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    Enzyme Activity of Phosphatase of Regenerating Liver (PRL-1) Is Controlled by Redox Environment and Its C-terminal Residues

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    Issue Date
    2009-05-26
    Author
    Skinner, Andria L.
    Vartia, Anthony Andrew
    Williams, Todd D.
    Laurence, Jennifer S.
    Publisher
    ACS
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2009 American Chemical Society
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    Abstract
    Phosphatase of regenerating liver-1 (PRL-1) belongs to a unique subfamily of protein tyrosine phosphatases (PTPases) associated with oncogenic and metastatic phenotypes. While considerable evidence exists to supports a role for PRL-1 in promoting proliferation, the biological regulators and effectors of PRL-1 activity remain unknown. PRL-1 activity is inhibited by disulfide bond formation at the active site in vitro, suggesting PRL-1 may be susceptible to redox regulation in vivo. Because PRL-1 has been observed to localize to several different subcellular locations and cellular redox conditions vary with tissue type, age, stage of cell cycle and subcellular location, we determined the reduction potential of the active site disulfide bond that controls phosphatase activity to better understand the function of PRL-1 in various cellular environments. We used high-resolution solution NMR spectroscopy to measure the potential and found it to be −364.3 ± 1.5 mV. Because normal cellular environments range from −170 to −320 mV, we concluded that nascent PRL-1 would be primarily oxidized inside cells. Our studies show that a significant conformational change accompanies activation, suggesting a post-translational modification may alter the reduction potential, conferring activity. We further demonstrate that alteration of the C-terminus renders the protein reduced and active in vitro, implying the C-terminus is an important regulator of PRL-1 function. These data provide a basis for understanding how subcellular localization regulates the activity of PRL-1 and, with further investigation, may help reveal how PRL-1 promotes unique outcomes in different cellular systems, including proliferation in both normal and diseased states.
    Description
    This publication was made possible by National Institutes of Health Grant P20 RR-17708 from the National Center for Research Resources and the Kansas University Center for Research. This work was additionally supported by fellowships for A.L.S. from Amgen and the Edith and Eleta Ernst Cancer Research Fellowship. The Q-Tof2tm instrument was purchased with support from KSTAR, Kansas-administered NSF EPSCoR, and the University of Kansas. The CapXL HPLC system was obtained with support from KCALSI.
    URI
    http://hdl.handle.net/1808/23685
    DOI
    https://doi.org/10.1021/bi900241k
    Collections
    • Pharmaceutical Chemistry Scholarly Works [319]
    Citation
    Skinner, A. L., Vartia, A. A., Williams, T. D., & Laurence, J. S. (2009). Enzyme Activity of Phosphatase of Regenerating Liver (PRL-1) Is Controlled by Redox Environment and Its C-terminal Residues. Biochemistry, 48(20), 4262–4272. http://doi.org/10.1021/bi900241k

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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