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Biological Validation of the CD45 Tyrosine Phosphatase as a Pharmaceutical Target

  • Chapter
Inhibitors of Protein Kinases and Protein Phosphates

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 167))

Abstract

The CD45 phosphotyrosine phosphatase is expressed on all nucleated haematopoietic cells and plays an important role in regulating immune receptor signalling thresholds. CD45 substrates include Src tyrosine kinase family members, and in T cells both p56lck and p59fyn are substrates. Src kinases such as p56lck have negative regulatory C-terminus Tyr phosphorylation sites that are phosphorylated by the c-Src kinase and dephosphorylated by CD45, thereby switching p56lck into a fully functional mode. Active p56lck, and to a lesser extent p59fyn, are involved in coupling the T cell antigen receptor to the intracellular signalling pathways that lead to T cell development and activation. In CD45-/- mice, the threshold for receptor signalling is high and there are significant defects in thymic development resulting in a greater than 90% reduction in the repertoire of mature peripheral T cells. Those CD45-/- T cells that do exit to the periphery are markedly non-responsive to mitogens. The p56lck kinase also has an activating autophosphorylation site that can be dephosphorylated by CD45 under some circumstances. However, the overall regulatory actions of CD45 on p56lck function in the context of T cell antigen receptor coupling are positive, and this is confirmed by restoration of the CD45-/- phenotype with the lckY505F transgene. Up to eight CD45 isoforms are generated by alternative splicing of which at least five are expressed on lymphocytes at significant levels. Differential CD45 isoform expression is tightly controlled during lymphocyte development and activation, but putative differences in the molecular actions of the different isoforms remain poorly understood. CD45 is an attractive therapeutic target as a means to suppress T cell activation, of relevance in autoimmunity, protection against organ graft rejection and inflammation. CD45 may also be of use in cancer therapies. Current therapeutic strategies utilise CD45 monoclonal antibodies or phosphatase inhibitors. Increasing knowledge of CD45 structure and function will facilitate a more systematic and rational approach to drug design.

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References

  • Akbar AN, Terry L, Timms A, Beverley PCL, Janossy G (1988) Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T-cells. J Immunol 140:2171–2178

    PubMed  CAS  Google Scholar 

  • Alexander D, Shiroo M, Robinson A, Biffen M, Shivnan E (1992) The role of CD45 in T-cell activation—resolving the paradoxes. Immunol Today 13:477–481

    Article  PubMed  CAS  Google Scholar 

  • Alexander DR (1997) The role of the CD45 phosphatase in lymphocyte signalling. In: Harnett MM, Rigley KP (eds) Lymphocyte signalling: mechanisms, subversion and manipulation. John Wiley and Sons, Sussex, pp 107–140

    Google Scholar 

  • Alexander DR (2000) The CD45 tyrosine phosphatase: a positive and negative regulator of immune cell function. Semin Immunol 12:349–359

    Article  PubMed  CAS  Google Scholar 

  • Alexander DR (2003) The CD45 Phosphotyrosine Phosphatase. In: Arino J, Alexander DR (eds) Signalling through protein phosphatases. Springer, Heidelberg, pp 231–252

    Google Scholar 

  • Alvi KA, Casey A, Nair BG (1998) Pulchellalactam: a CD45 protein tyrosine phosphatase inhibitor from the marine fungus Corollospora pulchella. J Antibiot (Tokyo) 51:515–517

    PubMed  CAS  Google Scholar 

  • Ashwell JD, Doro U (1999) CD45 and Src-family kinases: and now for something completely different. Immunol Today 20:412–416

    Article  PubMed  CAS  Google Scholar 

  • Auersvald LA, Rothstein DM, Oliveira SC, Khuong CQ, Onodera H, Lazarovits AI, Basadonna GP (1997) Indefinite islet allograft survival in mice after a short course of treatment with anti-CD45 monoclonal antibodies. Transplantation 63:1355–1358

    PubMed  CAS  Google Scholar 

  • Baker M, Gamble J, Tooze R, Higgins D, Yang FT, O’Brien PCM, Coleman N, Pingel S, Turner M, Alexander DR (2000) Development of T-leukaemias in CD45 tyrosine phosphatase-deficient mutant lck mice. EMBO J 19:4644–4654

    Article  PubMed  CAS  Google Scholar 

  • Basadonna GP, Auersvald L, Khuong CQ, Zheng XX, Kashio N, Zekzer D, Minozzo M, Qian HY, Visser L, Diepstra A, Lazarovits AI, Poppema S, Strom TB, Rothstein DM (1998) Antibody-mediated targeting of CD45 isoforms: a novel immunotherapeutic strategy. Proc Natl Acad Sci USA 95:3821–3826

    Article  PubMed  CAS  Google Scholar 

  • Batista FD, Iber D, Neuberger MS (2001) B cells acquire antigen from target cells after synapse formation. Nature 411:489–494

    Article  PubMed  CAS  Google Scholar 

  • Beers SA, Malloy EA, Wu W, Wachter MP, Gunnia U, Cavender D, Harris C, Davis J, Brosius R, Pellegrino-Gensey JL, Siekierka J (1997) Nitroarylhydroxymethylphosphonic acids as inhibitors of CD45. Bioorg Med Chem 5:2203–2211

    PubMed  CAS  Google Scholar 

  • Benatar T, Carsetti R, Furlonger C, Kamalia N, Mak T, Paige CJ (1996) Immunoglobulinmediated signal-transduction in B-cells from CD45-deficient mice. J Exp Med 183:329–334

    Article  PubMed  CAS  Google Scholar 

  • Berger SA, Mak TW, Paige CJ (1994) Leukocyte common antigen (CD45) is required for immunoglobulin E-mediated degranulation of mast cells. J Exp Med 180:471–476

    Article  PubMed  CAS  Google Scholar 

  • Biffen M, McMichael-Phillips D, Larson T, Venkitaraman A, Alexander D (1994) The CD45 tyrosine phosphatase regulates specific pools of antigen receptor-associated P59(Fyn) and CD4-associated P56(Lck) tyrosine kinases in human T-cells. EMBO J 13:1920–1929

    PubMed  CAS  Google Scholar 

  • Bonnard M, Maroun CR, Julius M (1997) Physical association of CD4 and CD45 in primary, resting CD4(+) Tcells. Cell Immunol 175:1–11

    Article  PubMed  CAS  Google Scholar 

  • Byth KF, Conroy LA, Howlett S, Smith AJH, May J, Alexander DR, Holmes N (1996) CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4(+)CD8(+) thymocytes, and in B-cell maturation. J Exp Med 183:1707–1718

    Article  PubMed  CAS  Google Scholar 

  • Conroy LA, Byth KF, Howlett S, Holmes N, Alexander DR (1996) Defective depletion of CD45-null thymocytes by the Staphylococcus aureus enterotoxin B superantigen. Immunol Lett 54:119–122

    Article  PubMed  CAS  Google Scholar 

  • Cooper JC, Morgan G, Harding S, Subramanyam M, Majeau GR, Moulder K, Alexander DR (2003) Alefacept selectively promotes NK cell-mediated deletion of CD45R0+ human Tcells. Eur J Immunol 33:666–675

    Article  PubMed  CAS  Google Scholar 

  • Cyster JG, Healy JI, Kishihara K, Mak TW, Thomas ML, Goodnow CC (1996) Regulation of B-lymphocyte negative and positive selection by tyrosine phosphatase CD45. Nature 381:325–328

    Article  PubMed  CAS  Google Scholar 

  • Dahlke MH, Lauth OS, Jager MD, Roeseler T, Timrott K, Jackobs S, Neipp M, Wonigeit K, Schlitt HJ (2002) In vivo depletion of hematopoietic stem cells in the rat by an anti-CD45 (RT7) antibody. Blood 99:3566–3572

    Article  PubMed  CAS  Google Scholar 

  • Davis SJ, van der Merwe PA (1996) The structure and ligand interactions of CD2: implications for T-cell function. Immunol Today 17:177–187

    Article  PubMed  CAS  Google Scholar 

  • DeKroon J, Depaus RA, Kluinnelemans HC, Kluin PM, Vanbergen CAM, Munro AJ, Hale G, Willemze R, Falkenburg JHF (1996) Anti-CD45 and Anti-Cd52 (Campath) monoclonal-antibodies effectively eliminate systemically disseminated human non-Hodgkins-lymphoma B-cells in Scid mice. Exp Hematol 24:919–926

    CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Desmarais S, Jia ZC, Ramachandran C (1998) Inhibition of protein tyrosine phosphatases PTP1B and CD45 by sulfotyrosyl peptides. Arch Biochem Biophys 354:225–231

    Article  PubMed  CAS  Google Scholar 

  • Doody GM, Bell S, Vigorito E, Clayton E, McAdam S, Tooze R, Fernandez C, Lee IJ, Turner M (2001) Vav-2 plays a role in the generation of the humoral immune response and collaborates with Vav-1 in signalling for B cell maturation. Nat Immunol 2:542–547

    Article  PubMed  CAS  Google Scholar 

  • Dornan S, Sebestyen Z, Gamble J, Nagy P, Bodnar A, Alldridge L, Doe S, Holmes N, Goff LK, Beverley P, Szollosi J, Alexander DR (2002) Differential association of CD45 isoforms with CD4 and CD8 regulates the actions of specific pools of p56lck tyrosine kinase in Tcell antigen receptor signal transduction. J Biol Chem 277:1912–1918

    Article  PubMed  CAS  Google Scholar 

  • Doro U, Ashwell JD (1999) Cutting edge: the CD45 tyrosine phosphatase is an inhibitor of Lck activity in thymocytes. J Immunol 162:1879–1883

    CAS  Google Scholar 

  • Doro U, Sakaguchi K, Appella E, Ashwell JD (1996) Mutational analysis of Lck in CD45-negative T-cells—dominant role of tyrosine-394 phosphorylation in kinase-activity. Mol Cell Biol 16:4996–5003

    CAS  Google Scholar 

  • Ehrlich LI, Ebert PJ, Krummel MF, Weiss A, Davis MM (2002) Dynamics of p56lck translocation to the Tcell immunological synapse following agonist and antagonist stimulation. Immunity 17:809–822

    Article  PubMed  CAS  Google Scholar 

  • Ellis CN, Krueger GG (2001) Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 345:248–255

    Article  PubMed  CAS  Google Scholar 

  • Fecteau S, Basadonna GP, Freitas A, Ariyan C, Sayegh MH, Rothstein DM (2001) CTLA-4 up-regulation plays a role in tolerance mediated by CD45. Nat Immunol 2:58–63

    Article  PubMed  CAS  Google Scholar 

  • Felberg J, Johnson P (1998) Characterization of recombinant CD45 cytoplasmic domain proteins—evidence for intramolecular and intermolecular interactions. J Biol Chem 273:17839–17845

    Article  PubMed  CAS  Google Scholar 

  • Felberg J, Johnson P (2000) Stable interdomain interaction within the cytoplasmic domain of CD45 increases enzyme stability. Biochem Biophys Res Commun 271:292–298

    Article  PubMed  CAS  Google Scholar 

  • Fortin M, Steff AM, Felberg J, Ding I, Schraven B, Johnson P, Hugo P (2002) Apoptosis mediated through CD45 is independent of its phosphatase activity and association with leukocyte phosphatase-associated phosphoprotein. J Immunol 168:6084–6089

    PubMed  CAS  Google Scholar 

  • Freiberg BA, Kupfer H, Maslanik W, Delli J, Kappler J, Zaller DM, Kupfer A (2002) Staging and resetting Tcell activation in SMACs. Nat Immunol 3:911–917

    Article  PubMed  CAS  Google Scholar 

  • Fukuhara K, Okumura M, Shiono H, Inoue M, Kadota Y, Miyoshi S, Matsuda H (2002) A study on CD45 isoform expression during T-cell development and selection events in the human thymus. Hum Immunol 63:394–404

    Article  PubMed  CAS  Google Scholar 

  • Furukawa T, Itoh M, Krueger NX, Streuli M, Saito H (1994) Specific interaction of the CD45 protein-tyrosine-phosphatase with tyrosine-phosphorylated CD3 zeta-chain. Proc Natl Acad Sci USA 91:10928–10932

    PubMed  CAS  Google Scholar 

  • Gao ZH, Zhong R, Jiang JF, Garcia B, Xing JJ, White MJ, Lazarovits AI (1999) Adoptively transferable tolerance induced by CD45RB monoclonal antibody. J Am Soc Nephrol 10:374–381

    PubMed  CAS  Google Scholar 

  • Ghosh J, Miller RA (1993) Suramin, an experimental chemotherapeutic drug, irreversibly blocks T-cell CD45-protein tyrosine phosphatase in-vitro. Biochem Biophys Res Commun 194:36–44

    Article  PubMed  CAS  Google Scholar 

  • Hamaguchi T, Takahashi A, Kagamizono T, Manaka A, Sato M, Osada H (2000) Synthesis and characterization of a potent and selective protein tyrosine phosphatase inhibitor, 2. Bioorg Med Chem Lett 10:2657–2660

    Article  PubMed  CAS  Google Scholar 

  • Hamaguchi T, Takahashi A, Manaka A, Sato M, Osada H (2001) TU-572, a potent and selective CD45 inhibitor, suppresses IgE-mediated anaphylaxis and murine contact hypersensitivity reactions. Int Arch Allergy Immunol 126:318–324

    Article  PubMed  CAS  Google Scholar 

  • Hartley DK, Hurley TR, Hardwick JS, Lund TC, Medveczky PG, Sefton BM (1999) Activation of the Lck tyrosine-protein kinase by the binding of the tip protein of herpesvirus Saimiri in the absence of regulatory tyrosine phosphorylation. J Biol Chem 274:20056–20059

    Article  PubMed  CAS  Google Scholar 

  • Hayami-Noumi K, Tsuchiya T, Moriyama Y, Noumi T (2000) Intra-and intermolecular interactions of the catalytic domains of human CD45 protein tyrosine phosphatase. FEBS Lett 468:68–72

    Article  PubMed  CAS  Google Scholar 

  • Hayward AR, Lee J, Beverley PCL (1989) Ontogeny of expression of Uchl1 antigen on TCR-1+ (CD4/8) and TCR-delta+ T-cells. Eur J Immunol 19:771–773

    PubMed  CAS  Google Scholar 

  • Hegedus Z, Chitu V, Toth GK, Finta C, Varadi G, Ando I, Monostori E (1999) Contribution of kinases and the CD45 phosphatase to the generation of tyrosine phosphorylation patterns in the T-cell receptor complex zeta chain. Immunol Lett 67:31–39

    PubMed  CAS  Google Scholar 

  • Hermiston ML, Xu Z, Weiss A (2003) CD45: a critical regulator of signaling thresholds in Immune Cells. Annu Rev Immunol 21:107–137

    Article  PubMed  CAS  Google Scholar 

  • Holdorf AD, Green JM, Levin SD, Denny MF, Straus DB, Link V, Changelian PS, Allen PM, Shaw AD (1999) Proline residues in CD28 and the Src homology (SH)3 domain of Lck are required for Tcell costimulation. J Exp Med 190:375–384

    Article  PubMed  CAS  Google Scholar 

  • Holdorf AD, Lee KH, Burack WR, Allen PM, Shaw AS (2002) Regulation of Lck activity by CD4 and CD28 in the immunological synapse. Nat Immunol 4:4

    Google Scholar 

  • Imoto M, Kakeya H, Sawa T, Hayashi C, Hamada M, Takeuchi T, Umezawa K (1993) Dephostatin, a novel protein-tyrosine-phosphatase inhibitor produced by streptomyces.1. Taxonomy isolation and characterization. J Antibiot (Tokyo) 46:1342–1346

    PubMed  CAS  Google Scholar 

  • Irie-Sasaki Jea (2001) CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409:349–354

    Article  PubMed  CAS  Google Scholar 

  • Irles C, Symons A, Michel F, Bakker TR, van der Merwe PA, Acuto O (2003) CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling. Nat Immunol 4:189–197

    Article  PubMed  CAS  Google Scholar 

  • Johnson KG, Bromley SK, Dustin ML, Thomas ML (2000) A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation. Proc Natl Acad Sci U S A 97:10138–10143

    PubMed  CAS  Google Scholar 

  • Johnson P, Ostergaard HL, Wasden C, Trowbridge IS (1992) Mutational analysis of CD45—a leukocyte-specific protein tyrosine phosphatase. J Biol Chem 267:8035–8041

    PubMed  CAS  Google Scholar 

  • Justement LB (2001) The role of the protein tyrosine phosphatase CD45 in regulation of B lymphocyte activation. Int Rev Immunol 20:713–738

    PubMed  CAS  Google Scholar 

  • Kaplon RJ, Hochman PS, Michler RE, Kwiatkowski PA, Edwards NM, Berger CL, Xu H, Meier W, Wallner BP, Chisholm P, Marboe CC (1996) Short course single agent therapy with an LFA-3-IgG1 fusion protein prolongs primate cardiac allograft survival. Transplantation 61:356–363

    PubMed  CAS  Google Scholar 

  • Kashio N, Matsumoto W, Parker S, Rothstein DM (1998) The second domain of the CD45 protein tyrosine phosphatase is critical for interleukin-2 secretion and substrate recruitment of TCR-zeta in vivo. J Biol Chem 273:33856–33863

    Article  PubMed  CAS  Google Scholar 

  • Katagiri T, Ogimoto M, Hasegawa K, Arimura Y, Mitomo K, Okada M, Clark MR, Mizuno K, Yakura H (1999) CD45 negatively regulates Lyn activity by dephosphorylating both positive and negative regulatory tyrosine residues in immature B cells. J Immunol 163:1321–1326

    PubMed  CAS  Google Scholar 

  • Kishihara K, Penninger J, Wallace VA, Kundig TM, Kawai K, Wakeham A, Timms E, Pfeffer K, Ohashi PS, Thomas ML, Furlonger C, Paige CJ, Mak TW (1993) Normal B-lymphocyte development but impaired T-cell maturation in CD45-exon 6 proteintyrosine-phosphatase deficient mice. Cell 74:143–156

    Article  PubMed  CAS  Google Scholar 

  • Klaus SJ, Sidorenko SP, Clark EA (1996) CD45 ligation induces programmed cell-death in T-lymphocyte and B-lymphocyte. J Immunol 156:2743–2753

    PubMed  CAS  Google Scholar 

  • Ko S, Jager MD, Tsui TY, Deiwick A, Dinkel A, Rohde F, Dahlke MH, Lauth O, Wonigeit K, Schlitt HJ (2001) Long-term allograft acceptance induced by single dose anti-leukocyte common antigen (RT7) antibody in the rat. Transplantation 71:1124–1131

    PubMed  CAS  Google Scholar 

  • Kong YY, Kishihara K, Sumichika H, Nakamura T, Kaneko M, Nomoto K (1995a) Differential requirements of CD45 for lymphocyte development and function. Eur J Immunol 25:3431–3436

    PubMed  CAS  Google Scholar 

  • Kong YY, Kishihara K, Yoshida H, Mak TW, Nomoto K (1995b) Generation of T-cells with differential responses to alloantigens in CD45 exon 6-deficient mice. J Immunol 154:5725–5735

    PubMed  CAS  Google Scholar 

  • Koretzky GA, Picus J, Thomas ML, Weiss A (1990) Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway. Nature 346:66–68

    Article  PubMed  CAS  Google Scholar 

  • Kozieradzki I, Kundig T, Kishihara K, Ong CJ, Chiu D, Wallace VA, Kawai K, Timms E, Ionescu J, Ohashi P, Marth JD, Mak TW, Penninger JM (1997) T cell development in mice expressing splice variants of the protein tyrosine phosphatase CD45. J Immunol 158:3130–3139

    PubMed  CAS  Google Scholar 

  • Kung C, Pingel JT, Heikinheimo M, Klemola T, Varkila K, Yoo LI, Vuopal K, Poyhonen M, Uhari M, Rogers M, Speck SH, Chatila T, Thomas ML (2000) Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med 6:343–345

    PubMed  CAS  Google Scholar 

  • Lazarovits AI, Poppema S, Zhang Z, Khandaker M, Lefeuvre SK, Garcia BM, Ogasa N, Jevnikar AM, White MJ, Singh G, Stiller CR, Zhong RZ (1996) Prevention and reversal of renal allograft rejection by antibody against CD45RB. Nature 380:717–720

    Article  PubMed  CAS  Google Scholar 

  • Lee K, Burke TR Jr (2003) CD45 protein-tyrosine phosphatase inhibitor development. Curr Top Med Chem 3:797–807

    PubMed  CAS  Google Scholar 

  • Leitenberg D, Novak TJ, Farber D, Smith BR, Bottomly K (1996) The extracellular domain of CD45 controls association with the CD4-T cell-receptor complex and the response to antigen-specific stimulation. J Exp Med 183:249–259

    Article  PubMed  CAS  Google Scholar 

  • Leitenberg D, Boutin Y, Lu DD, Bottomly K (1999) Biochemical association of CD45 with the Tcell receptor complex: regulation by CD45 isoform and during Tcell activation. Immunity 10:701–711

    Article  PubMed  CAS  Google Scholar 

  • Lesage S, Steff AM, Philippoussis F, Page M, Trop S, Mateo V, Hugo P (1997) CD4(+)CD8(+) thymocytes are preferentially induced to die following CD45 crosslinking, through a novel apoptotic pathway. J Immunol 159:4762–4771

    PubMed  CAS  Google Scholar 

  • Leupin O, Zaru R, Laroche T, Muller S, Valitutti S (2000) Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes. Curr Biol 10:277–280

    Article  PubMed  CAS  Google Scholar 

  • Liu P, Aitken K, Kong YY, Opavsky MA, Martino T, Dawood F, Wen WH, Kozieradzki I, Bachmaier K, Straus D, Mak TW, Penninger JM (2000) The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease. Nat Med 6:429–434

    PubMed  CAS  Google Scholar 

  • Majeti R, Bilwes AM, Noel JP, Hunter T, Weiss A (1998) Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. Science 279:88–91

    Article  PubMed  CAS  Google Scholar 

  • Majeti R, Xu Z, Parslow TG, Olson JL, Daikh DI, Killeen N, Weiss A (2000) An inactivating point mutation in the inhibitory wedge of CD45 causes lymphoproliferation and autoimmunity. Cell 103:1059–1070

    Article  PubMed  CAS  Google Scholar 

  • Markey AC, Allen MH, Pitzalis C, Macdonald DM (1990) T-cell inducer populations in cutaneous inflammation—a predominance of T-helper-inducer lymphocytes (Thi) in the infiltrate of inflammatory dermatoses. Br J Dermatol 122:325–332

    PubMed  CAS  Google Scholar 

  • Martin SM, Mehta IK, Yokoyama WM, Thomas ML, Lorenz RG (2001) Development of intestinal intraepithelial lymphocytes, NK cells, and NK 1.1(+) T cells in CD45-deficient mice. J Immunol 166:6066–6073

    PubMed  CAS  Google Scholar 

  • Matthews DC, Badger CC, Fisher DR, Hui TE, Nourigat C, Appelbaum FR, Martin PJ, Bernstein ID (1992) Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody. Cancer Res 52:1228–1234

    PubMed  CAS  Google Scholar 

  • Matthews DC, Appelbaum FR, Eary JF, Fisher DR, Durack LD, Hui TE, Martin PJ Mitchell D, Press OW, Storb, R, Bernstein ID (1999) Phase I study of I-131-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 94:1237–1247

    PubMed  CAS  Google Scholar 

  • Matthews N, Emery P, Pilling D, Akbar A, Salmon M (1993) Subpopulations of primed-T helper-cells in rheumatoid-arthritis. Arthritis Rheum 36:603–607

    PubMed  CAS  Google Scholar 

  • McFarland EDC, Hurley TR, Pingel JT, Sefton BM, Shaw A, Thomas ML (1993) Correlation between Src family member regulation by the protein-tyrosine-phosphatase CD45 and transmembrane signaling through the T-cell receptor. Proc Natl Acad Sci USA 90:1402–1406

    CAS  Google Scholar 

  • Meade J, Fernandez C, Turner M (2002) The tyrosine kinase Lyn is required for B cell development beyond the T1 stage in the spleen: rescue by over-expression of Bcl-2. Eur J Immunol 32:1029–1034

    Article  PubMed  CAS  Google Scholar 

  • Mee PJ, Turner M, Basson AM, Costello PS, Zamoyska R, Tybulewicz VLJ (1999) Greatly reduced efficiency of both positive and negative selection of thymocytes in CD45 tyrosine phosphatase-deficient mice. Eur J Immunol 29:2923–2933

    Article  PubMed  CAS  Google Scholar 

  • Miski M, Shen X, Cooper R, Gillum AM, Fisher DK, Miller RW, Higgins TJ (1995) Aporphine alkaloids, CD45 protein-tyrosine-phosphatase inhibitors, from Rollinia-ulei. Bioorg Med Chem Lett 5:1519–1522

    Article  CAS  Google Scholar 

  • Mittler RS, Rankin BM, Kiener PA (1991) Physical associations between CD45 and CD4 or CD8 occur as late activation events in antigen receptor-stimulated human T-cells. J Immunol 147:3434–3440

    PubMed  CAS  Google Scholar 

  • Monks CRF, Freiberg BA, Kupfer H, Sciaky N, Kupfer A (1998) Three-dimensional segregation of supramolecular activation clusters in Tcells. Nature 395:82–86

    PubMed  CAS  Google Scholar 

  • Murakami K, Sato S, Nagasawa S, Yamashita (2000) T Regulation of mast cell signaling through high-affinity IgE receptor by CD45 protein tyrosine phosphatase. Int Immunol 12:169–176

    Article  PubMed  CAS  Google Scholar 

  • Mustelin T, Altman A (1990) Dephosphorylation and activation of the T-cell tyrosine kinase p56lck by the leukocyte common antigen (CD45). Oncogene 5:809–813

    PubMed  CAS  Google Scholar 

  • Mustelin T, Coggeshall KM, Altman A (1989) Rapid activation of the T-cell tyrosine kinase pp56lck by the CD45 phosphotyrosine phosphatase. Proc Natl Acad Sci USA 86:6302–6306

    PubMed  CAS  Google Scholar 

  • Mustelin T, Williams S, Tailor P, Couture C, Zenner G, Burn P, Ashwell JD, Altman A (1995) Regulation of the P70(Zap) tyrosine protein-kinase in T-cells by the CD45 phosphotyrosine phosphatase. Eur J Immunol 25:942–946

    PubMed  CAS  Google Scholar 

  • Nemecek ER, Matthews DC (2002) Antibody-based therapy of human leukemia. Curr Opin Hematol 9:316–321

    Article  PubMed  Google Scholar 

  • Ng DHW, Maiti A, Johnson P (1995) Point mutation in the 2nd phosphatase domain of CD45 abrogates tyrosine phosphatase-activity. Biochem Biophys Res Commun 206:302–309

    Article  PubMed  CAS  Google Scholar 

  • Novak TJ, Farber D, Leitenberg D, Hong SC, Johnson P, Bottomly K (1994) Isoforms of the transmembrane tyrosine phosphatase CD45 differentially affect T-cell recognition. Immunity 1:109–119

    Article  PubMed  CAS  Google Scholar 

  • Ogilvy S, Louis-Dit-Sully C, Cooper J, Cassady RL, Alexander DR, Holmes N (2003) Either of the CD45RB and CD45RO isoforms are effective in restoring T cell, but not B cell, development and function in CD45-null mice. J Immunol 171:1792–1800

    PubMed  CAS  Google Scholar 

  • Ostergaard HL, Shackelford DA, Hurley TR, Johnson P, Hyman R, Sefton BM, Trowbridge IS (1989) 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

    PubMed  CAS  Google Scholar 

  • Pao LI, Cambier JC (1997) Syk, but not Lyn, recruitment to B cell antigen receptor and activation following stimulation of CD45(-) B cells. J Immunol 158:2663–2669

    PubMed  CAS  Google Scholar 

  • Pelosi M, DiBartolo V, Mounier V, Mege D, Pascussi JM, Dufour E, Blondel A, Acuto O (1999) Tyrosine 319 in the interdomain B of ZAP-70 is a binding site for the Src homology 2 domain of Lck. J Biol Chem 274:14229–14237

    Article  PubMed  CAS  Google Scholar 

  • Pingel JT, Thomas ML (1989) Evidence that the leukocyte-common antigen is required for antigen-induced lymphocyte-T proliferation. Cell 58:1055–1065

    Article  PubMed  CAS  Google Scholar 

  • Pingel S, Baker M, Turner M, Holmes N, Alexander DR (1999) The CD45 tyrosine phosphatase regulates CD3-induced signal transduction and Tcell development in recombinase-deficient mice: restoration of pre-TCR function by active p56(lck). Eur J Immunol 29:2376–2384

    Article  PubMed  CAS  Google Scholar 

  • Roach T, Slater S, Koval M, White L, McFarland EC, Okumura M, Thomas M, Brown E (1997) CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion. Curr Biol 7:408–417

    Article  PubMed  CAS  Google Scholar 

  • Rogers PR, Pilapil S, Hayakawa K, Romain PL, Parker DC (1992) CD45 alternative exon expression in murine and human CD4+ T-cell subsets. J Immunol 148:4054–4065

    PubMed  CAS  Google Scholar 

  • Ruffner KL, Martin PJ, Hussell S, Nourigat C, Fisher DR, Bernstein ID, Matthews DC (2001) Immunosuppressive effects of (131)I-anti-CD45 antibody in unsensitised and donor antigen-presensitised H2-matched, minor antigen-mismatched murine transplant models. Cancer Res 61:5126–5131

    PubMed  CAS  Google Scholar 

  • Sandmaier BM, Bethge WA, Wilbur DS, Hamlin DK, Santos EB, Brechbiel MW, Fisher DR, Storb R (2002) Bismuth 213-labeled anti-CD45 radioimmunoconjugate to condition dogs for nonmyeloablative allogeneic marrow grafts. Blood 100:318–326

    Article  PubMed  CAS  Google Scholar 

  • Seavitt JR, White LS, Murphy KM, Loh DY, Perlmutter RM, Thomas ML (1999) Expression of the p56(lck) Y505F mutation in CD45-deficient mice rescues thymocyte development. Mol Cell Biol 19:4200–4208

    PubMed  CAS  Google Scholar 

  • Seddon B, Zamoyska R (2002) TCR signals mediated by Src family kinases are essential for the survival of naive Tcells. J Immunol 169:2997–3005

    PubMed  CAS  Google Scholar 

  • Seddon B, Legname G, Tomlinson P, Zamoyska R (2000) Long-term survival but impaired homeostatic proliferation of naive T cells in the absence of p56lck. Science 290:127–131

    Article  PubMed  CAS  Google Scholar 

  • Shenoi H, Seavitt J, Zheleznyak A, Thomas ML, Brown EJ (1999) Regulation of integrinmediated T cell adhesion by the transmembrane protein tyrosine phosphatase CD45. J Immunol 162:7120–7127

    PubMed  CAS  Google Scholar 

  • Shiroo M, Goff L, Biffen M, Shivnan E, Alexander D (1992) CD45-tyrosine phosphataseactivated p59fyn couples the T-cell antigen receptor to pathways of diacylglycerol production, protein-kinase-C activation and calcium influx. EMBO J 11:4887–4897

    PubMed  CAS  Google Scholar 

  • Shivnan E, Biffen M, Shiroo M, Pratt E, Glennie M, Alexander D (1992) Does coaggregation of the CD45 and CD3 antigens inhibit T-cell antigen receptor complex-mediated activation of phospholipase-C and protein-kinase-C. Eur J Immunol 22:1055–1062

    PubMed  CAS  Google Scholar 

  • Sieh M, Bolen JB, Weiss A (1993) CD45 specifically modulates binding of Lck to a phosphopeptide encompassing the negative regulatory tyrosine Of Lck. EMBO J 12:315–321

    PubMed  CAS  Google Scholar 

  • Stone JD, Conroy LA, Byth KF, Hederer RA, Howlett S, Takemoto Y, Holmes N, Alexander DR (1997) Aberrant TCR-mediated signalling in CD45-null thymocytes involves dysfunctional regulation of Lck, Fyn, TCR-ζ and ZAP-70. J Immunol 158:5773–5782

    PubMed  CAS  Google Scholar 

  • Symons A, Willis AC, Barclay AN (1999) Domain organization of the extracellular region of CD45. Protein Eng 12:885–892

    PubMed  CAS  Google Scholar 

  • Takakura K, Beckman JS, MacMillanCrow LA, Crow JP (1999) Rapid and irreversible inactivation of protein tyrosine phosphatases PTP1B, CD45, and LAR by peroxynitrite. Arch Biochem Biophys 369:197–207

    Article  PubMed  CAS  Google Scholar 

  • Takeda A, Wu JJ, Maizel AL (1992) Evidence for monomeric and dimeric forms of CD45 associated with a 30-kDa phosphorylated protein. J Biol Chem 267:16651–16659

    PubMed  CAS  Google Scholar 

  • Tchilian EZ, Wallace DL, Wells RS, Flower DR, Morgan G, Beverley PC (2001) A deletion in the gene encoding the CD45 antigen in a patient with SCID. J Immunol 166:1308–1313

    PubMed  CAS  Google Scholar 

  • Thomas ML (1989) The leukocyte common antigen family. Annu Rev Immunol 7:339–369

    Article  PubMed  CAS  Google Scholar 

  • Thomas ML, Brown EJ (1999) Positive and negative regulation of Src-family membrane kinases by CD45. Immunol Today 20:406–411

    Article  PubMed  CAS  Google Scholar 

  • Trop S, Charron J, Arguin C, Hugo P (2000) Thymic selection generates T cells expressing self-reactive TCRs in the absence of CD45. J Immunol 165:3073–3079

    PubMed  CAS  Google Scholar 

  • Trowbridge IS, Thomas ML (1994) CD45— an emerging role as a protein-tyrosine-phosphatase required for lymphocyte-activation and development. Annu Rev Immunol 12:85–116

    Article  PubMed  CAS  Google Scholar 

  • Urbanek RA, Suchard SJ, Steelman GB, Knappenberger KS, Sygowski LA, Veale CA, Chapdelaine MJ (2001) Potent reversible inhibitors of the protein tyrosine phosphatase CD45. J Med Chem 44:1777–1793

    Article  PubMed  CAS  Google Scholar 

  • Vallera DA, Elson M, Brechbiel MW, Dusenbery KE, Burns LJ, Skubitz KM, Jaszcz WB, Ramsay NK, Panoskaltsis-Mortari A, Kuroki DW, Wagner JE, Kersey JH (2003) Preclinical studies targeting normal and leukemic hematopoietic cells with Yttrium-90-labeled anti-CD45 antibody in vitro and in vivo in nude mice. Cancer Biother Radiopharm 18:133–145

    Article  PubMed  CAS  Google Scholar 

  • Wallace VA, Penninger JM, Kishihara K, Timms E, Shahinian A, Pircher H, Kundig TM, Ohashi PS, Mak TW (1997) Alterations in the level of CD45 surface expression affect the outcome of thymic selection. J Immunol 158:3205–3214

    PubMed  CAS  Google Scholar 

  • Watanabe T, Takeuchi T, Otsuka M, Tanaka S, Umezawa K (1995) Synthesis and protein tyrosine phosphatase inhibitory activity of dephostatin analogs. J Antibiot (Tokyo) 48:1460–1466

    PubMed  CAS  Google Scholar 

  • Wonigeit K (1979a) Characterization of the RT-Ly-1 and RT-Ly-2 alloantigenic systems by congenic rat strains. Transplant Proc 11:1631–1635

    PubMed  CAS  Google Scholar 

  • Wonigeit K (1979b) Definition of lymphocyte antigens in rats: RT-Ly-1, RT-Ly-2, and a new MHC-linked antigen system. Transplant Proc 11:1334–1336

    PubMed  CAS  Google Scholar 

  • Wu L, Fu J, Shen SH (2002) SKAP55 coupled with CD45 positively regulates T-cell receptor-mediated gene transcription. Mol Cell Biol 22:2673–2686

    PubMed  CAS  Google Scholar 

  • Xu Z, Weiss A (2002) Negative regulation of CD45 by differential homodimerization of the alternatively spliced isoforms. Nat Immunol 3:764–771

    Article  PubMed  CAS  Google Scholar 

  • Yamada H, Kishihara K, Kong YY, Nomoto K (1996) Enhanced generation of NK cells with intact cytotoxic function in CD45 exon 6-deficient mice. J Immunol 157:1523–1528

    PubMed  CAS  Google Scholar 

  • Yamada T, Zhu D, Saxon A, Zhang K (2002) CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells through its function as a Janus kinase phosphatase. J Biol Chem 277:28830–28835

    PubMed  CAS  Google Scholar 

  • Yanagi S, Sugawara H, Kurosaki M, Sabe H, Yamamura H, Kurosaki T (1996) CD45 modulates phosphorylation of both autophosphorylation and negative regulatory tyrosines of Lyn in B-cells. J Biol Chem 271:30487–30492

    PubMed  CAS  Google Scholar 

  • Zhang J, Siraganian RP (1999) CD45 is essential for Fc epsilon RI signaling by ZAP70, but not Syk, in Syk-negative mast cells. J Immunol 163:2508–2516

    PubMed  CAS  Google Scholar 

  • Zhong RZ, Lazarovits AI (1998) Monoclonal antibody against CD45RB for the therapy of rejection and autoimmune diseases. J Mol Med 76:572–580

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

    D. R. Alexander

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  1. Dipartimento di Chimica Biologica, Università di Padova, Via Trieste 75, Padova, 35121, Italy

    Lorenzo A. Pinna

  2. MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, MSI/WTB Complex, Dow St., Dundee, DD1 5EH, Scotland, UK

    Patricia T.W. Cohen Ph.D. (Professor of Molecular Biology) (Professor of Molecular Biology)

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Alexander, D.R. (2005). Biological Validation of the CD45 Tyrosine Phosphatase as a Pharmaceutical Target. In: Pinna, L.A., Cohen, P.T. (eds) Inhibitors of Protein Kinases and Protein Phosphates. Handbook of Experimental Pharmacology, vol 167. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-26670-4_10

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