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Structural insights into molecular function of the metastasis-associated phosphatase PRL-3.

Kozlov G, Cheng J, Ziomek E, Banville D, Gehring K, Ekiel I
J Biol Chem 279 11882-9 (2004)
Cited: 70 times
EuropePMC logo PMID: 14704153

Abstract

Phosphatases and kinases are the cellular signal transduction enzymes that control protein phosphorylation. PRL phosphatases constitute a novel class of small (20 kDa), prenylated phosphatases with oncogenic activity. In particular, PRL-3 is consistently overexpressed in liver metastasis in colorectal cancer cells and represents a new therapeutic target. Here, we present the solution structure of PRL-3, the first structure of a PRL phosphatase. The structure places PRL phosphatases in the class of dual specificity phosphatases with closest structural homology to the VHR phosphatase. The structure, coupled with kinetic studies of site-directed mutants, identifies functionally important residues and reveals unique features, differentiating PRLs from other phosphatases. These differences include an unusually hydrophobic active site without the catalytically important serine/threonine found in most other phosphatases. The position of the general acid loop indicates the presence of conformational change upon catalysis. The studies also identify a potential regulatory role of Cys(49) that forms an intramolecular disulfide bond with the catalytic Cys(104) even under mildly reducing conditions. Molecular modeling of the highly homologous PRL-1 and PRL-2 phosphatases revealed unique surface elements that are potentially important for specificity.

Reviews - 1r6h mentioned but not cited (2)

  1. Targeting phosphatases of regenerating liver (PRLs) in cancer. Wei M, Korotkov KV, Blackburn JS. Pharmacol Ther 190 128-138 (2018)
  2. The double lives of phosphatases of regenerating liver: A structural view of their catalytic and noncatalytic activities. Gehring K, Kozlov G, Yang M, Fakih R. J Biol Chem 298 101471 (2022)

Articles - 1r6h mentioned but not cited (1)



Reviews citing this publication (17)

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  2. Regulation of intracellular signalling through cysteine oxidation by reactive oxygen species. Miki H, Funato Y. J Biochem 151 255-261 (2012)
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  5. Molecular mechanisms of the PRL phosphatases. Rios P, Li X, Köhn M. FEBS J 280 505-524 (2013)
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  9. Molecular function and biological importance of CNNM family Mg2+ transporters. Funato Y, Miki H. J Biochem 165 219-225 (2019)
  10. Small molecule targeting of PTPs in cancer. Lazo JS, McQueeney KE, Burnett JC, Wipf P, Sharlow ER. Int J Biochem Cell Biol 96 171-181 (2018)
  11. Regulatory mechanisms of phosphatase of regenerating liver (PRL)-3. Rubio T, Köhn M. Biochem Soc Trans 44 1305-1312 (2016)
  12. Investigational inhibitors of PTP4A3 phosphatase as antineoplastic agents. Sharlow ER, Wipf P, McQueeney KE, Bakan A, Lazo JS. Expert Opin Investig Drugs 23 661-673 (2014)
  13. Phosphatase of regenerating liver in hematopoietic stem cells and hematological malignancies. Kobayashi M, Chen S, Gao R, Bai Y, Zhang ZY, Liu Y. Cell Cycle 13 2827-2835 (2014)
  14. Structure and catalytic mechanism of human protein tyrosine phosphatome. Kim SJ, Ryu SE. BMB Rep 45 693-699 (2012)
  15. Phosphatase-independent role of phosphatase of regenerating liver in cancer progression. Funato Y, Hashizume O, Miki H. Cancer Sci 114 25-33 (2023)
  16. PRL3 as a therapeutic target for novel cancer immunotherapy in multiple cancer types. Chia PL, Ang KH, Thura M, Zeng Q. Theranostics 13 1876-1891 (2023)
  17. Protein Tyrosine Phosphatase PRL-3: A Key Player in Cancer Signaling. Liu H, Li X, Shi Y, Ye Z, Cheng X. Biomolecules 14 342 (2024)

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