 domain of TRP32
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