Differential redox regulation within the PTP superfamily.
The Protein Tyrosine Phosphatase (PTP) family comprises a large and diverse group of enzymes, regulating a range of biological processes through de-phosphorylation of many proteins and lipids. These enzymes share a catalytic mechanism that requires a reduced and reactive cysteine nucleophile, making them potentially sensitive to inactivation and regulation by oxidation. Analysis of ten PTPs identified substantial differences in the sensitivity of these enzymes to oxidation in vitro. More detailed experiments confirmed the following rank order of sensitivity: PTEN and Sac1>PTPL1/FAP-1>>myotubularins. When the apparent sensitivity to oxidation of these PTPs in cells treated with hydrogen peroxide was analysed, this correlated well with the observed sensitivities to oxidation in vitro. These data suggested that different PTPs may fall into at least three different classes with respect to mechanisms of cellular redox regulation. 1. PTEN and Sac1 were readily and reversibly oxidised in vitro and in cells treated with hydrogen peroxide 2. PTPL1 appeared to be resistant to oxidation in cells, correlating with its sensitivity to reduction by glutathione in vitro 3. The myotubularin family of lipid phosphatases was almost completely resistant to oxidation in vitro and in cells. Our results show that sensitivity to reversible oxidation is not a necessary characteristic of the PTPs and imply that such sensitivity has evolved as a regulatory mechanism for some of this large family, but not others.
Ross
Sarah H
SH
Division of Molecular Physiology, College of Life Sciences, University of Dundee, Dundee, UK.
Lindsay
Yvonne
Y
Safrany
Stephen T
ST
Lorenzo
Oscar
O
Villa
Fabrizio
F
Toth
Rachel
R
Clague
Michael J
MJ
Downes
C Peter
CP
Leslie
Nick R
NR
D000818:Animals; D002460:Cell Line; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation; D007700:Kinetics; D051379:Mice; D005810:Multigene Family; D010084:Oxidation-Reduction / Q000187:drug effects; D010716:Phosphatidylinositols / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000302:isolation & purification / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D010716:Phosphatidylinositols; D011993:Recombinant Fusion Proteins; D006861:Hydrogen Peroxide; D017027:Protein Tyrosine Phosphatases; D005978:Glutathione