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Protein-tyrosine phosphatases and cancer

Key Points

  • Protein-tyrosine phosphatases (PTPs) constitute a structurally diverse family of tightly regulated enzymes that are characterized by a conserved catalytic domain with an oxidation-sensitive active-site cysteine residue.

  • Different PTPs function as negative or positive mediators of signalling triggered by receptor-tyrosine kinases, integrins and cell-adhesion molecules.

  • The tumour-suppressive function of PTPs is indicated by frequent inactivating mutations of PTPs in colon cancer, and the identification of Ptprj as the gene that confers colon cancer susceptibility in STS/A mice. Also, inactivation of the genes that encode SHP1 and glomerular epithelial protein 1 (GLEPP1) by methylation has been described in haematological malignancies and solid tumours, respectively.

  • The oncogenic activity of a PTP is best characterized for the mutational activation of SHP2, which occurs in hereditary and sporadic leukaemias and, less frequently, in solid tumours.

  • Despite technical challenges, recent advances in the design of PTP inhibitors are encouraging with respect to the possibilities of developing novel cancer drugs that function by inhibiting oncogenic PTPs.

  • Other aspects of PTP biology that might be relevant to cancer research in the future are the regulation of PTPs by oxidation and the putative role of PTPs in angiogenesis.

Abstract

Tyrosine phosphorylation is an important signalling mechanism in eukaryotic cells. In cancer, oncogenic activation of tyrosine kinases is a common feature, and novel anticancer drugs have been introduced that target these enzymes. Tyrosine phosphorylation is also controlled by protein-tyrosine phosphatases (PTPs). Recent evidence has shown that PTPs can function as tumour suppressors. In addition, some PTPs, including SHP2, positively regulate the signalling of growth-factor receptors, and can be oncogenic. An improved understanding of how these enzymes function and how they are regulated might aid the development of new anticancer agents.

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Figure 1: Schematic representation of some of the protein-tyrosine phosphatase subfamilies.
Figure 2: Schematic illustration of the dual aspects of protein-tyrosine phosphatases in controlling cell proliferation, cell–matrix and cell–cell adhesion.
Figure 3: Schematic illustration of different mechanisms for protein-tyrosine phosphatase inactivation in cancer.
Figure 4: Mechanism of SHP2-mediated signal transduction and the effect of SHP2 mutations in leukaemia.

References

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

    CAS  PubMed  Google Scholar 

  2. Sawyers, C. Targeted cancer therapy. Nature 432, 294–297 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Tonks, N. K., Diltz, C. D. & Fischer, E. H. Purification of the major protein-tyrosine-phosphatases of human placenta. J. Biol. Chem. 263, 6722–6730 (1988).

    Article  CAS  PubMed  Google Scholar 

  4. Andersen, J. N. et al. Structural and evolutionary relationships among protein tyrosine phosphatase domains. Mol. Cell. Biol. 21, 7117–7136 (2001). Comprehensive review of the structural similarities and differences of PTPs, coupled with insightful discussions of functional significances.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Östman, A. & Böhmer, F. D. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatases. Trends Cell Biol. 11, 258–266 (2001).

    Article  PubMed  Google Scholar 

  6. Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Ducruet, A. P., Vogt, A., Wipf, P. & Lazo, J. S. Dual specificity protein phosphatases: therapeutic targets for cancer and Alzheimer's disease. Annu. Rev. Pharmacol. Toxicol. 45, 725–750 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Raugei, G., Ramponi, G. & Chiarugi, P. Low molecular weight protein tyrosine phosphatases: small, but smart. Cell. Mol. Life Sci. 59, 941–949 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Sulis, M. L. & Parsons, R. PTEN: from pathology to biology. Trends Cell Biol. 13, 478–483 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Mauro, L. J. & Dixon, J. E. 'Zip codes' direct intracellular protein tyrosine phosphatases to the correct cellular 'address'. Trends Biochem. Sci. 19, 151–155 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Zhang, Z. Y. et al. Substrate specificity of the protein tyrosine phosphatases. Proc. Natl Acad. Sci. USA 90, 4446–4450 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Flint, A. J., Tiganis, T., Barford, D. & Tonks, N. K. Development of “substrate-trapping” mutants to identify physiological substrates of protein tyrosine phosphatases. Proc. Natl Acad. Sci. USA 94, 1680–1685 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kovalenko, M. et al. Site-selective dephosphorylation of the platelet-derived growth factor β-receptor by the receptor-like protein-tyrosine phosphatase DEP-1. J. Biol. Chem. 275, 16219–16226 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Persson, C. et al. Site-selective regulation of platelet-derived growth factor β receptor tyrosine phosphorylation by T-cell protein tyrosine phosphatase. Mol. Cell. Biol. 24, 2190–201 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jia, Z., Barford, D., Flint, A. J. & Tonks, N. K. Structural basis for phosphotyrosine peptide recognition by protein tyrosine phosphatase 1B. Science 268, 1754–1758 (1995). The first example of PTP co-crystalized with substrate, providing insights into catalysis and determinants of substrate specificity.

    Article  CAS  PubMed  Google Scholar 

  16. Salmeen, A., Andersen, J. N., Myers, M. P., Tonks, N. K. & Barford, D. Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Mol. Cell 6, 1401–1412 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Haj, F. G., Verveer, P. J., Squire, A., Neel, B. G. & Bastiaens, P. I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708–1711 (2002). Technically elegant study demonstrating that interactions between PTPs and their substrate occur in a spatially restricted manner.

    Article  CAS  PubMed  Google Scholar 

  18. Frangioni, J. V., Oda, A., Smith, M., Salzman, E. W. & Neel, B. G. Calpain-catalyzed cleavage and subcellular relocation of protein phosphotyrosine phosphatase 1B (PTP-1B) in human platelets. EMBO J. 12, 4843–4856 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gulati, P., Markova, B., Göttlicher, M., Böhmer, F. D. & Herrlich, P. A. UVA inactivates protein tyrosine phosphatases by calpain-mediated degradation. EMBO Rep. 5, 812–817 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Desai, D. M., Sap, J., Schlessinger, J. & Weiss, A. Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase. Cell 73, 541–554 (1993).

    Article  CAS  PubMed  Google Scholar 

  21. Majeti, R., Bilwes, A. M., Noel, J. P., Hunter, T. & Weiss, A. Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279, 88–91 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Bilwes, A. M., den Hertog, J., Hunter, T. & Noel, J. P. Structural basis for inhibition of receptor protein-tyrosine phosphatase-α by dimerization. Nature 382, 555–559 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Jiang, G. et al. Dimerization inhibits the activity of receptor-like protein-tyrosine phosphatase-α. Nature 401, 606–610 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Nam, H. J., Poy, F., Krueger, N. X., Saito, H. & Frederick, C. A. Crystal structure of the tandem phosphatase domains of RPTP LAR. Cell 97, 449–457 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Nam, H. J., Poy, F., Saito, H. & Frederick, C. A. Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45. J. Exp. Med. 201, 441–452 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brady-Kalnay, S. M., Rimm, D. L. & Tonks, N. K. Receptor protein tyrosine phosphatase PTPm associates with cadherins and catenins in vivo. J. Cell. Biol. 130, 977–986 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Sap, J., Jiang, Y. P., Friedlander, D., Grumet, M. & Schlessinger, J. Receptor tyrosine phosphatase R-PTP-κ mediates homophilic binding. Mol. Cell. Biol. 14, 1–9 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sörby, M., Sandström, J. & Östman, A. An extracellular ligand increases the specific activity of the receptor-like protein tyrosine phosphatase DEP-1. Oncogene 20, 5219–5224 (2001).

    Article  PubMed  Google Scholar 

  29. Meng, K. et al. Pleiotrophin signals increased tyrosine phosphorylation of β-catenin through inactivation of the intrinsic catalytic activity of the receptor-type protein tyrosine phosphatase β/ζ. Proc. Natl Acad. Sci. USA 97, 2603–2608 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Haj, F. G., Markova, B., Klaman, L. D., Böhmer, F. D. & Neel, B. G. Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J. Biol. Chem. 278, 739–744 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Neel, B. G., Gu, H. & Pao, L. The 'Shp'ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Guo, W. & Giancotti, F. G. Integrin signalling during tumour progression. Nature Rev. Mol. Cell Biol. 5, 816–826 (2004).

    Article  CAS  Google Scholar 

  34. Cavallaro, U. & Christofori, G. Cell adhesion and signalling by cadherins and Ig-CAMs in cancer. Nature Rev. Cancer 4, 118–132 (2004).

    Article  CAS  Google Scholar 

  35. Lilien, J. & Balsamo, J. The regulation of cadherin-mediated adhesion by tyrosine phosphorylation/dephosphorylation of β-catenin. Curr. Opin. Cell Biol. 17, 459–465 (2005).

    Article  CAS  PubMed  Google Scholar 

  36. Sui, X. F. et al. Receptor protein tyrosine phosphatase μ regulates the paracellular pathway in human lung microvascular endothelia. Am. J. Pathol. 166, 1247–1258 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kappert, K., Peters, K. G., Böhmer, F. D. & Östman, A. Tyrosine phosphatases in vessel wall signaling. Cardiovasc. Res. 65, 587–598 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Larsen, M., Tremblay, M. L. & Yamada, K. M. Phosphatases in cell-matrix adhesion and migration. Nature Rev. Mol. Cell Biol. 4, 700–711 (2003).

    Article  CAS  Google Scholar 

  39. Brown-Shimer, S., Johnson, K. A., Hill, D. E. & Bruskin, A. M. Effect of protein tyrosine phosphatase 1B expression on transformation by the human neu oncogene. Cancer Res. 52, 478–482 (1992).

    CAS  PubMed  Google Scholar 

  40. Bardelli, A. et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300, 949 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Wang, Z. et al. Mutational analysis of the tyrosine phosphatome in colorectal cancers. Science 304, 1164–1166 (2004). A systematic and ambitious study demonstrating that inactivation of PTP is a frequent event in a common human tumour type.

    Article  CAS  PubMed  Google Scholar 

  43. Aricescu, A. R. et al. Molecular analysis of receptor protein tyrosine phosphatase μ mediated cell adhesion. EMBO J. 45, 701–712 (2006).

    Article  CAS  Google Scholar 

  44. Keane, M. M., Lowrey, G. A., Ettenberg, S. A., Dayton, M. A. & Lipkowitz, S. The protein tyrosine phosphatase DEP-1 is induced during differentiation and inhibits growth of breast cancer cells. Cancer Res. 56, 4236–4243 (1996).

    CAS  PubMed  Google Scholar 

  45. Trapasso, F. et al. Rat protein tyrosine phosphatase eta suppresses the neoplastic phenotype of retrovirally transformed thyroid cells through the stabilization of p27Kip1. Mol. Cell. Biol. 20, 9236–9246 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Iuliano, R. et al. An adenovirus carrying the rat protein tyrosine phosphatase e suppresses the growth of human thyroid carcinoma cell lines in vitro and in vivo. Cancer Res. 63, 882–886 (2003).

    CAS  PubMed  Google Scholar 

  47. Trapasso, F. et al. Restoration of receptor-type protein tyrosine phosphatase ε function inhibits human pancreatic carcinoma cell growth in vitro and in vivo. Carcinogenesis 25, 2107–2114 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Ruivenkamp, C. A. et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature Genet. 31, 295–300 (2002). A study that combines mouse genetics and analyses of human tumor samples and provides strong evidence for the tumour-suppressive functions of DEP1.

    Article  CAS  PubMed  Google Scholar 

  49. Moen, C. J., Groot, P. C., Hart, A. A., Snoek, M. & Demant, P. Fine mapping of colon tumor susceptibility (Scc) genes in the mouse, different from the genes known to be somatically mutated in colon cancer. Proc. Natl Acad. Sci. USA 93, 1082–1086 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ruivenkamp, C. et al. LOH of PTPRJ occurs early in colorectal cancer and is associated with chromosomal loss of 18q12–21. Oncogene 22, 3472–3474 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Iuliano, R. et al. The tyrosine phosphatase PTPRJ/DEP-1 genotype affects thyroid carcinogenesis. Oncogene 23, 8432–8438 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. van Puijenbroek, M. et al. Mass spectrometry-based loss of heterozygosity analysis of single-nucleotide polymorphism loci in paraffin embedded tumors using the MassEXTEND assay: single-nucleotide polymorphism loss of heterozygosity analysis of the protein tyrosine phosphatase receptor type J in familial colorectal cancer. J. Mol. Diagn. 7, 623–630 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Lesueur, F. et al. Allelic association of the human homologue of the mouse modifier Ptprj with breast cancer. Hum. Mol. Genet. 14, 2349–2356 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Palka, H. L., Park, M. & Tonks, N. K. Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase DEP-1. J. Biol. Chem. 278, 5728–5735 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Jandt, E., Denner, K., Kovalenko, M., Östman, A. & Böhmer, F. D. The protein-tyrosine phosphatase DEP-1 modulates growth factor-stimulated cell migration and cell–matrix adhesion. Oncogene 22, 4175–4185 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Grazia Lampugnani, M. et al. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, β-catenin, and the phosphatase DEP-1/CD148. J. Cell Biol. 161, 793–804 (2003).

    Article  PubMed  CAS  Google Scholar 

  57. Berset, T. A., Hoier, E. F. & Hajnal, A. The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions. Genes Dev. 19, 1328–1340 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Le Pera, I. et al. The rat tyrosine phosphatase e increases cell adhesion by activating c-Src through dephosphorylation of its inhibitory phosphotyrosine residue. Oncogene 24, 3187–3195 (2005).

    Article  CAS  Google Scholar 

  59. Holsinger, L. J., Ward, K., Duffield, B., Zachwieja, J. & Jallal, B. The transmembrane receptor protein tyrosine phosphatase DEP1 interacts with p120(ctn). Oncogene 21, 7067–7076 (2002).

    Article  CAS  PubMed  Google Scholar 

  60. MacKeigan, J. P., Murphy, L. O. & Blenis, J. Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance. Nature Cell Biol. 7, 591–600 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Takahashi, T. et al. A mutant receptor tyrosine phosphatase, CD148, causes defects in vascular development. Mol. Cell. Biol. 23, 1817–1831 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).

    Article  CAS  Google Scholar 

  63. Zhang, Q., Raghunath, P. N., Vonderheid, E., Odum, N. & Wasik, M. A. Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter. Am. J. Pathol. 157, 1137–1146 (2000). A study that identifies promoter methylation as a mechanism for PTP inactivation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Khoury, J. D., Rassidakis, G. Z., Medeiros, L. J., Amin, H. M. & Lai, R. Methylation of SHP1 gene and loss of SHP1 protein expression are frequent in systemic anaplastic large cell lymphoma. Blood 104, 1580–1581 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Oka, T. et al. Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res. 62, 6390–6394 (2002).

    CAS  PubMed  Google Scholar 

  66. Chim, C. S., Fung, T. K., Cheung, W. C., Liang, R. & Kwong, Y. L. SOCS1 and SHP1 hypermethylation in multiple myeloma: implications for epigenetic activation of the Jak–STAT pathway. Blood 103, 4630–4635 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, Q. et al. STAT3- and DNA methyltransferase 1-mediated epigenetic silencing of SHP-1 tyrosine phosphatase tumor suppressor gene in malignant T lymphocytes. Proc. Natl Acad. Sci. USA 102, 6948–6953 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Motiwala, T. et al. Suppression of the protein tyrosine phosphatase receptor type O gene (PTPRO) by methylation in hepatocellular carcinomas. Oncogene 22, 6319–6331 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Motiwala, T. et al. Protein tyrosine phosphatase receptor-type O (PTPRO) exhibits characteristics of a candidate tumor suppressor in human lung cancer. Proc. Natl Acad. Sci. USA 101, 13844–13849 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wharram, B. L. et al. Altered podocyte structure in GLEPP1 (Ptpro)-deficient mice associated with hypertension and low glomerular filtration rate. J. Clin. Invest. 106, 1281–1290 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Feng, G. S. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp. Cell. Res. 253, 47–54 (1999).

    Article  CAS  PubMed  Google Scholar 

  72. Zhan, Y. & O'Rourke, D. M. SHP-2-dependent mitogen-activated protein kinase activation regulates EGFRvIII but not wild-type epidermal growth factor receptor phosphorylation and glioblastoma cell survival. Cancer Res. 64, 8292–8298 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. D'Alessio, A. et al. The tyrosine phosphatase Shp-2 mediates intracellular signaling initiated by Ret mutants. Endocrinology 144, 4298–4305 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Agazie, Y. M., Movilla, N., Ischenko, I. & Hayman, M. J. The phosphotyrosine phosphatase SHP2 is a critical mediator of transformation induced by the oncogenic fibroblast growth factor receptor 3. Oncogene 22, 6909–6918 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Bentires-Alj, M. et al. A role for the scaffolding adapter GAB2 in breast cancer. Nature Med. 12, 114–121 (2006).

    Article  CAS  PubMed  Google Scholar 

  76. Sattler, M. et al. Critical role for Gab2 in transformation by BCR–ABL. Cancer Cell 1, 479–492 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Hatakeyama, M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature Rev. Cancer 4, 688–694 (2004).

    Article  CAS  Google Scholar 

  78. Klinghoffer, R. A. & Kazlauskas, A. Identification of a putative Syp substrate, the PDGFβ receptor. J. Biol. Chem. 270, 22208–22217 (1995). Analysis of PDGFR dephosphorylation by SHP2 in vitro showed a preferred dephoshorylation of the binding site for RASGAP. The authors propose that this might be the underlying mechanism for the positive regulation of Ras signalling by SHP2, a finding that was later extended by others to further RTKs.

    Article  CAS  PubMed  Google Scholar 

  79. Montagner, A. et al. A novel role for Gab1 and SHP2 in epidermal growth factor-induced Ras activation. J. Biol. Chem. 280, 5350–5360 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Zhang, S. Q. et al. Shp2 regulates SRC family kinase activity and Ras–Erk activation by controlling Csk recruitment. Mol. Cell 13, 341–355 (2004).

    Article  PubMed  Google Scholar 

  81. Ren, Y. et al. Roles of Gab1 and SHP2 in paxillin tyrosine dephosphorylation and Src activation in response to epidermal growth factor. J. Biol. Chem. 279, 8497–8505 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Kolli, S., Zito, C. I., Mossink, M. H., Wiemer, E. A. & Bennett, A. M. The major vault protein is a novel substrate for the tyrosine phosphatase SHP-2 and scaffold protein in epidermal growth factor signaling. J. Biol. Chem. 279, 29374–29385 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465–468 (2001). The discovery that missense mutations in PTPN11 cause Noonan syndrome, which is an autosomal-dominant disorder, in about 50% of patients. The position of amino-acid exchanges and modelling studies led the authors to suggest that these mutations might cause activation of SHP2.

    Article  CAS  PubMed  Google Scholar 

  84. Tartaglia, M. & Gelb, B. D. Germ-line and somatic PTPN11 mutations in human disease. Eur. J. Med. Genet. 48, 81–96 (2005).

    Article  PubMed  Google Scholar 

  85. Tartaglia, M. et al. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nature Genet. 34, 148–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  86. Loh, M. L. et al. Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis. Blood 103, 2325–2331 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Tartaglia, M. et al. Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia. Blood 104, 307–313 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Bentires-Alj, M. et al. Activating mutations of the noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Res. 64, 8816–8820 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Tartaglia, M. et al. Somatic PTPN11 mutations in childhood acute myeloid leukaemia. Br. J. Haematol. 129, 333–339 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Hof, P., Pluskey, S., Dhe-Paganon, S., Eck, M. J. & Shoelson, S. E. Crystal structure of the tyrosine phosphatase SHP-2. Cell 92, 441–450 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. O'Reilly, A. M., Pluskey, S., Shoelson, S. E. & Neel, B. G. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol. Cell. Biol. 20, 299–311 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Keilhack, H., David, F. S., McGregor, M., Cantley, L. C. & Neel, B. G. Diverse biochemical properties of Shp2 mutants: implications for disease phenotypes. J. Biol. Chem. 280, 30984–30993 (2005). A thorough biochemical analysis of different disease-associated SHP2 mutants showed unexpected properties, such as altered susceptibility to phosphopeptide ligand activation, and altered substrate selectivity.

    Article  CAS  PubMed  Google Scholar 

  93. Mohi, M. G. et al. Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. Cancer Cell 7, 179–191 (2005). A disease model using retroviral transduction of primary mouse bone marrow allowed to characterize different leukaemia-associated SHP2 variants and the role of different protein domains of SHP2 for leukaemogenesis.

    Article  CAS  PubMed  Google Scholar 

  94. Schubbert, S. et al. Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood 106, 311–317 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Araki, T. et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nature Med. 10, 849–857 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Niihori, T. et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J. Hum. Genet. 50, 192–202 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Chan, R. J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  99. Su, J., Muranjan, M. & Sap, J. Receptor protein tyrosine phosphatase α activates Src-family kinases and controls integrin-mediated responses in fibroblasts. Curr. Biol. 9, 505–511 (1999).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  101. Tabiti, K., Smith, D. R., Goh, H. S. & Pallen, C. J. Increased mRNA expression of the receptor-like protein tyrosine phosphatase α in late stage colon carcinomas. Cancer Lett. 93, 239–248 (1995).

    Article  CAS  PubMed  Google Scholar 

  102. Ardini, E. et al. Expression of protein tyrosine phosphatase α (RPTPα) in human breast cancer correlates with low tumor grade, and inhibits tumor cell growth in vitro and in vivo. Oncogene 19, 4979–4987 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Elson, A. Protein tyrosine phosphatase epsilon increases the risk of mammary hyperplasia and mammary tumors in transgenic mice. Oncogene 18, 7535–7542 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Gil-Henn, H. & Elson, A. Tyrosine phosphatase-epsilon activates Src and supports the transformed phenotype of Neu-induced mammary tumor cells. J. Biol. Chem. 278, 15579–15586 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Kroll, J. & Waltenberger, J. The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J. Biol. Chem. 272, 32521–32527 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Seo, D. W. et al. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114, 171–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Guo, D. Q. et al. Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. J. Biol. Chem. 275, 11216–11221 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Fachinger, G., Deutsch, U. & Risau, W. Functional interaction of vascular endothelial-protein-tyrosine phosphatase with the angiopoietin receptor Tie-2. Oncogene 18, 5948–53 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Lambeng, N. et al. Vascular endothelial-cadherin tyrosine phosphorylation in angiogenic and quiescent adult tissues. Circ. Res. 96, 384–391 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Waltenberger, J., Mayr, U., Pentz, S. & Hombach, V. Functional upregulation of the vascular endothelial growth factor receptor KDR by hypoxia. Circulation 94, 1647–1654 (1996).

    Article  CAS  PubMed  Google Scholar 

  111. Soeda, S. et al. An attempt to promote neo-vascularization by employing a newly synthesized inhibitor of protein tyrosine phosphatase. FEBS Lett. 524, 54–58 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Carr, A. N. et al. Tyrosine phosphatase inhibition augments collateral blood flow in a rat model of peripheral vascular disease. Am. J. Physiol. Heart Circ. Physiol. 287, H268–H276 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Eichmann, A., Le Noble, F., Autiero, M. & Carmeliet, P. Guidance of vascular and neural network formation. Curr. Opin. Neurobiol. 15, 108–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Klagsbrun, M. & Eichmann, A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev. 16, 535–548 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Johnson, K. G. & Van Vactor, D. Receptor protein tyrosine phosphatases in nervous system development. Physiol. Rev. 83, 1–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Chagnon, M. J., Uetani, N. & Tremblay, M. L. Functional significance of the LAR receptor protein tyrosine phosphatase family in development and diseases. Biochem. Cell Biol. 82, 664–675 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Miao, H., Burnett, E., Kinch, M., Simon, E. & Wang, B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nature Cell Biol. 2, 62–69 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. van Huijsduijnen, R. H., Bombrun, A. & Swinnen, D. Selecting protein tyrosine phosphatases as drug targets. Drug Discov. Today 7, 1013–1019 (2002).

    Article  Google Scholar 

  119. Bialy, L. & Waldmann, H. Inhibitors of protein tyrosine phosphatases: next-generation drugs? Angew Chem. Int. Ed. Engl. 44, 3814–3839 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Johnson, T. O., Ermolieff, J. & Jirousek, M. R. Protein tyrosine phosphatase 1B inhibitors for diabetes. Nature Rev. Drug Discov. 1, 696–709 (2002).

    Article  CAS  Google Scholar 

  121. Liang, F., Lee, S. Y., Liang, J., Lawrence, D. S. & Zhang, Z. Y. The role of protein-tyrosine phosphatase 1B in integrin signaling. J. Biol. Chem. 280, 24857–24863 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Liu, G. et al. Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor. J. Med. Chem. 46, 4232–4235 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Lund, I. K. et al. Structure-based design of selective and potent inhibitors of protein-tyrosine phosphatase β. J. Biol. Chem. 279, 24226–24235 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Imhof, D. et al. Design and biological evaluation of linear and cyclic phosphopeptide ligands of the N-terminal SH2 domain of protein tyrosine phosphatase SHP-1. J. Med. Chem. 48, 1528–1539 (2005). Modification of a natural phosphopeptide ligand of the N-terminal SH2 domain of SHP1 identified cyclic derivatives which bound with high affinity to the domain, but only poorly activated SHP1. Such ligands represent a novel class of inhibitors for the SH-domain PTPs that might be developed into novel types of drugs.

    Article  CAS  PubMed  Google Scholar 

  125. Tonks, N. K. Redox redux: revisiting PTPs and the control of cell signaling. Cell 121, 667–670 (2005).

    Article  CAS  PubMed  Google Scholar 

  126. Rhee, S. G. et al. Intracellular messenger function of hydrogen peroxide and its regulation by peroxiredoxins. Curr. Opin. Cell Biol. 17, 183–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor. Nature Med. 11, 1306–1313 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Dube, N. et al. Genetic ablation of protein tyrosine phosphatase 1B accelerates lymphomagenesis of p53-null mice through the regulation of B-cell development. Cancer Res. 65, 10088–10095 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Denu, J. M. & Tanner, K. G. Specific and reversible inactivation of protein tyrosine phosphatases by hydrogen peroxide: evidence for a sulfenic acid intermediate and implications for redox regulation. Biochemistry 37, 5633–5642 (1998). First chemical analysis of the PTP reversible oxidation state evoked by mild H 2 O 2 treatment.

    Article  CAS  PubMed  Google Scholar 

  130. Salmeen, A. et al. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature 423, 769–773 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Barrett, W. C. et al. Regulation of PTP1B via glutathionylation of the active site cysteine 215. Biochemistry 38, 6699–6705 (1999).

    Article  CAS  PubMed  Google Scholar 

  132. Barrett, D. M. et al. Inhibition of protein-tyrosine phosphatases by mild oxidative stresses is dependent on S-nitrosylation. J. Biol. Chem. 280, 14453–14461 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Meng, T. C., Fukada, T. & Tonks, N. K. Reversible oxidation and inactivation of protein tyrosine phosphatases in vivo. Mol. Cell 9, 387–399 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. & Finkel, T. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science 270, 296–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  135. Lee, S. R., Kwon, K. S., Kim, S. R. & Rhee, S. G. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J. Biol. Chem. 273, 15366–15372 (1998). First demonstration that reversible PTP oxidation occurs in intact cells as a consequence of growth factor stimulation.

    Article  CAS  PubMed  Google Scholar 

  136. Mahadev, K., Zilbering, A., Zhu, L. & Goldstein, B. J. Insulin-stimulated hydrogen peroxide reversibly inhibits protein-tyrosine phosphatase 1b in vivo and enhances the early insulin action cascade. J. Biol. Chem. 276, 21938–21942 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Singh, D. K. et al. The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal. Cell 121, 281–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  138. Gross, S. et al. Inactivation of protein-tyrosine phosphatases as mechanism of UV-induced signal transduction. J. Biol. Chem. 274, 26378–26386 (1999).

    Article  CAS  PubMed  Google Scholar 

  139. Persson, C. et al. Preferential oxidation of the second phosphatase domain of receptor-like PTP-α revealed by an antibody against oxidized protein tyrosine phosphatases. Proc. Natl Acad. Sci. USA 101, 1886–1891 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Choi, M. H. et al. Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 435, 347–353 (2005).

    Article  CAS  PubMed  Google Scholar 

  141. Groen, A. et al. Differential oxidation of protein-tyrosine phosphatases. J. Biol. Chem. 280, 10298–10304 (2005).

    Article  CAS  PubMed  Google Scholar 

  142. Elson, A. & Leder, P. Protein-tyrosine phosphatase ε. An isoform specifically expressed in mouse mammary tumors initiated by v-Ha-ras or neu. J. Biol. Chem. 270, 26116–26122 (1995).

    Article  CAS  PubMed  Google Scholar 

  143. Matozaki, T. et al. Molecular cloning of a human transmembrane-type protein tyrosine phosphatase and its expression in gastrointestinal cancers. J. Biol. Chem. 269, 2075–2081 (1994).

    Article  CAS  PubMed  Google Scholar 

  144. Noguchi, T. et al. Inhibition of cell growth and spreading by stomach cancer-associated protein-tyrosine phosphatase-1 (SAP-1) through dephosphorylation of p130cas. J. Biol. Chem. 276, 15216–15224 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Takada, T. et al. Induction of apoptosis by stomach cancer-associated protein-tyrosine phosphatase-1. J. Biol. Chem. 277, 34359–34366 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. Konishi, N. et al. Overexpression of leucocyte common antigen (LAR) P-subunit in thyroid carcinomas. Br. J. Cancer 88, 1223–1228 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Kulas, D. T., Goldstein, B. J. & Mooney, R. A. The transmembrane protein-tyrosine phosphatase LAR modulates signaling by multiple receptor tyrosine kinases. J. Biol. Chem. 271, 748–754 (1996).

    Article  CAS  PubMed  Google Scholar 

  148. Levea, C. M., McGary, C. T., Symons, J. R. & Mooney, R. A. PTP LAR expression compared to prognostic indices in metastatic and non-metastatic breast cancer. Breast Cancer Res. Treat. 64, 221–228 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Bjorge, J. D., Pang, A. & Fujita, D. J. 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. J. Biol. Chem. 275, 41439–41446 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. Wiener, J. R. et al. Overexpression of the protein tyrosine phosphatase PTP1B in human breast cancer: association with p185c-erbB-2 protein expression. J. Natl Cancer Inst. 86, 372–378 (1994).

    Article  CAS  PubMed  Google Scholar 

  151. Dube, N., Cheng, A. & Tremblay, M. L. The role of protein tyrosine phosphatase 1B in Ras signaling. Proc. Natl Acad. Sci. USA 101, 1834–1839 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Buckley, D. A., Cheng, A., Kiely, P. A., Tremblay, M. L. & O'Connor, R. Regulation of insulin-like growth factor type I (IGF-I) receptor kinase activity by protein tyrosine phosphatase 1B (PTP-1B) and enhanced IGF-I-mediated suppression of apoptosis and motility in PTP-1B-deficient fibroblasts. Mol. Cell. Biol. 22, 1998–2010 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Somani, A. K., Bignon, J. S., Mills, G. B., Siminovitch, K. A. & Branch, D. R. Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 272, 21113–21119 (1997).

    Article  CAS  PubMed  Google Scholar 

  154. Krautwald, S., Buscher, D., Kummer, V., Buder, S. & Baccarini, M. Involvement of the protein tyrosine phosphatase SHP-1 in Ras-mediated activation of the mitogen-activated protein kinase pathway. Mol. Cell. Biol. 16, 5955–5963 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Yip, S. S. et al. Up-regulation of the protein tyrosine phosphatase SHP-1 in human breast cancer and correlation with GRB2 expression. Int. J. Cancer 88, 363–368 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Zanke, B. et al. A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome 1q32.1. Leukemia 8, 236–244 (1994).

    CAS  PubMed  Google Scholar 

  157. Saxena, M., Williams, S., Tasken, K. & Mustelin, T. Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. Nature Cell Biol. 1, 305–310 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Work in the authors' laboratories is supported by grants from the Swedish Cancer Society (Cancerfonden) the Deutsche Krebshilfe (F.D.B.) and Karolinska Institutet (A.Ö.) the Swedish Research Council (C.H and A.Ö.), the Deutsche Forschungsgemeinschaft (F.D.B.), the Deutsche Krebshilfe (F.D.B.), and the German Ministry for Education and Research (F.D.B.). We are grateful to the colleagues mentioned in the text for sharing with us their unpublished results, and to A. Uecker and C. H. Heldin for critical reading of the manuscript.

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Box: Selected inhibitors for protein-tyrosine phosphatases (PDF 189 kb)

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DATABASES

National Cancer Institute

ALL

AML

breast cancer

colorectal cancer

lung cancer

lymphomas

thyroid cancer

OMIM

Noonan syndrome

FURTHER INFORMATION

Arne Östman's home page

Carina Hellberg's home page

Entry for PTPN11 in The Human Gene Mutation Database, Cardiff

Frank D. Böhmer's home page

GeneCards

InterPro

Novo Nordisk Science PTPs

Pfam database of protein families and hidden Markov models

Phosphobase

PTP resource

Uniprot

Glossary

Immunoglobulin-like domain

Protein domain of approximately 100 amino-acids that was originally identified in antibodies. Structural features include 7–10 β–strands and an internal disulphide bridge. One or more of these domains commonly occur in the extracellular parts of growth-factor receptors and other transmembrane cell surface proteins, where they are involved in protein–protein interactions.

Fibronectin type III domain

Protein domain with structural similarities to immunoglobulin-like domains, but lacking the internal disulphide. This domain is found in extracellular-matrix proteins, cell-surface receptors and enzymes, and often contains surface-exposed stretches of amino acids that are involved in protein–protein interactions, such as the prototypical RGD sequence in fibronectin that mediates integrin binding.

K M

The Michaelis constant, KM, is defined as the substrate concentration at which half the maximum reaction velocity is attained. A small KM indicates that the enzyme requires only a small amount of substrate to become saturated, and a large KM indicates the need for high substrate concentrations to achieve maximum reaction velocity. The substrate with the lowest KM on which the enzyme acts is frequently assumed to be the enzyme's natural substrate.

Substrate-trapping PTP

Variants of PTPs that have been experimentally altered so that they still bind their substrates but do not dephosphorylate them, which allows the identification of PTP substrates. This is most commonly achieved by substituting the active site cysteine residue with a serine (C/S mutant), or by substituting the conserved aspartic acid residue in the active site with an alanine residue (D/A mutant).

FAB-M5

M5 subgroup of acute myeloid leukaemia of the French–American–British group-classification system.

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Östman, A., Hellberg, C. & Böhmer, F. Protein-tyrosine phosphatases and cancer. Nat Rev Cancer 6, 307–320 (2006). https://doi.org/10.1038/nrc1837

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