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  • Review Article
  • Published:

Protein tyrosine phosphatases and the immune response

Nature Reviews Immunology volume 5, pages 43–57 (2005)Cite this article

Key Points

  • This review discusses the many protein tyrosine phosphatases (PTPs) that are expressed by T cells and our current understanding of their biology and roles in human disease.

  • T cells express ∼50–60 different PTPs.

  • CD45, SHP2 (SRC homology 2 (SH2)-domain-containing PTP 2), and LMPTP (low-molecular-weight PTP) mainly have positive roles in signalling through the T-cell receptor.

  • SHP1, LYP (lymphoid-specific PTP), PTP-PEST (PTP with PEST (proline-, glutamic-acid-, serine- and threonine-rich) domains), PTP-HSCF (PTP haematopoietic stem-cell fraction) and PTPH1 (PTP H1) are potent negative regulators of T-cell activation.

  • HEPTP (haematopoietic PTP) and many dual-specific PTPs dephosphorylate mitogen-activated protein kinases.

  • PTP-MEG2 (PTP megakaryocyte 2) regulates secretory vesicles.

  • A polymorphism in LYP is associated with autoimmune disease.

  • Some pathogens use PTPs for immune evasion.

Abstract

Reversible tyrosine phosphorylation of proteins is a key regulatory mechanism for numerous important aspects of eukaryotic physiology and is catalysed by kinases and phosphatases. Together, cells of the immune system express at least half of the 107 protein tyrosine phosphatase (PTP) genes in the human genome, most of which encode multidomain proteins that contain protein- and phospholipid-interaction domains. Here, we discuss the diverse but specific, and important, roles that PTPs have in immune cells, focusing mainly on T and B cells, and we highlight recent evidence that even subtle alterations in PTPs can cause immune dysfunction and human disease.

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Figure 1: The phosphorylation 'equation'.
Figure 2: Protein tyrosine phosphatases in lymphocytes.
Figure 3: CD45 in the dephosphorylation of SRC- and SYK-family PTKs, and modes of regulation of CD45.
Figure 4: Role of PTP-PEST in control of integrin and/or cytoskeleton interactions in the immune synapse.
Figure 5: Proposed functions of PTPH1 in T cells.
Figure 6: The circuitry of MAPK regulation by multiple PTPs.
Figure 7: Schematic model for the function of PTP-MEG2 in secretory-vesicle fusion with the plasma membrane.

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References

  1. Hunter, T. & Sefton, B. M. Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Proc. Natl Acad. Sci. USA 77, 1311–1315 (1980).

    Article  CAS  PubMed  Google Scholar 

  2. Mustelin, T., Abraham, R. T., Rudd, C. E., Alonso, A. & Merlo, J. J. Protein tyrosine phosphorylation in T cell signaling. Front. Biosci. 7, d918–d969 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Mustelin, T. Src Family Tyrosine Kinases in Leukocytes 1–155 (Landes, Austin, 1994).

    Google Scholar 

  4. Mustelin, T., Rahmouni, S., Bottini, N. & Alonso, A. Role of protein tyrosine phosphatases in T cell activation. Immunol. Rev. 191, 139–147 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Mustelin, T. & Taskén, K. Positive and negative regulation of T cell activation through kinases and phosphatases. Biochem. J. 371, 15–27 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alonso, A. et al. Protein tyrosine phosphatases in the human genome. Cell 117, 699–711 (2004). This paper reviews the entire complement of 107 PTP genes in the human genome.

    Article  CAS  PubMed  Google Scholar 

  7. Andersen, J. N. et al. A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage. FASEB J. 18, 8–13 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Samelson, L. E., Patel, M. D., Weissman, A. M., Harford, J. B. & Klausner, R. D. Antigen activation of murine T cells induces tyrosine phosphorylation of a polypeptide associated with the T cell antigen receptor. Cell 46, 1083–1090 (1986).

    Article  CAS  PubMed  Google Scholar 

  9. Hsi, E. D. et al. T cell activation induces rapid tyrosine phosphorylation of a limited number of cellular substrates. J. Biol. Chem. 264, 10836–10842 (1989).

    CAS  PubMed  Google Scholar 

  10. Mustelin, T., Coggeshall, K. M., Isakov, N. & Altman, A. Tyrosine phosphorylation is required for T cell antigen receptor-mediated activation of phospholipase C. Science 247, 1584–1587 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Saltzman, E. M., Thom, R. R. & Casnellie, J. E. Activation of a tyrosine protein kinase is an early event in the stimulation of T lymphocytes by interleukin-2. J. Biol. Chem. 263, 6956–6959 (1988).

    CAS  PubMed  Google Scholar 

  12. Gold, M. R., Matsuuchi, L., Kelly, R. B. & DeFranco, A. L. Tyrosine phosphorylation of components of the B cell antigen receptors following receptor crosslinking. Proc. Natl Acad. Sci. USA 88, 3436–3440 (1991).

    Article  CAS  PubMed  Google Scholar 

  13. Mustelin, T. T cell antigen receptor signaling: three families of tyrosine kinases and a phosphatase. Immunity 1, 351–356 (1994).

    Article  CAS  PubMed  Google Scholar 

  14. Weiss, A. T cell antigen receptor signal transduction: a tale of tails and cytoplasmic protein-tyrosine kinases. Cell 73, 209–212 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Mustelin, T. et al. Protein tyrosine phosphatases. Front. Biosci. 7, 85–142 (2002).

    Article  Google Scholar 

  16. Iivanainen, A. V., Lindqvist, C., Mustelin, T. & Andersson, L. C. Phosphotyrosine phosphatases are involved in reversion of T lymphoblastic proliferation. Eur. J. Immunol. 20, 2509–2512 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. O'Shea, J. J., McVicar, D. W., Bailey, T. L., Burns, C. & Smyth, M. J. Activation of human peripheral blood T lymphocytes by pharmacological induction of protein-tyrosine phosphorylation. Proc. Natl Acad. Sci. USA 89, 10306–10310 (1992).

    Article  CAS  PubMed  Google Scholar 

  18. Secrist, J. P., Burns, L. A., Karnitz, L., Koretzky, G. A. & Abraham, R. T. Stimulatory effects of the protein tyrosine phosphatase inhibitor, pervanadate, on T-cell activation events. J. Biol. Chem. 268, 5886–5893 (1993). References 17 and 18 were the first papers to show that acute inhibition of PTPs is sufficient to cause T-cell activation.

    CAS  PubMed  Google Scholar 

  19. Oetken., C. et al. Phenylarsine oxide augments tyrosine phosphorylation in hematopoietic cells. Eur. J. Haematol. 49, 208–214 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Earp, H. S., Austin, K. S., Buessow, S. C. & Gillespie, G. Y. Membranes from T and B lymphocytes have different patterns of tyrosine phosphorylation. Proc. Natl Acad. Sci. USA 81, 2347–2351 (1984).

    Article  CAS  PubMed  Google Scholar 

  21. Manning, G., Whyte, D. B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Gjörloff-Wingren, A. et al. Subcellular localization of intracellular protein tyrosine phosphatases in T cells. Eur. J. Immunol. 30, 2412–2421 (2000).

    Article  PubMed  Google Scholar 

  23. Gjörloff-Wingren, A., Saxena, M., Williams, S., Hammi, D. & Mustelin, T. Characterization of TCR-induced receptor-proximal signaling events negatively regulated by the protein tyrosine phosphatase PEP. Eur. J. Immunol. 29, 3845–3854 (1999).

    Article  PubMed  Google Scholar 

  24. Han, S., Williams, S. & Mustelin, T. Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling. Eur. J. Immunol. 30, 1318–1325 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Bottini, N. et al. Activation of ZAP-70 through specific dephosphorylation at the inhibitory Tyr-292 by the low molecular weight phosphotyrosine phosphatase (LMPTP). J. Biol. Chem. 277, 24220–24224 (2002).

    Article  CAS  PubMed  Google Scholar 

  26. Townley, R., Shen, S. -H., Banville, D. & Ramachandran, C. Inhibition of the activity of protein tyrosine phosphatase 1C by its SH2 domains. Biochemistry 32, 13414–13418 (1993).

    Article  CAS  PubMed  Google Scholar 

  27. Pei, D., Lorenz, U., Klingmüller, U., Neel, B. G. & Walsh, C. T. Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology 2 domains. Biochemistry 33, 15483–15493 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. Zhao, Z., Larocque, R., Ho, W. -T., Fischer, E. H. & Shen, S. -H. Purification and characterization of PTP2C, a widely distributed protein tyrosine phosphatase containing two SH2 domains. J. Biol. Chem. 269, 8780–8785 (1994).

    CAS  PubMed  Google Scholar 

  29. Pei, D., Wang, J. & Walsh, C. T. Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase SH-PTP1. Proc. Natl Acad. Sci. USA 93, 1141–1145 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. 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 

  31. Alonso, A. et al. VHY, a novel, myristoylated testis-restricted dual specificity protein phosphatase related to VHX. J. Biol. Chem. 279, 32586–32591 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Mustelin, T., Coggeshall, K. M. & Altman, A. Rapid activation of the T cell tyrosine protein kinase pp56lck by the CD45 phosphotyrosine phosphatase. Proc. Natl Acad. Sci. USA 86, 6302–6306 (1989). This paper was the first to show that the PTP CD45 can activate the PTK LCK by direct dephosphorylation.

    Article  CAS  PubMed  Google Scholar 

  33. Mustelin, T. & Altman, A. Dephosphorylation and activation of the T cell tyrosine kinase pp56lck by the leukocyte common antigen (CD45). Oncogene 5, 809–813 (1990).

    CAS  PubMed  Google Scholar 

  34. Mustelin, T. et al. Regulation of the p59fyn protein tyrosine kinase by the CD45 phosphotyrosine phosphatase. Eur. J. Immunol. 22, 1173–1178 (1992).

    Article  CAS  PubMed  Google Scholar 

  35. Brockdorff, J., Williams, S., Couture, C. & Mustelin, T. Dephosphorylation of ZAP-70 and inhibition of T cell activation by activated SHP1. Eur. J. Immunol. 29, 2539–2550 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Mustelin, T. & Hunter, T. Meeting at mitosis: cell cycle-specific regulation of c-Src by RPTPα. Sci. STKE [online] 2002, PE3 (2002).

    PubMed  Google Scholar 

  38. 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 

  39. van Montfort, R. L. M., Congreve, M., Tisi, D., Carr, R. & Jhoti, H. Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B. Nature 423, 773–777 (2003). References 38 and 39 report the crystallization of oxidized PTP1B and reveal that oxidation of the catalytic cysteine residue results in the formation of a sulphenyl amide moiety, which is resistant to further oxidation (which would be irreversible) and can be reduced back to the catalytically active free cysteinyl.

    Article  CAS  PubMed  Google Scholar 

  40. Meng, T. -C., Buckley, D. A., Galic, S., Tiganis, T. & Tonks, N. K. Regulation of insulin signaling through reversible oxidation of the protein-tyrosine phosphatases TC45 and PTP1B. J. Biol. Chem. 279, 37716–37725 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Wang, X. et al. The tumor suppressor PTEN regulates T cell survival and antigen receptor signaling by acting as a phosphatidylinositol 3-phosphatase. J. Immunol. 164, 1934–1939 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Qu, C. -K., Nguyen, S., Chen, J. & Feng, G. -S. Requirement of Shp-2 tyrosine phosphatase in lymphoid and hematopoietic cell development. Blood 97, 911–914 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Kishihara, K. et al. Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell 74, 143–156 (1993).

    Article  CAS  PubMed  Google Scholar 

  44. Gronda, M., Arab, S., Iafrate, B., Suzuki, H. & Zanke, B. Hematopoietic protein tyrosine phosphatase suppresses extracellular stimulus-regulated kinase activation. Mol. Cell. Biol. 21, 6851–6858 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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 

  46. You-Ten, K. E. et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J. Exp. Med. 186, 683–693 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Charbonneau, H., Tonks, N. K., Walsh, K. A. & Fischer, E. H. The leukocyte common antigen (CD45): a putative receptor-linked protein tyrosine phosphatase. Proc. Natl Acad. Sci. USA 85, 7182–7186 (1988).

    Article  CAS  PubMed  Google Scholar 

  48. Tonks, N. K., Charbonneau, H., Diltz, C. D., Fischer, E. H. & Walsh, K. A. Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase. Biochemistry 27, 8695–8701 (1988). Although reference 47 was the first to report that CD45 has a high degree of homology with the first identified PTP, PTP1B, and therefore was likely to be a PTP itself, reference 48 directly showed this by providing evidence that CD45 has tyrosine-phosphatase activity.

    Article  CAS  PubMed  Google Scholar 

  49. Pingel, J. T. & Thomas, M. L. Evidence that the leukocyte-common antigen is required for antigen-induced T lymphocyte proliferation. Cell 58, 1055–1065 (1989). This paper was the first to show that expression of CD45 is important for T-cell activation.

    Article  CAS  PubMed  Google Scholar 

  50. Hermiston, M. L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  51. Koretzky, G. A., Picus, J., Thomas, M. L. & Weiss, A. Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway. Nature 346, 66–68 (1990).

    Article  CAS  PubMed  Google Scholar 

  52. Volarevic, S. et al. The CD45 tyrosine phosphatase regulates phosphotyrosine homeostasis and its loss reveals a novel pattern of late T cell receptor-induced Ca2+ oscillations. J. Exp. Med. 176, 835–844 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. Ostergaard, H. L. et al. Expression of CD45 alters phosphorylation of the Lck-encoded tyrosine protein kinase in murine lymphoma T-cell lines. Proc. Natl Acad. Sci. USA 86, 8959–8963 (1989).

    Article  CAS  PubMed  Google Scholar 

  54. Seavitt, J. et al. Expression of the p56lck Y505F mutation in CD45-deficient mice rescues thymocyte development. Mol. Cell. Biol. 19, 4200–4208 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mustelin, T. & Burn, P. Regulation of src family tyrosine kinases in lymphocytes. Trends Biochem. Sci. 18, 215–220 (1993).

    Article  CAS  PubMed  Google Scholar 

  56. Davidson, D., Bakinowski, M., Thomas, M. L., Horejsi, V. & Veillette, A. Phosphorylation-dependent regulation of T cell activation by PAG/Cbp, a lipid raft-associated transmembrane adaptor. Mol. Cell. Biol. 23, 2017–2025 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kawabuchi, M. et al. Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404, 999–1003 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Brdicka, T. et al. Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adapter protein, binds the protein tyrosine kinase Csk and is involved in regulation of T cell activation. J. Exp. Med. 191, 1591–1604 (2000).

    Article  CAS  Google Scholar 

  59. Torgersen, K. M. et al. Release from tonic inhibition of T cell activation through transient displacement of C-terminal Src kinase (Csk) from lipid rafts. J. Biol. Chem. 276, 29313–29318 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Vang, T., Abrahamsen, H., Myklebust, S., Horejsi, V. & Taskén, K. Combined spatial and enzymatic regulation of Csk by cAMP and protein kinase A inhibits T cell receptor signaling. J. Biol. Chem. 278, 17597–17604 (2003).

    Article  CAS  PubMed  Google Scholar 

  61. Vang, T. et al. Knockdown of C-terminal Src kinase by siRNA-mediated RNA interference augments T cell receptor signaling in mature T cells. Eur. J. Immunol. 34, 2191–2199 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Zhang, S. Q. et al. Shp2 regulates Src family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell 13, 341–351 (2004).

    Article  PubMed  Google Scholar 

  63. Ledbetter, J. A., Tonks, N. K., Fischer, E. H. & Clark, E. A. CD45 regulates signal transduction and lymphocyte activation by specific association with receptor molecules on T or B cells. Proc. Natl Acad. Sci. USA 85, 8628–8633 (1988).

    Article  CAS  PubMed  Google Scholar 

  64. Kiener, P. A. & Mittler, R. S. CD45-protein tyrosine phosphatase cross-linking inhibits T cell receptor CD3-mediated activation in human T cells. J. Immunol. 143, 23–28 (1989).

    CAS  PubMed  Google Scholar 

  65. Ostergaard, H. L. & Trowbridge, I. S. Coclustering of CD45 with CD4 or CD8 alters the phosphorylation and kinase activity of p56lck. J. Exp. Med. 172, 347–350 (1990).

    Article  CAS  PubMed  Google Scholar 

  66. Volarevic, S. et al. Regulation of TCR signaling by CD45 lacking transmembrane and extracellular domains. Science 260, 541–544 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Furukawa, T., Itoh, M., Krueger, N. X., Streuli, M. & Saito, H. Specific interaction of the CD45 protein-tyrosine phosphatase with tyrosine phosphorylated CD3 ζ chain. Proc. Natl Acad. Sci. USA 91, 10928–10932 (1994).

    Article  CAS  PubMed  Google Scholar 

  68. Mustelin, T. et al. Regulation of the p70zap tyrosine protein kinase by the CD45 phosphotyrosine phosphatase in T cells. Eur. J. Immunol. 25, 942–946 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. D'Oro, U., Sakaguchi, K., Appella, E. & Ashwell, J. D. Mutational analysis of Lck in CD45-negative T cells: dominant role of tyrosine 394 phosphorylation in kinase activity. Mol. Cell. Biol. 16, 4996–5003 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Katagiri, T. et al. CD45 negatively regulates Lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells. J. Immunol. 163, 1321–1330 (1999).

    CAS  PubMed  Google Scholar 

  71. He, X., Woodford-Thomas, T. A., Johnson, K. G., Shah, D. D. & Thomas, M. L. Targeting of CD45 protein tyrosine phosphatase activity to lipid microdomains on the T cell surface inhibits TCR signaling. Eur. J. Immunol. 32, 2578–2584 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Montixi, C. et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 17, 5334–5340 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Edmonds, S. D. & Ostergaard, H. L. Dynamic association of CD45 with detergent-insoluble microdomains in T lymphocytes. J. Immunol. 169, 5036–5046 (2002).

    Article  PubMed  Google Scholar 

  74. Irles, C. et al. CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling. Nature Immunol. 4, 189–192 (2003).

    Article  CAS  Google Scholar 

  75. Freiberg, B. A. et al. Staging and resetting T cell activation in SMACs. Nature Immunol. 3, 911–916 (2002).

    Article  CAS  Google Scholar 

  76. 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 

  77. Majeti, R. et al. An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103, 1059–1069 (2000).

    Article  CAS  PubMed  Google Scholar 

  78. Xu, Z. & Weiss, A. Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nature Immunol. 3, 764–770 (2002).

    Article  CAS  Google Scholar 

  79. Dianzani, U. et al. Isoform-specific associations of CD45 with accessory molecules in human T lymphocytes. Eur. J. Immunol. 22, 365–371 (1992).

    Article  CAS  PubMed  Google Scholar 

  80. Matthews, R. J., Bowne, D. B., Flores, E. & Thomas, M. L. Characterization of hematopoietic intracellular protein tyrosine phosphatases: description of a phosphatase containing an SH2 domain and another enriched in proline-, glutamic acid-, serine-, and threonine-rich sequences. Mol. Cell. Biol. 12, 2396–2405 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Vivier, E. & Daëron, M. Immunoreceptor tyrosine-based inhibition motifs. Immunol. Today 18, 286–291 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Mustelin, T. et al. T cell activation: the coming of the phosphatases. Front. Biosci. 3, D1060–D1096 (1998).

    Article  CAS  PubMed  Google Scholar 

  83. Chiang, G. G. & Sefton, B. M. Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 276, 23173–23179 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Raab, M. & Rudd, C. E. Hematopoietic cell phosphatase (HCP) regulates p56LCK phosphorylation and ZAP-70 binding to T cell receptor ζ chain. Biochem. Biophys. Res. Commun. 222, 50–57 (1996).

    Article  CAS  PubMed  Google Scholar 

  85. Tsui, H. W., Siminovitch, K. A., de Souza, L. & Tsui, F. W. L. Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nature Genet. 4, 124–129 (1993).

    Article  CAS  PubMed  Google Scholar 

  86. Shultz, L. D. & Green, M. C. Motheaten, an immunodeficient mutant of the mouse. II. Depressed immune competence and elevated serum immunoglobulins. J. Immunol. 116, 936–943 (1976).

    CAS  PubMed  Google Scholar 

  87. Pani, G., Fischer, K. -D., Mlinaric-Rascan, I. & Siminovitch, K. A. Signaling capacity of the T cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase. J. Exp. Med. 184, 839–852 (1996).

    Article  CAS  PubMed  Google Scholar 

  88. Sathish, J. G. et al. CD22 is a functional ligand for SHP1 in primary T cells. J. Biol. Chem. 279, 47783–47791 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Roy, G., Matthews, J., Woodford-Thomas, T. & Thomas, M. L. The function of protein tyrosine phosphatases in immune regulation. Adv. Protein Phosphatases 9, 121–138 (1995).

    CAS  Google Scholar 

  90. Cloutier, J. -F. & Veillette, A. Association of inhibitory tyrosine protein kinase p50csk with protein tyrosine phosphatase PEP in T cells and other hemopoietic cells. EMBO J. 15, 4909–4918 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cloutier, J. -F. & Veillette, A. Cooperative inhibition of T-cell antigen receptor signaling by a complex between a kinase and a phosphatase. J. Exp. Med. 189, 111–121 (1999). References 90 and 91 document the high-stoichiometry association between the PEP phosphatase and the inhibitory kinase CSK. The papers conclude that the interaction between the two enzymes helps PEP reach its SRC-family PTK targets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cohen, S., Dadi, H., Shaoul, E., Sharfe, N. & Roifman, C. M. Cloning and characterization of a lymphoid-specific, inducible human protein tyrosine phosphatase, Lyp. Blood 93, 2013–2024 (1999).

    CAS  PubMed  Google Scholar 

  93. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type 1 diabetes. Nature Genet. 36, 337–338 (2004). This paper reports that a single amino-acid substitution at position 620 of the human PTP LYP is sufficient to cause a marked increase in the incidence of type 1 diabetes. This increase correlates with a loss of association with CSK.

    Article  CAS  PubMed  Google Scholar 

  94. Begovich, A. B. et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 75, 330–337 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kyogoku, C. et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am. J. Hum. Genet. 75, 504–507 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Smyth, D. et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 53, 3020–3023 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Hasegawa, K. et al. PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science 303, 685–689 (2004). This paper describes the defects in T-cell immunity that are found in Pep−/− mice.

    Article  CAS  PubMed  Google Scholar 

  98. Davidson, D., Cloutier, J. F., Gregorieff, A. & Veillette, A. Inhibitory tyrosine protein kinase p50csk is associated with protein-tyrosine phosphatase PTP-PEST in hemopoietic and non-hemopoietic cells. J. Biol. Chem. 272, 23455–23462 (1997).

    Article  CAS  PubMed  Google Scholar 

  99. Wang, B., Lemay, S., Tsai, S. & Veillette, A. SH2 domain-mediated interaction of inhibitory protein tyrosine kinase Csk with protein tyrosine phosphatase-HSCF. Mol. Cell. Biol. 21, 1077–1088 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cote, J. F., Charest, A., Wagner, J. & Tremblay, M. L. Combination of gene targeting and substrate trapping to identify substrates of protein tyrosine phosphatases using PTP-PEST as a model. Biochemistry 37, 13128–13137 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Garton, A. J., Flint, A. J. & Tonks, N. K. Identification of p130cas as a substrate for the cytosolic protein tyrosine phosphatase PTP-PEST. Mol. Cell. Biol. 16, 6408–6418 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Davidson, D. & Veillette, A. PTP-PEST, a scaffold protein tyrosine phosphatase, negatively regulates lymphocyte activation by targeting a unique set of substrates. EMBO J. 20, 3414–3426 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Spencer, S. et al. PSTPIP: a tyrosine phosphorylated cleavage furrow-associated protein that is a substrate for a PEST tyrosine phosphatase. J. Cell Biol. 138, 845–860 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sozio, M. S. et al. PTPH1 is a predominant protein-tyrosine phosphatase capable of interacting with and dephosphorylating the T cell receptor ζ subunit. J. Biol. Chem. 279, 7760–7768 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Zhang, S. -H., Liu, J., Kobayashi, R. & Tonks, N. K. Identification of the cell cycle regulator VCP (p97/CDC48) as a substrate of the band 4.1-related protein-tyrosine phosphatase PTPH1. J. Biol. Chem. 274, 17806–17812 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Egerton, M. et al. VCP, the mammalian homolog of CDC48, is tyrosine phosphorylated in response to T cell antigen receptor activation. EMBO J. 11, 3533–3540 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lavoie, C. et al. Tyrosine phosphorylation of p97 regulates transitional endoplasmic reticulum assembly in vitro. Proc. Natl Acad. Sci. USA 97, 13637–13642 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Zheng, Y., Schlondorff, J. & Blobel, C. P. Evidence for regulation of the tumor necrosis factor α-convertase (TACE) by protein-tyrosine phosphatase PTPH1. J. Biol. Chem. 277, 42463–42470 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Tailor, P., Williams, S., Gilman, J., Couture, C. & Mustelin, T. Regulation of the low molecular weight phosphotyrosine phosphatase (LMPTP) by phosphorylation at tyrosines 131 and 132. J. Biol. Chem. 272, 5371–5376 (1997).

    Article  CAS  PubMed  Google Scholar 

  110. Alonso, A., Saxena, M., Williams, S. & Mustelin, T. Inhibitory role for dual-specificity phosphatase VHR in T cell antigen receptor and CD28-induced Erk and Jnk activation. J. Biol. Chem. 276, 4766–4771 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Alonso, A. et al. Tyrosine phosphorylation of VHR phosphatase by ZAP-70. Nature Immunol. 4, 44–48 (2003).

    Article  CAS  Google Scholar 

  112. Saxena, M. & Mustelin, T. Extracellular signals and scores of phosphatases: all roads lead to MAP kinase. Semin. Immunol. 12, 387–396 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Saxena, M., Williams, S., Gilman, J. & Mustelin, T. Negative regulation of T cell antigen receptor signaling by hematopoietic tyrosine phosphatase (HePTP). J. Biol. Chem. 273, 15340–15344 (1998).

    Article  CAS  PubMed  Google Scholar 

  114. Saxena, M., Williams, S., Brockdorff, J., Gilman, J. & Mustelin, T. Inhibition of T cell signaling by MAP kinase-targeted hematopoietic tyrosine phosphatase (HePTP). J. Biol. Chem. 274, 11693–11700 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Saxena, M., Williams, S., Taskén, K. & Mustelin, T. Crosstalk between cAMP-dependent kinase and MAP kinase through hematopoietic protein tyrosine phosphatase (HePTP). Nature Cell Biol. 1, 305–311 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Nika, K. et al. Hematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase in T cells: dynamics and subcellular location. Biochem. J. 378, 335–342 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Klingmüller, U., Lorenz, U., Cantley, L. C., Neel, B. G. & Lodish, H. F. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell 80, 729–738 (1995).

    Article  PubMed  Google Scholar 

  118. Myers, M. P. et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J. Biol. Chem. 276, 47771–47774 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662–5668 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhu, W., Mustelin, T. & David, M. Arginine methylation of STAT1 regulates its dephosphorylation by TcPTP. J. Biol. Chem. 277, 35787–35790 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Wang, X. et al. Enlargement of secretory vesicles by protein tyrosine phosphatase PTP-MEG2 in RBL mast cells and Jurkat T cells. J. Immunol. 168, 4612–4619 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Huynh, H. et al. Homotypic secretory vesicle fusion induced by the protein tyrosine phosphatase MEG2 depends on polyphosphoinositides in T cells. J. Immunol. 171, 6661–6671 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Huynh, H. et al. Control of vesicle fusion by a tyrosine phosphatase. Nature Cell Biol. 6, 831–839 (2004).

    Article  CAS  PubMed  Google Scholar 

  124. Matsushita, M., Tsuchiya, N., Oka, T., Yamane, A. & Tokunaga, K. New variations of human SHP-1. Immunogenetics 49, 577–579 (1999).

    Article  CAS  PubMed  Google Scholar 

  125. Jury, E. C., Kabouridis, P. S., Flores-Borja, F., Mageed, R. A. & Isenberg, D. A. Altered lipid raft-associated signaling and ganglioside expression in T lymphocytes from patients with systemic lupus erythematosus. J. Clin. Invest. 113, 1176–1187 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Tchilian, E. Z. et al. A deletion in the gene encoding the CD45 antigen in a patient with SCID. J. Immunol. 166, 1308–1313 (2001).

    Article  CAS  PubMed  Google Scholar 

  127. Jacobsen, M. et al. A point mutation in PTPRC is associated with the development of multiple sclerosis. Nature Genet. 26, 495–499 (2000).

    Article  CAS  PubMed  Google Scholar 

  128. Barcellos, L. F. et al. PTPRC (CD45) is not associated with the development of multiple sclerosis in U.S. patients. Nature Genet. 29, 23–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Vorechovsky, I. et al. Does 77C→G in PTPRC modify autoimmune disorders linked to the major histocompatibility locus? Nature Genet. 29, 22–23 (2001).

    Article  CAS  PubMed  Google Scholar 

  130. Bottini, N., Bottini, E., Gloria-Bottini, F. & Mustelin, T. Low-molecular-weight protein tyrosine phosphatase and human disease: in search of biochemical mechanisms. Arch. Immunol. Ther. Exp. (Warsz.) 50, 95–104 (2002).

    CAS  Google Scholar 

  131. Bottini, N. et al. Genetic control of serum IgE levels: a study of low molecular weight protein tyrosine phosphatase. Clin. Genet. 63, 228–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  132. Cornelis, G. R. & Wolf-Watz, H. The Yersinia Yop virulon: a bacterial system for subverting eukaryotic cells. Mol. Microbiol. 23, 861–867 (1997).

    Article  CAS  PubMed  Google Scholar 

  133. Andersson, K. et al. YopH of Yersinia pseudotuberculosis interrupts early phosphotyrosine signalling associated with phagocytosis. Mol. Microbiol. 20, 1057–1069 (1996).

    Article  CAS  PubMed  Google Scholar 

  134. Yao, T., Mecsas, J., Healy, J. I., Falkow, S. & Chien, Y. Suppression of T and B lymphocyte activation by a Yersinia pseudotuberculosis virulence factor, YopH. J. Exp. Med. 190, 1343–1350 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Alonso, A. et al. Lck dephosphorylation at Y394 and inhibition of T cell antigen receptor signaling by Yersinia phosphatase YopH. J. Biol. Chem. 279, 4922–4928 (2004). References 134 and 135 show that the phosphatase YopH from Yersinia spp. is a potent inhibitor of T-cell activation. Reference 135 shows that the molecular mechanism of inhibition involves the dephosphorylation of Y394 of LCK, resulting in complete abrogation of signalling through the TCR.

    Article  CAS  PubMed  Google Scholar 

  136. Murli, S., Watson, R. O. & Galan, J. E. Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells. Cell. Microbiol. 3, 795–810 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Singh, R. et al. Disruption of MptpB impairs the ability of Mycobacterium tuberculosis to survive in guinea pigs. Mol. Microbiol. 50, 751–762 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Lazo, J. S. & Wipf, P. Small molecule regulation of phosphatase-dependent cell signaling pathways. Oncol. Res. 13, 347–352 (2003).

    Article  PubMed  Google Scholar 

  139. Liang, F. et al. Aurintricarboxylic acid blocks in vitro and in vivo activity of YopH, an essential virulent factor of Yersinia pestis, the agent of the plague. J. Biol. Chem. 278, 41734–41741 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize for being unable (owing to space limitations) to cite many important contributions made by our colleagues in the field. T.M. is supported by the National Institutes of Health, United States. T.V. is supported by The Norwegian Cancer Society. N.B. is supported by the American Italian Cancer Foundation, United States, and The Litta Foundation, Switzerland.

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  1. Program of Inflammation, Inflammatory and Infectious Disease Center, and Program of Signal Transduction, Cancer Center, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    Tomas Mustelin, Torkel Vang & Nunzio Bottini

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  1. Tomas Mustelin
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Correspondence to Tomas Mustelin.

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DATABASES

Entrez Gene

CD45

CSK

HEPTP

LCK

PTPH1

PTP-MEG2

PTP-PEST

SHP1

ZAP70

Glossary

POLYCLONALLY ACTIVATED

Activation of all T cells by mitogens in an antigen-independent manner.

BLASTOID MORPHOLOGY

The larger size and appearance of an activated T cell.

SRC FAMILY

A group of structurally related cytoplasmic and/or membrane-associated enzymes that are named after the prototypical member, SRC. In haematopoietic cells, SRC kinases — such as LCK, FYN and LYN — are the first protein tyrosine kinases that are activated after stimulation through the immunoreceptors. They phosphorylate ITAMs (immunoreceptor tyrosine-based activation motifs) that are present in the signal-transducing subunits of the immunoreceptors, thereby providing binding sites for SRC homology 2 (SH2)-domain-containing molecules, such as SYK (spleen tyrosine kinase).

SRC HOMOLOGY 2 DOMAIN

(SH2 domain). A protein domain that is commonly found in signal-transduction molecules. It specifically recognizes phosphotyrosine-containing peptide sequences in proteins.

SH3 DOMAIN

(SRC homology 3 domain). A protein domain that is commonly found in signal-transduction molecules. It specifically interacts with certain proline-containing peptides. Classically, it contains either (R/K)XXPXXP or PXXPXR motifs, where X denotes any amino acid.

ERM DOMAIN

A protein–protein interaction domain found in ezrin, radixin and moesin.

N-LINKED CARBOHYDRATES

Sugars that are attached to asparagine residues of proteins.

O-LINKED CARBOHYDRATES

Sugars that are attached to serine and/or threonine residues of proteins.

MYRISTOYLATION

The covalent attachment of a hydrophobic myristoyl group to the amino-terminal glycine residue of a nascent polypeptide.

FARNESYLATION

The covalent addition of farnesyl (15 carbon) isoprenoids to proteins at cysteine residues by farnesyl transferases, which leads to their constitutive association with the plasma membrane.

LIPID RAFT

Area of the plasma membrane that is rich in cholesterol, glycosphingolipids, several signalling proteins (such as SRC kinases, RAS, LAT and PAG) and glycosylphosphatidylinositol-anchored proteins. Also known as glycolipid-enriched membrane domains (GEMs) and detergent-insoluble glycolipid-enriched membranes (DIGs).

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). This is used to measure protein–protein interactions microscopically or by a FACS (fluorescence-activated cell sorter)-based method. Proteins fused to cyan, yellow or red fluorescent proteins are expressed and assessed for interaction by measuring the energy transfer between fluorophores, which can only occur if proteins physically interact. FRET can also be used to examine the activation state of certain proteins if their activation results in specific protein–protein interactions.

cSMAC

(Central supramolecular activation cluster). The central region of the immune synapse.

RNA INTERFERENCE

(RNAi). The use of double-stranded RNAs with sequences that precisely match a given gene to 'knock-down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.

FOCAL ADHESION PLAQUE

The closest contact site of a cell with its environment, which is formed by integrin clustering. The integrins link the extracellular environment to the actin cytoskeleton by a complex assembly of adaptor proteins.

PDZ DOMAIN

(PSD95, DLGA and ZO1 homology domain). A protein domain that is commonly found in signal-transduction molecules. It can interact with different amino-acid motifs that are present at the carboxyl terminus of proteins. PDZ domains can also interact with other PDZ domains, with certain internal peptide sequences and even with lipids.

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Mustelin, T., Vang, T. & Bottini, N. Protein tyrosine phosphatases and the immune response. Nat Rev Immunol 5, 43–57 (2005). https://doi.org/10.1038/nri1530

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