CD45: new jobs for an old acquaintance

Identified as the first and prototypic transmembrane protein tyrosine phosphatase (PTPase), CD45 has been extensively studied for over two decades and is thought to be important for positively regulating antigen-receptor signaling via the dephosphorylation of Src kinases. However, new evidence indicates that CD45 can function as a Janus kinase PTPase that negatively controls cytokine-receptor signaling. A point mutation in CD45, which appears to affect CD45 dimerization, and a genetic polymorphism that affects alternative CD45 splicing are implicated in autoimmunity in mice and multiple sclerosis in humans. CD45 is expressed in multiple isoforms and the modulation of specific CD45 splice variants with antibodies can prevent transplant rejections. In addition, loss of CD45 can affect microglia activation in a mouse model for Alzheimer's disease. Thus, CD45 is moving rapidly back into the spotlight as a drug target and central regulator involved in differentiation of multiple hematopoietic cell lineages, autoimmunity and antiviral immunity.

[1]  L. Baum,et al.  Apoptosis of T cells mediated by galectin-1 , 1995, Nature.

[2]  M. Thomas,et al.  The leukocyte common antigen family. , 1989, Annual review of immunology.

[3]  G. Koretzky,et al.  Identification of the Sites of Interaction between Lymphocyte Phosphatase-associated Phosphoprotein (LPAP) and CD45 (*) , 1996, The Journal of Biological Chemistry.

[4]  Jonathan A. Cooper,et al.  Potential positive and negative autoregulation of p60c-src by intermolecular autophosphorylation. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[5]  T. Chatila,et al.  Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease , 2000, Nature Medicine.

[6]  M. Mullan,et al.  CD45 Opposes β-Amyloid Peptide-Induced Microglial Activation via Inhibition of p44/42 Mitogen-Activated Protein Kinase , 2000, The Journal of Neuroscience.

[7]  T. Owens,et al.  Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis. , 1994, International immunology.

[8]  I. Trowbridge,et al.  CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development. , 1994, Annual review of immunology.

[9]  D. Sgroi,et al.  CD22, a B cell-specific immunoglobulin superfamily member, is a sialic acid-binding lectin. , 1993, The Journal of biological chemistry.

[10]  S. Kanner,et al.  CD45 modulates T cell receptor/CD3‐induced activation of human thymocytes via regulation of tyrosine phosphorylation , 1992, European journal of immunology.

[11]  S. Ratnofsky,et al.  LPAP, a novel 32-kDa phosphoprotein that interacts with CD45 in human lymphocytes. , 1994, The Journal of biological chemistry.

[12]  P. W. Janes,et al.  Aggregation of Lipid Rafts Accompanies Signaling via the T Cell Antigen Receptor , 1999, The Journal of cell biology.

[13]  A. Kupfer,et al.  TCR signaling induces selective exclusion of CD43 from the T cell-antigen-presenting cell contact site. , 1998, Journal of immunology.

[14]  T. Hunter,et al.  Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface , 2000, Molecular and Cellular Biology.

[15]  T. Mak,et al.  CD45RA and CD45RBhigh expression induced by thymic selection events , 1992, The Journal of experimental medicine.

[16]  P. Veys,et al.  Severe combined immunodeficiency with abnormalities in expression of the common leucocyte antigen, CD45 , 1997, Archives of disease in childhood.

[17]  N. Harris,et al.  Hodgkin's disease presenting as a solitary bone tumor: A report of four cases and review of the literature , 1996, Cancer.

[18]  G. Koretzky,et al.  Rescue of signaling by a chimeric protein containing the cytoplasmic domain of CD45. , 1993, Science.

[19]  A. Diepstra,et al.  Antibody-mediated targeting of CD45 isoforms: a novel immunotherapeutic strategy. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Noel,et al.  Dimerization-induced inhibition of receptor protein tyrosine phosphatase function through an inhibitory wedge. , 1998, Science.

[21]  M. Mullan,et al.  CD45 Inhibits CD40L-induced Microglial Activation via Negative Regulation of the Src/p44/42 MAPK Pathway* , 2000, The Journal of Biological Chemistry.

[22]  Michael J. Eck,et al.  Structure of the regulatory domains of the Src-family tyrosine kinase Lck , 1994, Nature.

[23]  J. Wang,et al.  Prolongation of xenograft survival using monoclonal antibody CD45RB and cyclophosphamide in rat-to-mouse kidney and heart transplant models. , 2000, Transplantation.

[24]  D. Flower,et al.  A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID , 2001, The Journal of Immunology.

[25]  Paul J Hertzog,et al.  SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine , 1999, Cell.

[26]  S. Bromley,et al.  A supramolecular basis for CD45 tyrosine phosphatase regulation in sustained T cell activation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Xiangdong Xu,et al.  SC35 plays a role in T cell development and alternative splicing of CD45. , 2001, Molecular cell.

[28]  S. Dzik,et al.  The immunological synapse: A molecular machine controlling T cell activation , 2000 .

[29]  Ying Wang,et al.  Phosphorylation of CD45 by Casein Kinase 2 , 1999, The Journal of Biological Chemistry.

[30]  S. Poppema,et al.  Prevention and reversal of renal allograft rejection by antibody against CD45RB , 1996, Nature.

[31]  J. Seavitt,et al.  CD45‐associated protein is not essential for the regulation of antigen receptor‐mediated signal transduction , 1999, European journal of immunology.

[32]  Toshifumi Takao,et al.  Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases , 2000, Nature.

[33]  D. Stover,et al.  Protein-tyrosine phosphatase activity of CD45 is activated by sequential phosphorylation by two kinases , 1994, Molecular and cellular biology.

[34]  Colin R. F. Monks,et al.  Three-dimensional segregation of supramolecular activation clusters in T cells , 1998, Nature.

[35]  R. Eisenberg,et al.  Lpr and gld: single gene models of systemic autoimmunity and lymphoproliferative disease. , 1991, Annual review of immunology.

[36]  C. June,et al.  Regulation of TCR signaling by CD45 lacking transmembrane and extracellular domains. , 1993, Science.

[37]  J. Dennis,et al.  Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation , 2001, Nature.

[38]  J. Noel,et al.  Structural basis for inhibition of receptor protein-tyrosine phosphatase-α by dimerization , 1996, Nature.

[39]  K. Alitalo,et al.  Tyrosine phosphorylation of CD45 phosphotyrosine phosphatase by p50csk kinase creates a binding site for p56lck tyrosine kinase and activates the phosphatase , 1994, Molecular and cellular biology.

[40]  W. Rodgers,et al.  Exclusion of CD45 inhibits activity of p56lck associated with glycolipid-enriched membrane domains , 1996, The Journal of cell biology.

[41]  P. Bedossa,et al.  Role of CD4+CD45RA+ T cells in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse. , 1993, International immunology.

[42]  Michael Loran Dustin,et al.  Making the T cell receptor go the distance: a topological view of T cell activation. , 1997, Immunity.

[43]  W. Leonard,et al.  Jaks and STATs: biological implications. , 1998, Annual review of immunology.

[44]  M. Neidhart,et al.  CD45 isoforms expression on CD4+ and CD8+ peripheral blood T-lymphocytes is related to auto-immune processes and hematological manifestations in systemic lupus erythematosus. , 1996, Schweizerische medizinische Wochenschrift.

[45]  N. Sinclair.  CTLA-4 up-regulation plays a role in tolerance mediated by CD45 , 2001, Nature Immunology.

[46]  Takaho A. Endo,et al.  A new protein containing an SH2 domain that inhibits JAK kinases , 1997, Nature.

[47]  T. Kurosaki,et al.  CD45 Modulates Phosphorylation of Both Autophosphorylation and Negative Regulatory Tyrosines of Lyn in B Cells* , 1996, The Journal of Biological Chemistry.

[48]  A. Weiss,et al.  Tyrosine phosphatase CD45 is required for T-cell antigen receptor and CD2-mediated activation of a protein tyrosine kinase and interleukin 2 production. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[49]  R. Zaru,et al.  Exclusion of CD45 from the T-cell receptor signaling area in antigen-stimulated T lymphocytes , 2000, Current Biology.

[50]  T. Mustelin,et al.  Dephosphorylation and activation of the T cell tyrosine kinase pp56lck by the leukocyte common antigen (CD45). , 1990, Oncogene.

[51]  Bernhard Hemmer,et al.  A point mutation in PTPRC is associated with the development of multiple sclerosis , 2000, Nature Genetics.

[52]  J. Harbott,et al.  Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia , 1998, Annals of Hematology.

[53]  Y. Kong,et al.  Enhanced generation of NK cells with intact cytotoxic function in CD45 exon 6-deficient mice. , 1996, Journal of immunology.

[54]  T. Giese,et al.  Biochemical and functional analysis of mice deficient in expression of the CD45‐associated phosphoprotein LPAP , 1999, European journal of immunology.

[55]  S. Volarevic,et al.  Intimate association of Thy-1 and the T-cell antigen receptor with the CD45 tyrosine phosphatase. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[56]  A. Weiss,et al.  Tyrosine phosphatase CD45 is essential for coupling T-cell antigen receptor to the phosphatidyl inositol pathway , 1990, Nature.

[57]  C. Czerkinsky,et al.  Differential effect of cholera toxin on CD45RA+ and CD45RO+ T cells: specific inhibition of cytokine production but not proliferation of human naive T cells , 2000, Clinical and experimental immunology.

[58]  Josef M. Penninger,et al.  CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling , 2001, Nature.

[59]  A. Yoshimura,et al.  SOCS1 Deficiency Causes a Lymphocyte-Dependent Perinatal Lethality , 1999, Cell.

[60]  A. Yoshimura,et al.  The JAK‐binding protein JAB inhibits Janus tyrosine kinase activity through binding in the activation loop , 1999, The EMBO journal.

[61]  G. Downey,et al.  Inhibition of CD45 during neutrophil activation. , 1997, Journal of immunology.

[62]  T. Roach,et al.  CD45 regulates Src family member kinase activity associated with macrophage integrin-mediated adhesion , 1997, Current Biology.

[63]  D. Alexander,et al.  Development of T‐leukaemias in CD45 tyrosine phosphatase‐deficient mutant lck mice , 2000, The EMBO journal.

[64]  A. Barclay,et al.  Characterization of the interaction between galectin-1 and lymphocyte glycoproteins CD45 and Thy-1. , 2000, Glycobiology.

[65]  P. Johnson,et al.  CD45: a leukocyte-specific member of the protein tyrosine phosphatase family. , 1991, Biochimica et biophysica acta.

[66]  D. Rothstein,et al.  Indefinite islet allograft survival in mice after a short course of treatment with anti-CD45 monoclonal antibodies. , 1997, Transplantation.

[67]  J. Seavitt,et al.  Expression of the p56lckY505F Mutation in CD45-Deficient Mice Rescues Thymocyte Development , 1999, Molecular and Cellular Biology.

[68]  N. Tonks,et al.  Protein-tyrosine-phosphatase CD45 is phosphorylated transiently on tyrosine upon activation of Jurkat T cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[69]  E. Brown,et al.  Positive and negative regulation of Src-family membrane kinases by CD45. , 1999, Immunology today.

[70]  J. Ashwell,et al.  Cutting edge: the CD45 tyrosine phosphatase is an inhibitor of Lck activity in thymocytes. , 1999, Journal of immunology.

[71]  D. Alexander,et al.  CD45-null transgenic mice reveal a positive regulatory role for CD45 in early thymocyte development, in the selection of CD4+CD8+ thymocytes, and B cell maturation , 1996, The Journal of experimental medicine.

[72]  T. Mak,et al.  Normal B lymphocyte development but impaired T cell maturation in CD45-Exon6 protein tyrosine phosphatase-deficient mice , 1993, Cell.

[73]  D. Sgroi,et al.  The B lymphocyte adhesion molecule CD22 interacts with leukocyte common antigen CD45RO on T cells and α2–6 sialyltransferase, CD75, on B cells , 1991, Cell.

[74]  R. Aebersold,et al.  Demonstration of a Direct Interaction between p56 and the Cytoplasmic Domain of CD45 in Vitro(*) , 1996, The Journal of Biological Chemistry.

[75]  P. Johnson,et al.  Characterization of Recombinant CD45 Cytoplasmic Domain Proteins , 1998, The Journal of Biological Chemistry.

[76]  T. Boone,et al.  Interleukin-4 induces expression of the CD45RA antigen on human thymocyte subpopulations. , 1990, International immunology.

[77]  A. Matsuda,et al.  Disruption of Lymphocyte Function and Signaling in CD45–associated Protein–null Mice , 1998, The Journal of experimental medicine.

[78]  R. Majeti,et al.  An Inactivating Point Mutation in the Inhibitory Wedge of CD45 Causes Lymphoproliferation and Autoimmunity , 2000, Cell.

[79]  N. Tonks,et al.  Demonstration that the leukocyte common antigen CD45 is a protein tyrosine phosphatase. , 1988, Biochemistry.

[80]  J. Schlessinger,et al.  Ligand-mediated negative regulation of a chimeric transmembrane receptor tyrosine phosphatase , 1993, Cell.

[81]  T. Mak,et al.  Leukocyte common antigen (CD45) is required for immunoglobulin E- mediated degranulation of mast cells , 1994, The Journal of experimental medicine.

[82]  Bryan R. G. Williams,et al.  Protein-tyrosine Phosphatase Shp-1 Is a Negative Regulator of IL-4- and IL-13-dependent Signal Transduction* , 1998, Journal of Biological Chemistry.

[83]  R. Jove,et al.  Constitutive Activation of JAK1 in Src-transformed Cells* , 1997, The Journal of Biological Chemistry.

[84]  C. Peschle,et al.  Signal transduction and glycophosphatidylinositol-linked proteins (lyn, lck, CD4, CD45, G proteins, and CD55) selectively localize in Triton-insoluble plasma membrane domains of human leukemic cell lines and normal granulocytes. , 1996, Blood.

[85]  Cynthia,et al.  Structural variants of human T200 glycoprotein (leukocyte‐common antigen). , 1987, The EMBO journal.

[86]  Y. Takayama,et al.  Transmembrane Phosphoprotein Cbp Positively Regulates the Activity of the Carboxyl-terminal Src Kinase, Csk* , 2000, The Journal of Biological Chemistry.

[87]  Michael A. Bookman,et al.  The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56 lck , 1988, Cell.

[88]  S. Meuer,et al.  Biochemical analysis of the CD45-p56(lck) complex in Jurkat T cells lacking expression of lymphocyte phosphatase-associated phosphoprotein. , 1998, International immunology.

[89]  E. Reddy,et al.  Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs , 1997, Molecular and cellular biology.

[90]  H. Ishikawa,et al.  Proliferation of Immature Myeloma Cells by Interleukin-6 Is Associated with CD45 Expression in Human Multiple Myeloma , 2000, Leukemia & lymphoma.

[91]  P. Socha,et al.  Deficiency of the expression of CD45RA isoform of CD45 common leukocyte antigen in CD4+ T lymphocytes in children with infantile cholestasis. , 2001, Immunology Letters.

[92]  Karel Drbal,et al.  Phosphoprotein Associated with Glycosphingolipid-Enriched Microdomains (Pag), a Novel Ubiquitously Expressed Transmembrane Adaptor Protein, Binds the Protein Tyrosine Kinase Csk and Is Involved in Regulation of T Cell Activation , 2000, The Journal of experimental medicine.

[93]  M. Fournel,et al.  Negative regulation of T-cell receptor signalling by tyrosine protein kinase p50csk , 1993, Nature.

[94]  Warren S. Alexander,et al.  A family of cytokine-inducible inhibitors of signalling , 1997, Nature.

[95]  E. Bell,et al.  Interconversion of CD45R subsets of CD4 T cells in vivo , 1990, Nature.

[96]  Ursula Klingmüller,et al.  Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals , 1995, Cell.

[97]  A. Veillette,et al.  Src-related protein tyrosine kinases and T-cell receptor signalling. , 1992, Trends in genetics : TIG.

[98]  J. Altin,et al.  The role of CD45 and CD45‐associated molecules in T cell activation , 1997, Immunology and cell biology.

[99]  T. Mak,et al.  T cell development in mice expressing splice variants of the protein tyrosine phosphatase CD45. , 1997, Journal of immunology.

[100]  J. Partanen,et al.  The human p50csk tyrosine kinase phosphorylates p56lck at Tyr‐505 and down regulates its catalytic activity. , 1992, The EMBO journal.

[101]  E. Petricoin,et al.  Antiproliferative action of interferon-α requires components of T-cell-receptor signalling , 1997, Nature.