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Targeting PTPs with small molecule inhibitors in cancer treatment

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Abstract

Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the phosphatase of regenerating liver (PRL) phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed.

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Abbreviations

PTK:

protein tyrosine kinase

PTP:

protein tyrosine phosphatase

SH2:

Src homology-2

PRL:

phosphatase of regenerating liver

References

  1. Hunter, T. (2000). Signaling—2000 and beyond. Cell, 100, 113–127.

    Article  PubMed  CAS  Google Scholar 

  2. Tonks, N. K. (2006). Protein tyrosine phosphatases: from genes, to function, to disease. Nature Reviews. Molecular Cell Biology, 7, 833–846.

    Article  PubMed  CAS  Google Scholar 

  3. Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., et al. (2004). Protein tyrosine phosphatases in the human genome. Cell, 117, 699–711.

    Article  PubMed  CAS  Google Scholar 

  4. Hunter, T. (1998). The phosphorylation of proteins on tyrosine: its role in cell growth and disease. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 353, 583–605.

    Article  PubMed  CAS  Google Scholar 

  5. Zhang, Z.-Y. (2001). Protein tyrosine phosphatases: prospects for therapeutics. Current Opinion in Chemical Biology, 5, 416–423.

    Article  PubMed  CAS  Google Scholar 

  6. Arena, S., Benvenuti, S., & Bardelli, A. (2005). Genetic analysis of the kinome and phosphatome in cancer. Cellular and Molecular Life Sciences, 62, 2092–2099.

    Article  PubMed  CAS  Google Scholar 

  7. Ventura, J. J., & Nebreda, A. R. (2006). Protein kinases and phosphatases as therapeutic targets in cancer. Clinical & translational oncology: official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 8, 153–160.

    CAS  Google Scholar 

  8. Krause, D. S., & Van Etten, R. A. (2005). Tyrosine kinases as targets for cancer therapy. New England Journal of Medicine, 353, 172–187.

    Article  PubMed  CAS  Google Scholar 

  9. Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., et al. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 275, 1943–1947.

    Article  PubMed  CAS  Google Scholar 

  10. Steck, P. A., Pershouse, M. A., Jasser, S. A., Yung, W. K. A., Lin, H., Ligon, A. H., et al. (1997). Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23 that is mutated in multiple advanced cancers. Nature Genetics, 15, 356–362.

    Article  PubMed  CAS  Google Scholar 

  11. Wang, Z., Shen, D., Parsons, D. W., Bardelli, A., Sager, J., Szabo, S., et al. (2004). Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science, 304, 1164–1166.

    Article  PubMed  CAS  Google Scholar 

  12. Zheng, X. M., Wang, Y., & Pallen, C. J. (1992). Cell transformation and activation of pp60c-src by overexpression of a protein tyrosine phosphatase. Nature, 359, 336–339.

    Article  PubMed  CAS  Google Scholar 

  13. Ponniah, S., Wang, D. Z., Lim, K. L., & Pallen, C. J. (1999). Targeted disruption of the tyrosine phosphatase PTPalpha leads to constitutive downregulation of the kinases Src and Fyn. Current Biology, 9, 535–538.

    Article  PubMed  CAS  Google Scholar 

  14. Su, J., Muranjan, M., & Sap, J. (1999). Receptor protein tyrosine phosphatase alpha activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Current Biology, 9, 505–511.

    Article  PubMed  CAS  Google Scholar 

  15. Noguchi, T., Matozaki, T., Horita, K., Fujioka, Y., & Kasuga, M. (1994). Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. Molecular and Cell Biology, 14, 6674–6682.

    CAS  Google Scholar 

  16. Tang, T. L., Freeman Jr., R. M., O’Reilly, A. M., Neel, B. G., & Sokol, S. Y. (1995). The SH2-containing protein-tyrosine phosphatase SH-PTP2 is required upstream of MAP kinase for early Xenopus development. Cell, 80, 473–483.

    Article  PubMed  CAS  Google Scholar 

  17. Bennett, A. M., Hausdorff, S. F., O’Reilly, A. M., Freeman, R. M., & Neel, B. G. (1996). Multiple requirements for SHPTP2 in epidermal growth factor-mediated cell cycle progression. Molecular and Cell Biology, 16, 1189–1202.

    CAS  Google Scholar 

  18. Shi, Z. Q., Yu, D. H., Park, M., Marshall, M., & Feng, G. S. (2000). Molecular mechanism for the Shp-2 tyrosine phosphatase function in promoting growth factor stimulation of Erk activity. Molecular and Cell Biology, 20, 1526–1536.

    Article  CAS  Google Scholar 

  19. Tartaglia, M., Mehler, E. L., Goldberg, R., Zampino, G., Brunner, H. G., Kremer, H., et al. (2001). Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP2, cause Noonan syndrome. Nature Genetics, 29, 465–468.

    Article  PubMed  CAS  Google Scholar 

  20. Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., et al. (2003). Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genetics, 34, 148–150.

    Article  PubMed  CAS  Google Scholar 

  21. Bentires-Alj, M., Paez, J. G., David, F. S., Keilhack, H., Halmos, B., Naoki, K., et al. (2004). Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Research, 64, 8816–8820.

    Article  PubMed  CAS  Google Scholar 

  22. Stephens, B. J., Han, H., Gokhale, V., & Von Hoff, D. D. (2005). PRL phosphatases as potential molecular targets in cancer. Advanced Thailand Geographic, 4, 1653–1661.

    CAS  Google Scholar 

  23. Blume-Jensen, P., & Hunter, T. (2001). Oncogenic kinase signaling. Nature, 411, 355–365.

    Article  PubMed  CAS  Google Scholar 

  24. Druker, B. J. (2004). Imatinib as a paradigm of targeted therapies. Advanced Cancer Research, 91, 1–30.

    Article  CAS  Google Scholar 

  25. Lynch, T. J., Bell, D. W., Sordella, R., Gurubhagavatula, S., Okimoto, R. A., Brannigan, B. W., et al. (2004). Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine, 350, 2129–2139.

    Article  PubMed  CAS  Google Scholar 

  26. Ostman, A., Hellberg, C., & Bohmer, F. D. (2006). Protein-tyrosine phosphatases and cancer. Nature Reviews. Nature Reviews. Cancer, 6, 307–320.

    Article  PubMed  CAS  Google Scholar 

  27. Elchelby, M., Payette, P., Michaliszyn, E., Cromlish, W., Collins, S., Lee Loy, A., et al. (1999). Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science, 283, 1544–1548.

    Article  Google Scholar 

  28. Klaman, L. D., Boss, O., Peroni, O. D., Kim, J. K., Martino, J. L., Zabolotny, J. M., et al. (2000). Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Molecular and Cellular Biology, 20, 5479–5489.

    Article  PubMed  CAS  Google Scholar 

  29. Zinker, B. A., Rondinone, C. M., Trevillyan, J. M., Gum, R. J., Clampit, J. E., Waring, J. F., et al. (2002). PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America, 99, 11357–11362.

    Article  PubMed  CAS  Google Scholar 

  30. Flint, A. J., Tiganis, T., Barford, D., & Tonks, N. K. (1997). Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases. Proceedings of the National Academy of Sciences of the United States of America, 94, 1680–1685.

    Article  PubMed  CAS  Google Scholar 

  31. Liu, F., & Chernoff, J. (1997). Protein tyrosine phosphatase 1B interacts with and is tyrosine phosphorylated by the epidermal growth factor receptor. Biochemical Journal, 327, 139–145.

    PubMed  CAS  Google Scholar 

  32. Bjorge, J. D., Pang, A., & Fujita, D. J. (2000). Identification of protein-tyrosine phosphatase 1B as the major tyrosine phosphatase activity capable of dephosphorylating and activating c-Src in several human breast cancer cell lines. Journal of Biological Chemistry, 275, 41439–41446.

    Article  PubMed  CAS  Google Scholar 

  33. Cheng, A., Bal, G. S., Kennedy, B. P., & Tremblay, M. L. (2001). Attenuation of adhesion-dependent signaling and cell spreading in transformed fibroblasts lacking protein tyrosine phosphatase-1B. Journal of Biological Chemistry, 276, 25848–25855.

    Article  PubMed  CAS  Google Scholar 

  34. Liang, F., Lee, S.-Y., Liang, J., Lawrence, D. S., & Zhang, Z. Y. (2005). The role of PTP1B in integrin signaling. Journal of Biological Chemistry, 280, 24857–24863.

    Article  PubMed  CAS  Google Scholar 

  35. Dube, N., Cheng, A., & Tremblay, M. L. (2004). The role of protein tyrosine phosphatase 1B in Ras signaling. Proceedings of the National Academy of Sciences of the United States of America, 101, 1834–1839.

    Article  PubMed  CAS  Google Scholar 

  36. Yarden, Y. (2001). Biology of HER2 and its importance in breast cancer. Oncology, 61(Suppl 2), 1–13.

    Article  PubMed  CAS  Google Scholar 

  37. Hynes, N. E., & Lane, H. A. (2005). ERBB receptors and cancer: the complexity of targeted inhibitors. Nature Reviews. Cancer, 5, 341–354.

    Article  PubMed  CAS  Google Scholar 

  38. Zhai, Y. F., Beittenmiller, H., Wang, B., Gould, M. N., Oakley, C., Esselman, W. J., et al. (1993). Increased expression of specific protein tyrosine phosphatases in human breast epithelial cells neoplastically transformed by the neu oncogene. Cancer Research, 53, 2272–2278.

    PubMed  CAS  Google Scholar 

  39. Wiener, J. R., Kerns, B. J., Harvey, E. L., Conaway, M. R., Iglehart, J. D., Berchuck, A., et al. (1994). Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. Journal of the National Cancer Institute, 86, 372–378.

    Article  PubMed  CAS  Google Scholar 

  40. Julien, S. G., Dubé, N., Read, M., Penney, J., Paquet, M., Han, Y., et al. (2007). Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nature Genetics, 39, 338–346.

    Article  PubMed  CAS  Google Scholar 

  41. Bentires-Alj, M., & Neel, B. G. (2007). Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. Cancer Research, 67, 2420–2424.

    Article  PubMed  CAS  Google Scholar 

  42. Zhu, S., Bjorge, J. D., & Fujita, D. J. (2007). PTP1B contributes to oncogenic properties of colon cancer cells through Src activation. Cancer Research, 67, 10129–10137.

    Article  PubMed  CAS  Google Scholar 

  43. Zhang, S., & Zhang, Z.-Y. (2007). PTP1B as a drug target: recent development in PTP1B inhibitor discovery. Drug Discovery Today, 12, 373–381.

    Article  PubMed  CAS  Google Scholar 

  44. Shen, K., Keng, Y. F., Wu, L., Guo, X. L., Lawrence, D. S., & Zhang, Z.-Y. (2001). Acquisition of a specific and potent PTP1B inhibitor from a novel combinatorial library and screening procedure. Journal of Biological Chemistry, 276, 47311–47319.

    Article  PubMed  CAS  Google Scholar 

  45. Sun, J.-P., Fedorov, A. A., Lee, S.-Y., Guo, X.-L., Shen, K., Lawrence, D. S., et al. (2003). Crystal structure of PTP1B in complex with a potent and selective bidentate inhibitor. Journal of Biological Chemistry, 278, 12406–12414.

    Article  PubMed  CAS  Google Scholar 

  46. Xie, L., Lee, S.-Y., Andersen, J. N., Waters, S., Shen, K., Guo, X.-L., et al. (2003). Cellular effects of small molecule PTP1B inhibitors on insulin signalling. Biochemistry, 42, 12792–12804.

    Article  PubMed  CAS  Google Scholar 

  47. Lee, S.-Y., Liang, F., Guo, X.-L., Xie, L., Cahill, S. M., Blumenstein, M., et al. (2005). Design, construction, and intracellular activation of an intramolecularly self-silenced signal transduction inhibitor. Angewandte Chemie. International Edition, 44, 4242–4244.

    Article  CAS  Google Scholar 

  48. Boutselis, I. G., Yu, X., Zhang, Z. Y., & Borch, R. (2007). Synthesis and cell-based activity of a potent and selective PTP1B inhibitor prodrug. Journal of Medicinal Chemistry, 50, 856–864.

    Article  PubMed  CAS  Google Scholar 

  49. Morrison, C. D., White, C. L., Wang, Z., Lee, S.-Y., Lawrence, D. S., Cefalu, W. T., et al. (2007). Increased hypothalamic PTP1B contribute to leptin resistance with age. Endocrinology, 148, 433–440.

    Article  PubMed  CAS  Google Scholar 

  50. Black, E., Breed, J., Breeze, A. L., Embrey, K., Garcia, R., Gero, T. W., et al. (2005). Structure-based design of protein tyrosine phosphatase-1B inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 2503–2507.

    Article  CAS  Google Scholar 

  51. Combs, A. P., Yue, E. W., Bower, M., Ala, P. J., Wayland, B., Douty, B., et al. (2005). Structure-based design and discovery of protein tyrosine phosphatase inhibitors incorporating novel isothiazolidinone heterocyclic phosphotyrosine mimetics. Journal of Medicinal Chemistry, 48, 6544–6548.

    Article  PubMed  CAS  Google Scholar 

  52. Yue, E. W., Wayland, B., Douty, B., Crawley, M. L., McLaughlin, E., Takvorian, A., et al. (2006). Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: synthesis and structure-activity relationships of a peptide scaffold. Bioorganic & Medicinal Chemistry, 14, 5833–5849.

    Article  CAS  Google Scholar 

  53. Combs, A. P., Zhu, W., Crawley, M. L., Glass, B., Polam, P., Sparks, R. B., et al. (2006). Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic. Journal of Medicinal Chemistry, 49, 3774–3789.

    Article  PubMed  CAS  Google Scholar 

  54. Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M. J., & Shoelson, S. E. (1998). Cell, 92, 441–450.

    Article  PubMed  CAS  Google Scholar 

  55. Mohi, M. G., & Neel, B. G. (2007). The role of Shp2 (PTPN11) in cancer. Current Opinion in Genetics & Development, 17, 23–30.

    Article  CAS  Google Scholar 

  56. Hatakeyama, M. (2004). Oncogenic mechanisms of the Helicobacter pyroli CagA protein. Nature Reviews. Cancer, 4, 688–694.

    Article  PubMed  CAS  Google Scholar 

  57. Stommel, J. M., Kimmelman, A. C., Ying, H., Nabioullin, R., Ponugoti, A. H., Wiedemeyer, R., et al. (2007). Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science, 318, 287–290.

    Article  PubMed  CAS  Google Scholar 

  58. Chen, L., Sung, S. S., Yip, M. L., Lawrence, H. R., Ren, Y., Guida, W. C., et al. (2006). Discovery of a novel shp2 protein tyrosine phosphatase inhibitor. Molecular Pharmacology, 70, 562–570.

    Article  PubMed  CAS  Google Scholar 

  59. Coleman, T. R., & Dunphy, W. G. (1994). Cdc2 regulatory factors. Current Opinion in Cell Biology, 6, 877–882.

    Article  PubMed  CAS  Google Scholar 

  60. Hoffmann, I., & Karsenti, E. (1994). The role of cdc25 in checkpoints and feedback controls in the eukaryotic cell cycle. Journal of Cell Science. Supplement, 18, 75–79.

    PubMed  CAS  Google Scholar 

  61. Nilsson, I., & Hoffmann, I. (2000). Cell cycle regulation by the Cdc25 phosphatase family. Progress in Cell Cycle Research, 4, 107–114.

    PubMed  CAS  Google Scholar 

  62. Ma, Z. Q., Chua, S. S., DeMayo, F. J., & Tsai, S. Y. (1999). Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B. Oncogene, 18, 4564−4576.

    PubMed  Google Scholar 

  63. Yao, Y., Slosberg, E. D., Wang, L., Hibshoosh, H., Zhang, Y.-J., Xing, W.-Q., et al. (1999). Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice. Oncogene, 18, 5159−5166.

    PubMed  Google Scholar 

  64. Galaktionov, K., Lee, A. K., Eckstein, J., Draetta, G., Meckler, J., Loda, M., et al. (1995). Cdc25 phosphatases as potential human oncogenes. Science, 269, 1575–1577.

    Article  PubMed  CAS  Google Scholar 

  65. Cangi, M. G., Cukor, B., Soung, P., Signoretti, S., Moreira Jr., G., Ranashinge, M., et al. (2000). Role of the Cdc25A phosphatase in human breast cancer. Journal of Clinical Investigation, 106, 753–761.

    Article  PubMed  CAS  Google Scholar 

  66. Lyon, M. A., Ducruet, A. P., Wipf, P., & Lazo, J. S. (2002). Dual-specificity phosphatases as targets for antineoplastic agents. Nature reviews. Nature reviews. Drug discovery, 1, 961–976.

    Article  PubMed  CAS  Google Scholar 

  67. Ducruet, A. P., Vogt, A., Wipf, P., & Lazo, J. S. (2005). Dual specificity protein phosphatases: therapeutic targets for cancer and Alzheimer’s disease. Annual Review of Pharmacology and Toxicology, 45, 725–750.

    Article  PubMed  CAS  Google Scholar 

  68. Gunasekera, S. P., McCarty, P. J., Kelly-Borges, M., Lobkovsky, E., & Clardy, J. (1996). Dysidiolide: a novel protein phosphatase inhibitor from the Caribbean sponge Dysidea etheria de Laubenfels. Journal of the American Chemical Society, 118, 8759–8760.

    Article  CAS  Google Scholar 

  69. Dodo, K., Takahashi, M., Yamada, Y., Sugimoto, Y., Hashimoto, Y., & Shirai, R. (2000). Synthesis of a novel class of cdc25A inhibitors from vitamin D3. Bioorganic & Medicinal Chemistry Letters, 10, 615–617.

    Article  CAS  Google Scholar 

  70. Horiguchi, T., Nishi, K., Hakoda, S., Tanida, S., Nagata, A., & Okayama, H. (1994). Dnacin A1 and dnacin B1 are antitumor antibiotics that inhibit cdc25B phosphatase activity. Biochemical Pharmacology, 48, 2139–2141.

    Article  PubMed  CAS  Google Scholar 

  71. Loukaci, A., Le Saout, I., Samadi, M., Leclerc, S., Damiens, E., Meijer, L., et al. (2001). Coscinosulfate, a CDC25 phosphatase inhibitor from the sponge Coscinoderma mathewsi. Bioorganic & Medicinal Chemistry, 9, 3049–3054.

    Article  CAS  Google Scholar 

  72. Ham, S. W., Park, H. J., & Lim, D. H. (1997). Studies on menadione as an inhibitor of the cdc25 phosphatase. Bioorganic Chemistry, 25, 33–36.

    Article  CAS  Google Scholar 

  73. Lazo, J. S., Nemoto, K., Pestell, K. E., Cooley, K., Southwick, E. C., Mitchell, D. A., et al. (2002). Identification of a potent and selective pharmacophore for Cdc25 dual specificity phosphatase inhibitors. Molecular Pharmacology, 61, 720–728.

    Article  PubMed  CAS  Google Scholar 

  74. Contour-Galcera, M. O., Sidhu, A., Prevost, G., Bigg, D., & Ducommun, B. (2007). What’s new on Cdc25 phosphatase inhibitors. Pharmacology & Therapeutics, 115, 1–12.

    Article  CAS  Google Scholar 

  75. Sohn, J., Kiburz, B., Li, Z., Deng, L., Safi, A., Pirrung, M. C. et al. (2003). Inhibition of Cdc25 phosphatases by indolyldihydroxyquinones. Journal of Medicinal Chemistry, 46, 2580–2588.

    Article  PubMed  CAS  Google Scholar 

  76. Diamond, R. H., Cressman, D. E., Laz, T. M., Abrams, C. S., & Taub, R. (1994). PRL-1, a unique nuclear protein tyrosine phosphatase, affects cell growth. Molecular and Cellular Biology, 14, 3752–3762.

    PubMed  CAS  Google Scholar 

  77. Wang, J., Kirby, C. E., & Herbst, R. (2002). The tyrosine phosphatase PRL-1 localizes to the endoplasmic reticulum and the mitotic spindle and is required for normal mitosis. Journal of Biological Chemistry, 277, 46659–46668.

    Article  PubMed  CAS  Google Scholar 

  78. Cates, C. A., Michael, R. L., Stayrook, K. R., Harvey, K. A., Burke, Y. D., Randall, S. K., et al. (1996). Prenylation of oncogenic human PTP(CAAX) protein tyrosine phosphatase. Cancer Letters, 110, 49–55.

    Article  PubMed  CAS  Google Scholar 

  79. Matter, W. F., Estridge, T., Zhang, C., Belagaje, R., Stancato, L., Dixon, J., et al. (2001). Role of PRL-3, a human muscle-specific tyrosine phosphatase, in angiotensin-II signaling. Biochemical and Biophysical Research Communications, 283, 1061–1068.

    Article  PubMed  CAS  Google Scholar 

  80. Zeng, Q., Dong, J. M., Guo, K., Li, J., Tan, H. X., Koh, V., et al. (2003). PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. Cancer Research, 63, 2716–2722.

    PubMed  CAS  Google Scholar 

  81. Werner, S. R., Lee, P. A., DeCamp, M. W., Crowell, D. N., Randall, S. K., & Crowell, P. L. (2003). Enhanced cell cycle progression and down regulation of p21(Cip1/Waf1) by PRL tyrosine phosphatases. Cancer Letters, 202, 201–211.

    Article  PubMed  CAS  Google Scholar 

  82. Saha, S., Bardelli, A., Buckhaults, P., Velculescu, V. E., Rago, C., St Croix, B., et al. (2001). A phosphatase associated with metastasis of colorectal cancer. Science, 294, 1343–1346.

    Article  PubMed  CAS  Google Scholar 

  83. Bardelli, A., Saha, S., Sager, J. A., Romans, K. E., Xin, B., Markowitz, S. D., et al. (2003). PRL-3 expression in metastatic cancers. Clinical Cancer Research, 9, 5607–5615.

    PubMed  CAS  Google Scholar 

  84. Kato, H., Semba, S., Miskad, U. A., Seo, Y., Kasuga, M., & Yokozaki, H. (2004). High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases. Clinical Cancer Research, 10, 7318–7328.

    Article  PubMed  CAS  Google Scholar 

  85. Liang, F., Liang, J., Wang, W. Q., Sun, J. P., Udho, E., & Zhang, Z. Y. (2007). PRL3 promotes cell invasion and proliferation by down-regulation of Csk leading to Src activation. Journal of Biological Chemistry, 282, 5413–5419.

    Article  PubMed  CAS  Google Scholar 

  86. Fiordalisi, J. J., Keller, P. J., & Cox, A. D. (2006). PRL tyrosine phosphatases regulate rho family GTPases to promote invasion and motility. Cancer Research, 66, 3153–3161.

    Article  PubMed  Google Scholar 

  87. Achiwa, H., & Lazo, J. S. (2007). PRL-1 tyrosine phosphatase regulates c-Src levels, adherence, and invasion in human lung cancer cells. Cancer Research, 67, 643–650.

    Article  PubMed  CAS  Google Scholar 

  88. Rouleau, C., Roy, A., St Martin, T., Dufault, M. R., Boutin, P., Liu, D., et al. (2006). Protein tyrosine phosphatase PRL-3 in malignant cells and endothelial cells: expression and function. Clinical Cancer Research, 5, 219–229.

    CAS  Google Scholar 

  89. Pathak, M. K., Dhawan, D., Lindner, D. J., Borden, E. C., Farver, C., & Yi, T. (2002). Pentamidine is an inhibitor of PRL phosphatases with anticancer activity. Molecular Cancer Therapeutics, 1, 1255–1264.

    PubMed  CAS  Google Scholar 

  90. Ahn, J. H., Kim, S. J., Park, W. S., Cho, S. Y., Ha, J. D., Kim, S. S., et al. (2006). Synthesis and biological evaluation of rhodanine derivatives as PRL-3 inhibitors. Bioorganic & Medicinal Chemistry Letters, 16, 2996–2999.

    Article  CAS  Google Scholar 

  91. Choi, S. K., Oh, H. M., Lee, S. K., Jeong, D. G., Ryu, S. E., Son, K. H., et al. (2006). Biflavonoids inhibited phosphatase of regenerating liver-3 (PRL-3). Natural Product Research, 20, 341–346.

    Article  PubMed  CAS  Google Scholar 

  92. Jeong, D. G., Kim, S. J., Kim, J. H., Son, J. H., Park, M. R., Lim, S. M., et al. (2005). Trimeric structure of PRL1 phosphatase reveals an active enzyme conformation and regulation mechanisms. Journal of Molecular Biology, 345, 401–413.

    Article  PubMed  CAS  Google Scholar 

  93. Sun, J. P., Wang, W. Q., Yang, H., Liu, S., Liang, F., Fedorov, A. A., et al. (2005). Structure and biochemical properties of PRL1, a phosphatase implicated in cell growth, differentiation, and tumor invasion. Biochemistry, 44, 12009–12021.

    Article  PubMed  CAS  Google Scholar 

  94. Sun, J.-P., Luo, Y., Yu, X., Wang, W.-Q., Zhou, B., Liang, F., et al. (2007). Phosphatase activity, trimerization, and the C-terminal polybasic region are all required for the PRL1-mediated cell growth and migration. Journal of Biological Chemistry, 282, 29043–29051.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH Grants CA69202 and DK68447.

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  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA

    Zhong-Xing Jiang & Zhong-Yin Zhang

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Jiang, ZX., Zhang, ZY. Targeting PTPs with small molecule inhibitors in cancer treatment. Cancer Metastasis Rev 27, 263–272 (2008). https://doi.org/10.1007/s10555-008-9113-3

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  • DOI: https://doi.org/10.1007/s10555-008-9113-3

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