|List |< first << previous [record 31 of 511] next >> last >||
|Coordinate||138,137,493 bp (GRCm38)|
|Base Change||T ⇒ A (forward strand)|
|Gene Name||protein tyrosine phosphatase, receptor type, C|
|Synonym(s)||B220, Ly-5, Lyt-4, CD45, T200|
|Chromosomal Location||138,062,861-138,175,708 bp (-)|
|MGI Phenotype||Homozygous null mutants have defective T cell, B cell, and NK cell morphology and physiology. Mice carrying an engineered point mutation exhibit lymphoproliferation and autoimmunity that leads to premature death.|
|Amino Acid Change||Lysine changed to Stop codon|
|Institutional Source||Beutler Lab|
K422* in Ensembl: ENSMUSP00000027645 (fasta)
K283* in Ensembl: ENSMUSP00000107667 (fasta)
|Gene Model||not available|
|Phenotypic Category||Autosomal Recessive|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Local Stock||Sperm, gDNA|
|Last Updated||2018-04-02 9:19 PM by Diantha La Vine|
|Record Created||2009-07-17 12:00 AM|
Belittle is an independent mutation, detected by an aberrant phenotype within the maladaptive pedigree, but distinct from the Rag1 mutation. The belittle phenotype is defined by a near complete absence of T cells, and the presence of normal percentages of CD45-deficient B cells (Figure 1). A mutation of Ptprc was suspected on this basis.
|Nature of Mutation|
The Ptprc gene was sequenced, and an A to T transversion identified at position 74078 of the genomic DNA sequence (Genbank genomic region NC_000067 for linear genomic DNA sequence of Ptprc). Several isoforms of Ptprc are expressed due to alternative splicing. Originally, only exons 4-6 were found to be alternatively spliced (1), but some evidence suggests that exons 7, 8, and 10 may also be alternatively spliced (see Protein Prediction) (2;3). NCBI Genbank contains sequences for two isoforms, one containing all 33 exons (isoform 1, NM_001111316), and one lacking exons 4, 5, and 6 (isoform 2, NM_011210). The belittle mutation occurs in exon 13 of 33 total exons in isoform 1, and exon 10 of 30 total exons in isoform 2. The mutated residue corresponds to nucleotide 1407 and nucleotide 990, respectively, in the cDNA sequences of Ptprc isoform 1 and isoform 2.
The mutated nucleotide is indicated in red lettering, and converts lysine 422 (isoform 1) or 283 (isoform 2) of the CD45 protein to a stop.
The extracellular domain of CD45 consists of five heavily glycosylated regions, and is observed to form an extended rod-like structure when visualized by electron microscopy after low-angle rotary shadowing (12). The three membrane proximal domains are members of the type III fibronectin (fnIII) domain family, and are conserved in all species examined (10;11). Following the three fnIII domains is a cysteine-rich region that appears to form a globular domain with high β-sheet content but no α-helices (13). The cysteine-rich region contains five cysteines conserved in all mammalian CD45 molecules, which form two intradomain disulfide bonds, and one disulfide bond with the adjacent fnIII domain (13). Following these four structural domains is the most N-terminal domain, furthest from the cell membrane, containing all of the variation represented by the several protein isoforms. These isoforms are generated by alternative splicing of at least three exons (4, 5, and 6), which encode peptides (designated A, B, and C, respectively) ~50 amino acids in length. The protein isoforms are commonly named based on the exons included, with the largest isoform (RABC) including all three exons, RAB including exons 4 and 5, etc., and the smallest isoform lacking all three exons designated RO. In contrast to the cysteine-rich and fnIII domains that are N-glycosylated, the three alternative exons encode multiple sites of O-linked glycosylation and are variably modified by sialic acid (10;14;15). As a result, the various isoforms have molecular weights ranging from 180 kD (RO) to 240 kD (RABC), and differ in size, shape, and negative charge. The differential glycosylation of CD45 may influence its interactions with lectins, its organization into cell surface microdomains, and subsequent downstream signaling (16;17).
The cytoplasmic domain of CD45 contains a juxtamembrane region followed by tandem PTP domains of ~240 residues (D1 and D2) separated by a short spacer and a C-terminal tail. Mutation of the catalytic cysteine (residue 828) in D1 abolishes the phosphatase activity of the protein, demonstrating that only D1 is catalytically active (18). However, optimal phosphatase activity in cells requires both domains (19). Within the second PTP domain is a unique acidic region of 19 residues that contains multiple sites for serine phosphorylation by casein kinase II (20;21). This modification is important for optimal CD45 phosphatase activity toward a model substrate in vitro and for cellular signaling leading to Ca2+ flux in Jurkat T cells, although the mechanistic basis for these effects is unknown. The D2 domain may also modulate substrate access and localization, as suggested by the interaction of D2 with the CD45 substrate Lck (22).
The crystal structure of the CD45 cytoplasmic domain lacking the C-terminal tail has shown that domains D1 and D2 adopt similar structures, with core conformations resembling those of other PTP domains (23). The domains consist of a highly twisted nine-stranded β-sheet flanked by six α-helices, four on one side and two on the other (Figure 3; PDB ID 1YGU). When crystallized in the presence of monomeric phosphotyrosine or the phosphorylated membrane proximal immunoreceptor tyrosine-based activation motif (ITAM) of the CD3ζ chain, only the D1 active site of CD45 is filled while D2 remains empty. Substrate residues between pY-3 and pY+2 bind in the active site pocket of D1 and determine phosphatase specificity, with optimal binding for substrates containing a hydrophilic residue at the pY-1 position, and negatively charged residues located around the pY-2 position. Inspection of the structure of the D2 domain supports the finding that it is catalytically inactive, since compared to that of D1, its active site pocket is significantly altered in shape and unable to accommodate a phosphoryl group. Loops surrounding the D2 active site also differ substantially in structure from those around the D1 active site. Two extra loops in D2, the acidic and basic loops, may help to recruit substrates to the active site of D1.
The cytoplasmic juxtamembrane region of CD45 forms a helix-turn-helix “wedge” structure, observed in receptor-like PTP α (RPTPα) and leukocyte common antigen-related (LAR) receptor proteins (24;25). In its crystal structure, dimerization of RPTPα results in an inactive phosphatase due to reciprocal blockage of active sites by the wedge structure of opposing monomers (24). Such wedge-mediated dimeric interaction is not supported by the monomeric CD45 crystal structure, which suggests that steric constraints would prevent the structural deformation required for this intermolecular interaction (23). However, negative regulation of CD45 by dimerization is supported by several studies employing cells and/or mice, although involvement of the wedge was not definitively demonstrated (26-28). CD45 lacking the entire cytoplasmic domain, or containing a point mutation of the wedge, is capable of dimerizing, demonstrating that the extracellular and transmembrane domains are sufficient to mediate dimerization (29). Further studies are needed to determine the role of the wedge in CD45 regulation.
The belittle mutation is a premature stop introduced at residue 422 of the 1291-residue full length CD45 protein (containing all exons). The mutation resides in the middle fnIII domain.
CD45 expression is restricted to all nucleated hematopoietic cells (30). Expression of individual isoforms is controlled in a cell type-specific manner that is conserved through mammalian evolution (9;31). In general, B lymphocytes of humans, mice, rats, and sheep express only the highest molecular weight form containing all exons, T cells express a mix of isoforms, and thymocytes remove exons 4, 5, and 6, and express the lowest molecular weight form. It is estimated that up to 10% of lymphocyte surface is occupied by CD45. Myeloid lineage cells express the CD45RO isoform until activated, when they upregulate exon A-containing isoforms (32-34).
CD45 isoform expression has been best studied in T lineage cells, where it is regulated in a developmental and activation state-dependent manner. In mice, CD4+CD8+ double positive (DP) thymocytes express predominantly CD45RO, along with lesser amounts of CD45RB and CD45RBC (35). Positive selection is associated with a twofold increase in total CD45 expression (35;36). Human CD45 expression on developing thymocytes is similar to that in mouse, with CD4+CD8+ DP thymocytes expressing predominantly CD45RO and CD45RB (37). Thymic T cell maturation is associated with maintenance of CD45RB expression, slight downregulation of CD45RO, and increased expression of higher molecular weight CD45 isoforms containing the A exon product (35;37;38).
Mature quiescent T cells predominantly express CD45RO and CD45RB, although lower levels of exon A-containing isoforms are also expressed (39;40). CD8+ T cells appear to express the higher molecular weight forms more abundantly than do CD4+ T cells (35). Upon T cell activation, protein expression of mixed larger (exon A-containing) isoforms transiently increases during the first day post-stimulation. Over the subsequent three days, CD45 isoforms containing exons A, B, and C are downregulated and replaced by CD45RO (41-43). The switch to expression of CD45RO is reportedly dependent on Ras and protein kinase C (44). CD45RO is an accepted marker for memory T cells (45;46).
CD45 was identified in the 1970s as the major specificity of anti-lymphocyte sera and as an allotypic marker [reviewed in (9;47)]. It was also identified in protein gels of lymphocyte membranes. cDNA sequencing revealed that the cytoplasmic tandem repeats were similar in sequence to human placental PTP1B, and subsequently CD45 was shown to have phosphatase activity (7;8). Since then, much work has focused on the different forms of CD45, their source, and their functions both in isolated cells and in mice.
CD45 alternative splicing, tissue and cell-specific isoform expression, and the cis- and trans-acting factors regulating them have been extensively studied. Counting exons 4, 5, 6, 7, 8, and 10 as candidates for alternative splicing, the number of possible isoforms is quite large. However, significant expression of only six isoforms has been detected at the protein level in T lineage cells where it has been best studied. The existence of RO, RB, RAB, RBC, and RABC is well established, whereas E3_8, which lacks exons 4-7, is consistently observed at the mRNA level (35;37) but has not been definitively demonstrated at the protein level (48). As mentioned above (Expression/Localization), CD45 protein isoform expression is regulated in a cell type and developmental stage-specific manner, and reflects the levels of alternatively spliced CD45 transcripts. The regulation of mRNA expression requires sequences within and flanking exons 4, 5, and 6, and is thought to be mediated by cell-specific factors (40;49-52).
Both positive and negative trans-acting regulatory factors have been implicated in the control of CD45 alternative splicing (40;49). The SR proteins, characterized by the presence of one or two RNA recognition motifs and an arginine- and serine-rich (RS) domain, are essential components of the spliceosome, functioning in constitutive and alternative splicing (53). The SR proteins also play an important role in splice site selection via binding to elements known as ESEs and ISEs (exonic and intronic splicing enhancers) and ESSs and ISSs (exonic and intronic splicing silencers) within the pre-mRNA. Using a heterologous system expressing a CD45 minigene, it has been demonstrated that overexpression of the SR proteins SRp20 and 9G8 can facilitate exon inclusion, whereas SWAP, SF2/ASF, SC35, SRp30C, SRp40, and SRp75 can promote exon exclusion (54-56). Studies of a human Ptprc polymorphism located in exon 4 (C77G) led to the discovery of a specific nucleotide sequence motif in exons 4, 5, and 6 that is necessary and sufficient to induce exon skipping (57;58). This sequence, termed exonic splicing silencer (ESS1) or activation-responsive sequence (ARS), has been shown to bind in vitro to heterogeneous nuclear ribonucleoprotein L-like (hnRNPLL) protein, hnRNPL, and PTB-associated splicing factor (PSF) (52;59-61). A point mutation of Hnrpll in mice (mutated in thunder) alters the proportions of naïve and memory T cells, and impairs Ptprc exon silencing needed to generate CD45RO in memory T cells (62).
The physiological function of CD45 has been examined most extensively in T cells. Studies with CD45-deficient cell lines identified CD45 as an obligate positive regulator of antigen receptor signaling, since T cells lacking CD45 failed to proliferate or produce cytokines in response to TCR stimulation (63;64). The generation of CD45-deficient mice through targeted deletion exons 6, 9, or 12 confirmed these data. Ptprc-/- mice have profound defects in thymic development due to dysfunctional signaling through the preTCR and TCR, leading to a block in thymocyte development at β selection and at the DP stage (65-67). As a result, the absolute number of DP thymocytes is reduced twofold, and the number of single positive (SP) thymocytes is reduced five-fold. An ENU-induced mutation in Ptprc that results in insertion of 26 amino acids before a premature stop codon, designated lochy, results in normal numbers of B cells and bone marrow B220+CD19+ cells, reduced numbers of bone marrow B220loCD19+ cells, a block in thymocyte DP to SP transition, reduced numbers of CD4+ and CD8+ SP thymocytes, reduced numbers of naïve CD8+ T cells, and a shift toward an activated/memory CD8+ T cell phenotype in homozygous mutant mice.
Interestingly, the level of CD45 expression may determine cellular outcome, as suggested by the finding that CD45-deficient mice reconstituted with different expression levels of transgenic CD45RO required only 3% of wild type CD45 activity to restore normal T cell numbers and normal cytotoxic T cell responses (75). Expression of 30% of wild type CD45 levels, however, resulted in augmented production of CD4 and CD8 SP cells. Preferential hyperphosphorylation of the inhibitory tyrosine of Lck in was observed in CD45-deficient, or low expressing transgenic mice, but a near equal level of activation loop and C-terminal tyrosine phosphorylation was observed in mice with intermediate CD45 expression. These data suggest that much less phosphatase activity is required to dephosphorylate the C-terminal inhibitory tyrosine and “prime” the kinase, than to dephosphorylate the activation loop tyrosine and inhibit kinase activation. The high levels of CD45 expression on lymphocytes are hypothesized to be required to dephosphorylate the activation loop tyrosine and suppress aberrant positive selection and hyperactivity of T cells. The complicated mechanisms of Lck (and Fyn) regulation by CD45 are further highlighted by the different phenotypes of CD45- and double mutant Lck/Fyn-deficient mice. Lck/Fyn-deficient thymocytes are predominantly blocked at the DN stage, while CD45-deficient thymocytes are blocked at the DP stage.
CD45 deficiency has less severe consequences for B cells than for T cells. Peripheral B cell numbers are actually increased in CD45-deficient mice (65-67). Marginal zone B cells are increased, while B1 cell production is decreased, and B cell development is blocked at the transitional 2 (T2) to mature follicular B cell transition (28). CD45 does not appear to be a simple positive regulator of Src family kinases in B cells, consistent with the fact that mice lacking Blk, Lyn, and Fyn, the predominant B cell Src family kinases, exhibit a different phenotype (severe block in B cell development at the pro-B cell stage) than CD45-deficient mice. Studies of CD45-deficient mice expressing transgenes for CD45RO, CD45RB, or CD45RABC, again suggest that the levels of CD45 expression influence cellular outcome. Expression of any of the three transgenes at a level lower than wild type is able to rescue thymic development and peripheral T cell function, but fails to permit normal B cell maturation (76;77). In contrast, transgenic expression of a CD45 minigene at wild type levels in CD45-deficient mice rescues both T and B cell functions (78).
As mentioned above, CD45 negatively regulates Src family kinases in macrophages to control integrin-mediated cell adhesion (72). Additional roles for CD45 in cells of the myeloid lineage have been reported. In mast cells, CD45 deficiency results in defective histamine degranulation after IgE receptor cross-linking, although the mechanism remains unclear (79). Dendritic cells (DC) lacking CD45 display altered responses to Toll-like receptor (TLR) stimulation, producing reduced amounts of interleukin (IL)-12p70, tumor necrosis factor (TNF)-α, and IL-6 in response to TLR4 stimulation, but increased amounts of TNF-α and IL-6 in response to TLR1/2, TLR3 or TLR9 stimulation (80;81). In contrast, interferon (IFN)-β production by CD45-deficient DC in response to TLR3 stimulation was reduced compared to that of wild type DC (80). IFN-α production by CD45-deficient DC was reportedly normal in response to TLR3 or TLR9 stimulation (81). It has been hypothesized that CD45 positively regulates MyD88-independent signaling, and negatively regulates MyD88-dependent signaling (80). Whether CD45 signaling impinges on Src family kinases, NF-κB, MAPKs, or other TLR signaling pathway components to modulate cytokine production is not established. A role for CD45 in cytokine production in natural killer (NK) cells is suggested by the severely impaired IFN-γ production of CD45-deficient NK cells in response to stimulation with anti-NKG2D, Ly49D, or NK1.1 antibodies, but not PMA/ionomycin (82;83). Surprisingly, CD45-deficient NK cells are fully competent in killing NK cell targets in vitro. A defect in ERK and JNK activation following NK cell stimulation may underlie the impaired cytokine production (82;83).
Ligand binding, localization, and dimerization have been hypothesized as mechanisms to control CD45 activity in cells. Although the expression of multiple CD45 isoforms suggested that ligand-regulated activation may be important, so far no specific ligand has been identified. There is evidence that CD45 function is regulated, via interactions with proteins such as spectrin and ankyrin (84), through localization in cell surface microdomains including TCR-containing lipid rafts and central supramolecular activation clusters (cSMAC) of the immunological synapse (85;86). Dimerization as a means to negatively regulate phosphatase activity is supported by many reports (26-28). The cytoplasmic wedge of CD45 has been proposed to mediate dimerization and inhibition by binding to the catalytic site of another CD45 molecule. To test the importance of the wedge, a point mutation was introduced into the tip of the wedge in human CD45 and found to eliminate the inhibitory effects of forced dimerization (26). Introduction of the analogous mutation (E613R) in mice of mixed C57BL/6-129 background resulted in a dominant phenotype characterized by lymphoproliferative disease with polyclonal T and B lymphocyte activation and autoimmune nephritis with autoantibody production, leading to premature death (27). Interestingly, these phenotypes were conferred by mutant B cells, since genetic elimination of B cells but not T cells in CD45 E613R mice abrogated the lymphoproliferation (28). Despite these findings, the involvement of the wedge in dimerization and inhibition is uncertain, since the extracellular domain alone can mediate dimerization, and steric hindrance between D1 and D2 domains may preclude wedge-mediated dimerization (25;29).
Humans deficient in CD45 develop severed combined immunodeficiency (SCID) with defects in T and B cell development and function (OMIM #608971) (87;88). Polymorphisms in CD45 may also influence immune functions in humans [(89) and references therein]. A rare, translationally silent polymorphism, C77G in exon 4 of CD45, has been associated with multiple sclerosis, autoimmune hepatitis, HIV, Langerhans cell histiocytosis, and systemic sclerosis in some ethnic backgrounds but not in others. The mutation lies in the ESS of exon 4 and prevents its exclusion from the mature transcript (58). It has also been found in four patients with systemic lupus erythematosus, one with myasthenia gravis, and in families with hemophagocytic lymphohistiocytosis. In one study, the C77G polymorphism occured twice as frequently among hepatitis C virus-infected patients than in healthy individuals (90). A second polymorphism, A138G in exon 6, results a threonine to alanine substitution of residue 47, a potential glycosylation site, and may cause exon skipping. The allele is found at a frequency of 20% in Asian populations, and carriers exhibit increased expression of CD45RO in both CD8+ and CD4+ T cells (91). It has been associated with a protective effect in hepatitis B virus infection and autoimmune Graves’ thyroiditis (92).
The belittle mutation creates a premature stop codon within the first third of the Ptprc transcript that is likely to result in nonsense-mediated decay of the aberrant mRNA. Staining of belittle B cells with a pan-specific CD45 antibody (anti-CD45.2, clone 104, eBioscience), or an antibody specific to exon A-containing molecules (anti-B220, clone RA3-6B2, eBioscience), revealed no CD45 is expressed on CD19+ B cells. Homozygous belittle mice have a drastic reduction of T cells similar to that observed in CD45 null animals, supporting the idea that belittle mice do not express CD45.
|Primers||Primers cannot be located by automatic search.|
Belittle genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transversion.
belittle (F): 5’-TGTCTTCTCTACGCACAATTAAAGCCC -3’
belittle (R): 5’- AGTCACAGATTCCACCTTACTCCAGG -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C ∞
Primers for sequencing
belittle_seq(F): 5’- TACACACACCTGAAGATTTGGAG -3’
belittle_seq(R): 5’- GGACATCATTAAGTGTCTAGCTGC -3’
The following sequence of 1039 nucleotides (from Genbank genomic region NC_000067 for linear genomic sequence of Ptprc, sense strand) is amplified:
73720 t gtcttctcta cgcacaatta
73741 aagccctctc cacatttctc atcttcctct tcatgtcacc tatatcctgc ccttctgccc
73801 tttccctctc tagatgcccc cttccctgtc cttttttttt ttttttttaa tggtcctggt
73861 ttctgcagtt actctaggtt gtatacacac acctgaagat ttggagctag gagcacagac
73921 tagagaaaac atgttgtttt tgcctttctg tataaattcc ctcaatattt ggagtctgct
73981 tgggatcata ttatgtaaac atcaagttat ctgcacaggg atcctgactt tcagaaactt
74041 actaactcag gctttctttt taattctaga aaaatgtaaa agtttgccta ataatgtgac
74101 cagttttgag gtggaaagct tgaaacctta taaatactat gaagtgtccc tacttgccta
74161 tgtcaatggg aagattcaaa gaaatgggac tgctgagaag tgcaattttc acacaaaagc
74221 agatcgtaag tttttggctt taatatttct tccatgaatg gcaaatgaca tttttatgtg
74281 aaatgcattg ctctttctac ttctgctggc acgtttgttt acttctgaag ttttaaataa
74341 tttaatagaa aattatttaa ccactgcaaa tcaaggttca ctgtatctat ctgatagagt
74401 gacagagttg aagtaacaaa gcaggaggcc tcaccagcca gtgtacttcc taaggcttca
74461 aacacttaat taagcatctc agcaacttag attaaaaatt ctcactttag tatctagaaa
74521 cacaaactgc agctagacac ttaatgatgt cctacagaac cctgatagaa catttcataa
74581 tataaagcat gttttggtac ttatttcatg ttatgttttt cgctggaaat tttaatggtc
74641 ttgcttctcg tgtggccttg ctgaaataag gctaagttat gtctccctgg taactgctta
74701 atctcaatta gggtcaggga agaagaaaga gtcctggagt aaggtggaat ctgtgact
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated A is indicated in red.
1. Saga, Y., Furukawa, K., Rogers, P., Tung, J. S., Parker, D., and Boyse, E. A. (1990) Further Data on the Selective Expression of Ly-5 Isoforms. Immunogenetics. 31, 296-306.
2. Chang, H. L., Lefrancois, L., Zaroukian, M. H., and Esselman, W. J. (1991) Developmental Expression of CD45 Alternate Exons in Murine T Cells. Evidence of Additional Alternate Exon use. J. Immunol. 147, 1687-1693.
3. Virts, E., Barritt, D., and Raschke, W. C. (1998) Expression of CD45 Isoforms Lacking Exons 7, 8 and 10. Mol. Immunol. 35, 167-176.
4. Trowbridge, I. S., and Mazauskas, C. (1976) Immunological Properties of Murine Thymus-Dependent Lymphocyte Surface Glycoproteins. Eur. J. Immunol. 6, 557-562.
5. Coffman, R. L., and Weissman, I. L. (1981) B220: A B Cell-Specific Member of Th T200 Glycoprotein Family. Nature. 289, 681-683.
6. Komuro, K., Itakura, K., Boyse, E. A., and John, M. (1974) Ly-5: A New T-Lymphocyte Antigen System. Immunogenetics. 1, 452-456.
7. Charbonneau, H., Tonks, N. K., Walsh, K. A., and Fischer, E. H. (1988) The Leukocyte Common Antigen (CD45): A Putative Receptor-Linked Protein Tyrosine Phosphatase. Proc. Natl. Acad. Sci. U. S. A. 85, 7182-7186.
8. Tonks, N. K., Charbonneau, H., Diltz, C. D., Fischer, E. H., and Walsh, K. A. (1988) Demonstration that the Leukocyte Common Antigen CD45 is a Protein Tyrosine Phosphatase. Biochemistry. 27, 8695-8701.
10. Okumura, M., Matthews, R. J., Robb, B., Litman, G. W., Bork, P., and Thomas, M. L. (1996) Comparison of CD45 Extracellular Domain Sequences from Divergent Vertebrate Species Suggests the Conservation of Three Fibronectin Type III Domains. J. Immunol. 157, 1569-1575.
11. Nagata, T., Suzuki, T., Ohta, Y., Flajnik, M. F., and Kasahara, M. (2002) The Leukocyte Common Antigen (CD45) of the Pacific Hagfish, Eptatretus Stoutii: Implications for the Primordial Function of CD45. Immunogenetics. 54, 286-291.
12. Woollett, G. R., Williams, A. F., and Shotton, D. M. (1985) Visualisation by Low-Angle Shadowing of the Leucocyte-Common Antigen. A Major Cell Surface Glycoprotein of Lymphocytes. EMBO J. 4, 2827-2830.
13. Symons, A., Willis, A. C., and Barclay, A. N. (1999) Domain Organization of the Extracellular Region of CD45. Protein Eng. 12, 885-892.
14. Sato, T., Furukawa, K., Autero, M., Gahmberg, C. G., and Kobata, A. (1993) Structural Study of the Sugar Chains of Human Leukocyte Common Antigen CD45. Biochemistry. 32, 12694-12704.
15. Furukawa, K., Funakoshi, Y., Autero, M., Horejsi, V., Kobata, A., and Gahmberg, C. G. (1998) Structural Study of the O-Linked Sugar Chains of Human Leukocyte Tyrosine Phosphatase CD45. Eur. J. Biochem. 251, 288-294.
16. van Vliet, S. J., Gringhuis, S. I., Geijtenbeek, T. B., and van Kooyk, Y. (2006) Regulation of Effector T Cells by Antigen-Presenting Cells Via Interaction of the C-Type Lectin MGL with CD45. Nat. Immunol. 7, 1200-1208.
17. Chen, I. J., Chen, H. L., and Demetriou, M. (2007) Lateral Compartmentalization of T Cell Receptor Versus CD45 by Galectin-N-Glycan Binding and Microfilaments Coordinate Basal and Activation Signaling. J. Biol. Chem. 282, 35361-35372.
18. Streuli, M., Krueger, N. X., Thai, T., Tang, M., and Saito, H. (1990) Distinct Functional Roles of the Two Intracellular Phosphatase Like Domains of the Receptor-Linked Protein Tyrosine Phosphatases LCA and LAR. EMBO J. 9, 2399-2407.
19. Desai, D. M., Sap, J., Silvennoinen, O., Schlessinger, J., and Weiss, A. (1994) The Catalytic Activity of the CD45 Membrane-Proximal Phosphatase Domain is Required for TCR Signaling and Regulation. EMBO J. 13, 4002-4010.
20. Wang, Y., Guo, W., Liang, L., and Esselman, W. J. (1999) Phosphorylation of CD45 by Casein Kinase 2. Modulation of Activity and Mutational Analysis. J. Biol. Chem. 274, 7454-7461.
21. Greer, S. F., Wang, Y., Raman, C., and Justement, L. B. (2001) CD45 Function is Regulated by an Acidic 19-Amino Acid Insert in Domain II that Serves as a Binding and Phosphoacceptor Site for Casein Kinase 2. J. Immunol. 166, 7208-7218.
22. Wang, Y., and Johnson, P. (2005) Expression of CD45 Lacking the Catalytic Protein Tyrosine Phosphatase Domain Modulates Lck Phosphorylation and T Cell Activation. J. Biol. Chem. 280, 14318-14324.
23. Nam, H. J., Poy, F., Saito, H., and Frederick, C. A. (2005) Structural Basis for the Function and Regulation of the Receptor Protein Tyrosine Phosphatase CD45. J. Exp. Med. 201, 441-452.
24. Bilwes, A. M., den Hertog, J., Hunter, T., and Noel, J. P. (1996) Structural Basis for Inhibition of Receptor Protein-Tyrosine Phosphatase-Alpha by Dimerization. Nature. 382, 555-559.
25. Nam, H. J., Poy, F., Krueger, N. X., Saito, H., and Frederick, C. A. (1999) Crystal Structure of the Tandem Phosphatase Domains of RPTP LAR. Cell. 97, 449-457.
26. Majeti, R., Bilwes, A. M., Noel, J. P., Hunter, T., and Weiss, A. (1998) Dimerization-Induced Inhibition of Receptor Protein Tyrosine Phosphatase Function through an Inhibitory Wedge. Science. 279, 88-91.
27. Majeti, R., Xu, Z., Parslow, T. G., Olson, J. L., Daikh, D. I., Killeen, N., and Weiss, A. (2000) An Inactivating Point Mutation in the Inhibitory Wedge of CD45 Causes Lymphoproliferation and Autoimmunity. Cell. 103, 1059-1070.
28. Hermiston, M. L., Tan, A. L., Gupta, V. A., Majeti, R., and Weiss, A. (2005) The Juxtamembrane Wedge Negatively Regulates CD45 Function in B Cells. Immunity. 23, 635-647.
29. Xu, Z., and Weiss, A. (2002) Negative Regulation of CD45 by Differential Homodimerization of the Alternatively Spliced Isoforms. Nat. Immunol. 3, 764-771.
30. Scheid, M. P., and Triglia, D. (1979) Further Description of the Ly-5 System. Immunogenetics. 9, 423-433.
31. Thomas, M. L., and Lefrancois, L. (1988) Differential Expression of the Leucocyte-Common Antigen Family. Immunol. Today. 9, 320-326.
32. Anderson, K. L., Nelson, S. L., Perkin, H. B., Smith, K. A., Klemsz, M. J., and Torbett, B. E. (2001) PU.1 is a Lineage-Specific Regulator of Tyrosine Phosphatase CD45. J. Biol. Chem. 276, 7637-7642.
33. Schwinzer, R., Schraven, B., Kyas, U., Meuer, S. C., and Wonigeit, K. (1992) Phenotypical and Biochemical Characterization of a Variant CD45R Expression Pattern in Human Leukocytes. Eur. J. Immunol. 22, 1095-1098.
34. Brohee, D., and Higuet, N. (1992) In Vitro Stimulation of Peripheral Blood Mononuclear Cells by Phytohaemagglutinin A Induces CD45RA Expression on Monocytes. Cytobios. 71, 105-111.
35. McNeill, L., Cassady, R. L., Sarkardei, S., Cooper, J. C., Morgan, G., and Alexander, D. R. (2004) CD45 Isoforms in T Cell Signalling and Development. Immunol. Lett. 92, 125-134.
36. Kirberg, J., and Brocker, T. (1996) CD45 Up-Regulation during Lymphocyte Maturation. Int. Immunol. 8, 1743-1749.
37. Fukuhara, K., Okumura, M., Shiono, H., Inoue, M., Kadota, Y., Miyoshi, S., and 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.
38. Lefrancois, L., and Goodman, T. (1987) Developmental Sequence of T200 Antigen Modifications in Murine T Cells. J. Immunol. 139, 3718-3724.
39. Hathcock, K. S., Laszlo, G., Dickler, H. B., Sharrow, S. O., Johnson, P., Trowbridge, I. S., and Hodes, R. J. (1992) Expression of Variable Exon A-, B-, and C-Specific CD45 Determinants on Peripheral and Thymic T Cell Populations. J. Immunol. 148, 19-28.
40. Rothstein, D. M., Saito, H., Streuli, M., Schlossman, S. F., and Morimoto, C. (1992) The Alternative Splicing of the CD45 Tyrosine Phosphatase is Controlled by Negative Regulatory Trans-Acting Splicing Factors. J. Biol. Chem. 267, 7139-7147.
41. Rothstein, D. M., Yamada, A., Schlossman, S. F., and Morimoto, C. (1991) Cyclic Regulation of CD45 Isoform Expression in a Long Term Human CD4+CD45RA+ T Cell Line. J. Immunol. 146, 1175-1183.
42. Birkeland, M. L., Johnson, P., Trowbridge, I. S., and Pure, E. (1989) Changes in CD45 Isoform Expression Accompany Antigen-Induced Murine T-Cell Activation. Proc. Natl. Acad. Sci. U. S. A. 86, 6734-6738.
43. Akbar, A. N., Terry, L., Timms, A., Beverley, P. C., and Janossy, G. (1988) Loss of CD45R and Gain of UCHL1 Reactivity is a Feature of Primed T Cells. J. Immunol. 140, 2171-2178.
44. Lynch, K. W., and Weiss, A. (2000) A Model System for Activation-Induced Alternative Splicing of CD45 Pre-mRNA in T Cells Implicates Protein Kinase C and Ras. Mol. Cell. Biol. 20, 70-80.
45. Michie, C. A., McLean, A., Alcock, C., and Beverley, P. C. (1992) Lifespan of Human Lymphocyte Subsets Defined by CD45 Isoforms. Nature. 360, 264-265.
46. Hamann, D., Baars, P. A., Rep, M. H., Hooibrink, B., Kerkhof-Garde, S. R., Klein, M. R., and van Lier, R. A. (1997) Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells. J. Exp. Med. 186, 1407- 1418.
47. Trowbridge, I. S. (1991) CD45. A Prototype for Transmembrane Protein Tyrosine Phosphatases. J. Biol. Chem. 266, 23517-23520.
49. Saga, Y., Lee, J. S., Saraiya, C., and Boyse, E. A. (1990) Regulation of Alternative Splicing in the Generation of Isoforms of the Mouse Ly-5 (CD45) Glycoprotein. Proc. Natl. Acad. Sci. U. S. A. 87, 3728-3732.
50. Tsai, A. Y., Streuli, M., and Saito, H. (1989) Integrity of the Exon 6 Sequence is Essential for Tissue-Specific Alternative Splicing of Human Leukocyte Common Antigen Pre-mRNA. Mol. Cell. Biol. 9, 4550-4555.
51. Streuli, M., and Saito, H. (1989) Regulation of Tissue-Specific Alternative Splicing: Exon-Specific Cis-Elements Govern the Splicing of Leukocyte Common Antigen Pre-mRNA. EMBO J. 8, 787-796.
52. Tong, A., Nguyen, J., and Lynch, K. W. (2005) Differential Expression of CD45 Isoforms is Controlled by the Combined Activity of Basal and Inducible Splicing-Regulatory Elements in each of the Variable Exons. J. Biol. Chem. 280, 38297-38304.
53. Long, J. C., and Caceres, J. F. (2009) The SR Protein Family of Splicing Factors: Master Regulators of Gene Expression. Biochem. J. 417, 15-27.
54. Sarkissian, M., Winne, A., and Lafyatis, R. (1996) The Mammalian Homolog of Suppressor-of-White-Apricot Regulates Alternative mRNA Splicing of CD45 Exon 4 and Fibronectin IIICS. J. Biol. Chem. 271, 31106-31114.
55. Lemaire, R., Winne, A., Sarkissian, M., and Lafyatis, R. (1999) SF2 and SRp55 Regulation of CD45 Exon 4 Skipping during T Cell Activation. Eur. J. Immunol. 29, 823-837.
56. ten Dam, G. B., Zilch, C. F., Wallace, D., Wieringa, B., Beverley, P. C., Poels, L. G., and Screaton, G. R. (2000) Regulation of Alternative Splicing of CD45 by Antagonistic Effects of SR Protein Splicing Factors. J. Immunol. 164, 5287-5295.
57. Rothrock, C., Cannon, B., Hahm, B., and Lynch, K. W. (2003) A Conserved Signal-Responsive Sequence Mediates Activation-Induced Alternative Splicing of CD45. Mol. Cell. 12, 1317-1324.
58. Lynch, K. W., and Weiss, A. (2001) A CD45 Polymorphism Associated with Multiple Sclerosis Disrupts an Exonic Splicing Silencer. J. Biol. Chem. 276, 24341-24347.
59. Oberdoerffer, S., Moita, L. F., Neems, D., Freitas, R. P., Hacohen, N., and Rao, A. (2008) Regulation of CD45 Alternative Splicing by Heterogeneous Ribonucleoprotein, hnRNPLL. Science. 321, 686-691.
60. Topp, J. D., Jackson, J., Melton, A. A., and Lynch, K. W. (2008) A Cell-Based Screen for Splicing Regulators Identifies hnRNP LL as a Distinct Signal-Induced Repressor of CD45 Variable Exon 4. RNA. 14, 2038-2049.
61. Melton, A. A., Jackson, J., Wang, J., and Lynch, K. W. (2007) Combinatorial Control of Signal-Induced Exon Repression by hnRNP L and PSF. Mol. Cell. Biol. 27, 6972-6984.
62. Wu, Z., Jia, X., de la Cruz, L., Su, X. C., Marzolf, B., Troisch, P., Zak, D., Hamilton, A., Whittle, B., Yu, D., Sheahan, D., Bertram, E., Aderem, A., Otting, G., Goodnow, C. C., and Hoyne, G. F. (2008) Memory T Cell RNA Rearrangement Programmed by Heterogeneous Nuclear Ribonucleoprotein hnRNPLL. Immunity. 29, 863-875.
63. Pingel, J. T., and Thomas, M. L. (1989) Evidence that the Leukocyte-Common Antigen is Required for Antigen-Induced T Lymphocyte Proliferation. Cell. 58, 1055-1065.
64. Weaver, C. T., Pingel, J. T., Nelson, J. O., and Thomas, M. L. (1991) CD8+ T-Cell Clones Deficient in the Expression of the CD45 Protein Tyrosine Phosphatase have Impaired Responses to T-Cell Receptor Stimuli. Mol. Cell. Biol. 11, 4415-4422.
65. Mee, P. J., Turner, M., Basson, M. A., Costello, P. S., Zamoyska, R., and Tybulewicz, V. L. (1999) Greatly Reduced Efficiency of both Positive and Negative Selection of Thymocytes in CD45 Tyrosine Phosphatase-Deficient Mice. Eur. J. Immunol. 29, 2923-2933.
66. Byth, K. F., Conroy, L. A., Howlett, S., Smith, A. J., May, J., Alexander, D. R., and 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 B Cell Maturation. J. Exp. Med. 183, 1707-1718.
67. Kishihara, K., Penninger, J., Wallace, V. A., Kundig, T. M., Kawai, K., Wakeham, A., Timms, E., Pfeffer, K., Ohashi, P. S., and Thomas, M. L. (1993) Normal B Lymphocyte Development but Impaired T Cell Maturation in CD45-exon6 Protein Tyrosine Phosphatase-Deficient Mice. Cell. 74, 143-156.
68. Koretzky, G. A., Picus, J., Schultz, T., and Weiss, A. (1991) Tyrosine Phosphatase CD45 is Required for T-Cell Antigen Receptor and CD2-Mediated Activation of a Protein Tyrosine Kinase and Interleukin 2 Production. Proc. Natl. Acad. Sci. U. S. A. 88, 2037-2041.
69. Ostergaard, H. L., Shackelford, D. A., Hurley, T. R., Johnson, P., Hyman, R., Sefton, B. M., and Trowbridge, I. S. (1989) Expression of CD45 Alters Phosphorylation of the Lck-Encoded Tyrosine Protein Kinase in Murine Lymphoma T-Cell Lines. Proc. Natl. Acad. Sci. U. S. A. 86, 8959-8963.
70. Hurley, T. R., Hyman, R., and Sefton, B. M. (1993) Differential Effects of Expression of the CD45 Tyrosine Protein Phosphatase on the Tyrosine Phosphorylation of the Lck, Fyn, and c-Src Tyrosine Protein Kinases. Mol. Cell. Biol. 13, 1651-1656.
71. Cahir McFarland, E. D., Hurley, T. R., Pingel, J. T., Sefton, B. M., Shaw, A., and Thomas, M. L. (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. U. S. A. 90, 1402-1406.
72. Roach, T., Slater, S., Koval, M., White, L., Cahir McFarland, E. D., Okumura, M., Thomas, M., and Brown, E. (1997) CD45 Regulates Src Family Member Kinase Activity Associated with Macrophage Integrin-Mediated Adhesion. Curr. Biol. 7, 408-417.
73. Seavitt, J. R., White, L. S., Murphy, K. M., Loh, D. Y., Perlmutter, R. M., and Thomas, M. L. (1999) Expression of the p56(Lck) Y505F Mutation in CD45-Deficient Mice Rescues Thymocyte Development. Mol. Cell. Biol. 19, 4200-4208.
74. Pingel, S., Baker, M., Turner, M., Holmes, N., and Alexander, D. R. (1999) The CD45 Tyrosine Phosphatase Regulates CD3-Induced Signal Transduction and T Cell Development in Recombinase-Deficient Mice: Restoration of Pre-TCR Function by Active p56(Lck). Eur. J. Immunol. 29, 2376-2384.
75. McNeill, L., Salmond, R. J., Cooper, J. C., Carret, C. K., Cassady-Cain, R. L., Roche-Molina, M., Tandon, P., Holmes, N., and Alexander, D. R. (2007) The Differential Regulation of Lck Kinase Phosphorylation Sites by CD45 is Critical for T Cell Receptor Signaling Responses. Immunity. 27, 425-437.
76. Ogilvy, S., Louis-Dit-Sully, C., Cooper, J., Cassady, R. L., Alexander, D. R., and 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.
77. Tchilian, E. Z., Dawes, R., Hyland, L., Montoya, M., Le Bon, A., Borrow, P., Hou, S., Tough, D., and Beverley, P. C. (2004) Altered CD45 Isoform Expression Affects Lymphocyte Function in CD45 Tg Mice. Int. Immunol. 16, 1323-1332.
78. Virts, E. L., Diago, O., and Raschke, W. C. (2003) A CD45 Minigene Restores Regulated Isoform Expression and Immune Function in CD45-Deficient Mice: Therapeutic Implications for Human CD45-Null Severe Combined Immunodeficiency. Blood. 101, 849-855.
79. Berger, S. A., Mak, T. W., and Paige, C. J. (1994) Leukocyte Common Antigen (CD45) is Required for Immunoglobulin E-Mediated Degranulation of Mast Cells. J. Exp. Med. 180, 471-476.
80. Cross, J. L., Kott, K., Miletic, T., and Johnson, P. (2008) CD45 Regulates TLR-Induced Proinflammatory Cytokine and IFN-Beta Secretion in Dendritic Cells. J. Immunol. 180, 8020-8029.
81. Piercy, J., Petrova, S., Tchilian, E. Z., and Beverley, P. C. (2006) CD45 Negatively Regulates Tumour Necrosis Factor and Interleukin-6 Production in Dendritic Cells. Immunology. 118, 250-256.
82. Hesslein, D. G., Takaki, R., Hermiston, M. L., Weiss, A., and Lanier, L. L. (2006) Dysregulation of Signaling Pathways in CD45-Deficient NK Cells Leads to Differentially Regulated Cytotoxicity and Cytokine Production. Proc. Natl. Acad. Sci. U. S. A. 103, 7012-7017.
83. Huntington, N. D., Xu, Y., Nutt, S. L., and Tarlinton, D. M. (2005) A Requirement for CD45 Distinguishes Ly49D-Mediated Cytokine and Chemokine Production from Killing in Primary Natural Killer Cells. J. Exp. Med. 201, 1421-1433.
84. Pradhan, D., and Morrow, J. (2002) The Spectrin-Ankyrin Skeleton Controls CD45 Surface Display and Interleukin-2 Production. Immunity. 17, 303-315.
85. Varma, R., Campi, G., Yokosuka, T., Saito, T., and Dustin, M. L. (2006) T Cell Receptor-Proximal Signals are Sustained in Peripheral Microclusters and Terminated in the Central Supramolecular Activation Cluster. Immunity. 25, 117-127.
86. He, X., Woodford-Thomas, T. A., Johnson, K. G., Shah, D. D., and Thomas, M. L. (2002) Targeting of CD45 Protein Tyrosine Phosphatase Activity to Lipid Microdomains on the T Cell Surface Inhibits TCR Signaling. Eur. J. Immunol. 32, 2578-2587.
87. Kung, C., Pingel, J. T., Heikinheimo, M., Klemola, T., Varkila, K., Yoo, L. I., Vuopala, K., Poyhonen, M., Uhari, M., Rogers, M., Speck, S. H., Chatila, T., and Thomas, M. L. (2000) Mutations in the Tyrosine Phosphatase CD45 Gene in a Child with Severe Combined Immunodeficiency Disease. Nat. Med. 6, 343-345.
88. Tchilian, E. Z., Wallace, D. L., Wells, R. S., Flower, D. R., Morgan, G., and Beverley, P. C. (2001) A Deletion in the Gene Encoding the CD45 Antigen in a Patient with SCID. J. Immunol. 166, 1308-1313.
89. Tchilian, E. Z., and Beverley, P. C. (2006) Altered CD45 Expression and Disease. Trends Immunol. 27, 146-153.
90. Dawes, R., Hennig, B., Irving, W., Petrova, S., Boxall, S., Ward, V., Wallace, D., Macallan, D. C., Thursz, M., Hill, A., Bodmer, W., Beverley, P. C., and Tchilian, E. Z. (2006) Altered CD45 Expression in C77G Carriers Influences Immune Function and Outcome of Hepatitis C Infection. J. Med. Genet. 43, 678-684.
91. Stanton, T., Boxall, S., Hirai, K., Dawes, R., Tonks, S., Yasui, T., Kanaoka, Y., Yuldasheva, N., Ishiko, O., Bodmer, W., Beverley, P. C., and Tchilian, E. Z. (2003) A High-Frequency Polymorphism in Exon 6 of the CD45 Tyrosine Phosphatase Gene (PTPRC) Resulting in Altered Isoform Expression. Proc. Natl. Acad. Sci. U. S. A. 100, 5997-6002.
92. Boxall, S., Stanton, T., Hirai, K., Ward, V., Yasui, T., Tahara, H., Tamori, A., Nishiguchi, S., Shiomi, S., Ishiko, O., Inaba, M., Nishizawa, Y., Dawes, R., Bodmer, W., Beverley, P. C., and Tchilian, E. Z. (2004) Disease Associations and Altered Immune Function in CD45 138G Variant Carriers. Hum. Mol. Genet. 13, 2377-2384.
|Science Writers||Eva Marie Y. Moresco|
|Illustrators||Diantha La Vine|
|Authors||Owen M. Siggs, Bruce Beutler|
|List |< first << previous [record 31 of 511] next >> last >||