Disease relevance of Ptprc

• The lpr mouse develops lupus-like symptoms and massive lymphadenopathy due to accumulation of abnormal CD4-/CD8- T lymphocytes, which are unusual in coexpressing Thy1 and B220 [1].
• The CD45 E613R mutation causes polyclonal lymphocyte activation leading to lymphoproliferation and severe autoimmune nephritis with autoantibody production, resulting in death [2].
• We now show that mice expressing active lck(F505) at non-oncogenic levels develop aggressive thymic lymphomas on a CD45(-/-) background [3].
• Expression of the CD45 Ag in hemopoietic cells is essential for normal development and function of lymphocytes, and both mice and humans lacking expression exhibit SCID [4].
• Human genetic variants of CD45, the exon 4 C77G and exon 6 A138G alleles, which alter the pattern of CD45 isoform expression, are associated with autoimmune and infectious diseases [4].
• To date, this is the first report demonstrating that reduced levels of host phosphatase CD45 modulate anthrax pathogenesis [5].

Psychiatry related information on Ptprc

• In addition, we show that T cells from CD45RO and CD45ABC mice accumulate in lymph nodes but not in the spleen, liver, or skin, indicating that the CD45 phosphatase may control the homing behavior and trafficking of T cells [6].
• Reactive microglia have been suggested to play a role in the Alzheimer's disease (AD) process, and previous studies have shown that expression of CD45, a membrane-bound protein-tyrosine phosphatase (PTP), is elevated in microglia in AD brain compared with controls [7].
• Administration of B-220 1 h before TPA promotion resulted in a prolonged latency period of tumor appearance and a significantly reduced (up to 15% of positive controls) papilloma yield at 20 weeks [8].
• In reactive disorders, a population of activated neutrophils with high CD45 and CD18 expression was detected [9].

High impact information on Ptprc

• CD45, the first and prototypic receptor-like protein tyrosine phosphatase, is expressed on all nucleated hematopoietic cells and plays a central role in this process [10].
• Recent work has focused on regulation of CD45 expression and alternative splicing, isoform-specific differences in signal transduction, and regulation of phosphatase activity [10].
• It is now known that CD45 also modulates signals emanating from integrin and cytokine receptors [10].
• The dramatic phenotype of CD45 E613R mice demonstrates the in vivo importance of negative regulation of CD45 by dimerization, supporting the model for regulation of CD45, and RPTPs in general [2].
• A model has been proposed for the regulation of CD45, and by homology other RPTPs, in which dimerization inhibits phosphatase activity through symmetrical interactions between an inhibitory structural wedge and the catalytic site [2].

Chemical compound and disease context of Ptprc

• The present study addressed T-cell-independent B cell responses in CD45-deficient mice using the glycoprotein (G) of vesicular stomatitis virus (VSV) as a model antigen [11].
• Recently a gain of function mutation in CD45 that may enhance activity of Src family tyrosine kinases has also been found to cause autoimmune disease, suggesting that the level of Src family tyrosine kinase activity is an important determinant of immune tolerance [12].
• Fractionation of membrane vesicles prepared from BW5147 lymphoma cells by sedimentation through sucrose density gradients show that antigens T25 and T200 are in fractions enriched with plasma membrane [13].
• Here we present evidence that the transmembrane phosphotyrosine phosphatase CD45 critically regulates TCR-induced signals in thymic differentiation and present data to show defective depletion of CD45-null transgenic TCR-Vbeta8 DP thymocytes in FTOC by the Staphylococcus aureus Enterotoxin B (SEB) superantigen [14].

Biological context of Ptprc

• However, BCR-elicited increases in the tyrosine phosphorylation of several SHP-1-associated phosphoproteins, including CD19, were substantially enhanced in CD45-/SHP-1-, compared to wild-type and CD45- cells [15].
• The cytosolic SHP-1 and transmembrane CD45 protein tyrosine phosphatases (PTP) play critical roles in regulating signal transduction via the B cell antigen receptor (BCR) [15].
• Stimulation via the major histocompatibility complex I-binding receptor, Ly49D on CD45(-/-) primary NK cells resulted in the activation of phosphoinositide-3-kinase and normal cytotoxicity but failed to elicit a range of cytokines and chemokines [16].
• Recent evidence suggests that dimerization of CD45 down-regulates its function [17].
• After serial passage, one Thy 1- tumor altered its cell surface phenotype to Thy 1low B220- [18].

Anatomical context of Ptprc

• Furthermore, HSCs in Runx1(+/-) embryos are heterogeneous and include CD45(+) cells, endothelial cells, and mesenchymal cells [19].
• To determine whether these PTPs act independently or coordinately in modulating the physiologic outcome of BCR engagement, we assessed B cell development and signaling in CD45-deficient mev (CD45-/SHP-1-) mice [15].
• In this study we investigate the role of the cell surface phosphatase CD45 in NK cell development and intracellular signaling from activating receptors [16].
• RNA transfer blotting using a cDNA probe encoding this sequence established that the predominant T200 mRNA species from B cells and cytotoxic T-cell clones but not T-helper cell clones or thymocytes contain all or part of the insert [20].
• Here we describe in I/RC hearts a population of small spindle-shaped fibroblasts that were highly proliferative and expressed collagen I and alpha-smooth muscle actin (myofibroblast markers), CD34 (a precursor marker), and CD45 (a hematopoietic marker) [21].

Associations of Ptprc with chemical compounds

• In addition, Syk function required the CD45 transmembrane protein tyrosine phosphatase [22].
• The complete cDNA sequence of mouse T200 glycoprotein from the pre-B-cell line 70Z/3 has been determined [20].
• CD45 is a transmembrane phosphotyrosine phosphatase expressed on all nucleated hemopoietic cells [23].
• However, TCR-induced signaling was not ablated, and significant inositol phosphate and calcium signals were observed in CD45-null thymocytes [23].
• Here, we report the phenotype of mice with a single point mutation, glutamate 613 to arginine, that inactivates the inhibitory wedge of CD45 [2].
• These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56(lck) tyrosine kinase phosphorylation sites [24].

Physical interactions of Ptprc

• To investigate the molecular bases for the dichotomies between naive and memory CD4 T cells and to understand how the T cell receptor (TCR) directs diverse functional outcomes, we investigated proximal signaling events triggered through the TCR/CD3 complex in naive and memory CD4 T cell subsets isolated on the basis of CD45 isoform expression [25].
• The results of our studies showed that in T-cells, CD45-AP is part of a multimolecular complex that includes not only CD45, but also TCR, the CD4 and CD8 coreceptors, and p56(lck) [26].
• Fyn co-immunoprecipitated with CD45 from differentiating wild-type OPCs in vitro, while CD45-deficient OPCs failed to differentiate [27].
• Rather, UV radiation selectively activated lymph node B cells, with these cells being larger and expressing higher levels of both anti-major histocompatibility complex II and B220 but not co-stimulatory molecules [28].

Enzymatic interactions of Ptprc

• CD45 preferentially dephosphorylated Tyr-394 over Tyr-505 in Lck [29].
• A CD45-associated 30-kDA phosphorylated protein (CD45-AP) was purified by virtue of its specific association with CD45, and its mouse cDNA was cloned by using the internal amino acid sequence information [30].

Regulatory relationships of Ptprc

• CD45-associated protein inhibits CD45 dimerization and up-regulates its protein tyrosine phosphatase activity [17].
• Taken together, these results indicate that Pax7 is necessary and sufficient to induce the myogenic specification of CD45(+) stem cells resident in adult skeletal muscle [31].
• 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) [32].
• Peripheral T cells undergoing superantigen-induced apoptosis in vivo express B220 and upregulate Fas and Fas ligand [33].
• The majority of the Flk-1-positive cells were hematopoietic-derived cells that coexpressed CD45 [34].

Other interactions of Ptprc

• The motheaten mutation rescues B cell signaling and development in CD45-deficient mice [15].
• Therefore, our results support a model in which binding of CD45-AP to inactive CD45 dimers converts them to active monomers [17].
• Loss of c-kit accompanies B-lineage commitment and acquisition of CD45R by most murine B-lymphocyte precursors [35].
• Selective regulation of Lyn tyrosine kinase by CD45 in immature B cells [36].
• CD45 modulates the activity of Src family protein-tyrosine kinases involved at the onset of antigen receptor-mediated signaling by dephosphorylating their regulatory tyrosyl residues [37].

Analytical, diagnostic and therapeutic context of Ptprc

• Enzymatically isolated cells were characterized by fluorescence-activated cell sorting on the basis of cell surface antigen expression, and were sorted as a CD34+ and CD45- fraction [38].
• We therefore used the GFP transgenic model in combination with allelic variants of CD45 and the hemoglobin beta (Hbb) chain to develop a model system that allows all blood lineages to be followed in a mouse model of bone marrow transplantation (BMT) [39].
• Immunocytochemistry was performed to identify the bone marrow origin of the cells in the RPE using antibodies for CD45, Sca-1, and c-kit, as well as the expression of the RPE-specific marker, RPE-65 [40].
• The cell surface of a cloned NS cell line was examined using immunofluorescence staining, and was strongly positive for the Thy-1.2, Ly-5, and asialo-GM1 antigens [41].
• In addition, we demonstrate that CD45-null thymocytes are severely impaired in their apoptotic response to cross-linking signals via T cell receptor (TCR) in fetal thymic organ culture [42].

References