Disease relevance of PTPRC

• A point mutation in exon A (C to G transversion at position 77) of human PTPRC (CD45) has recently been associated with the development of multiple sclerosis (MS) for at least a subgroup of patients [1].
• The mutation was found with significantly enhanced frequency in patients suffering from SSc suggesting that PTPRC could play a role as susceptibility gene not only in MS but also in other autoimmune diseases [1].
• A deletion in the gene encoding the CD45 antigen in a patient with SCID [2].
• CD45 and CD3 colocalized on large islands on apoptotic blebs protruding from the cell surface [3].
• Consistent with these data, insulin receptor signaling is increased when the CD45-related PTPase LAR is reduced by antisense suppression in a rat hepatoma cell line [4].

Psychiatry related information on PTPRC

• In addition, loss of CD45 can affect microglia activation in a mouse model for Alzheimer's disease [5].
• In an examination of T cell expression of these two CD45 isoforms during human development, the RO+RA- "memory" T cells were infrequent in the newborn blood and spleen, but comprised approximately half of the T cells in adult tissues [6].
• Of the patients with CJD, two with a subacute spongiform encephalopathic type and short-survival periods after onset of the disease showed an increased number of reactive microglia labeled with anti-MHC class II Ag or LCA in the affected cerebral cortex [7].

High impact information on PTPRC

• Finally, a deficiency of CD45, a critical regulator of signaling thresholds in immune cells, also causes SCID [8].
• In addition, genetic evidence has demonstrated the requirement of the transmembrane PTPase, CD45, for TCR function [9].
• In particular, evidence from genetic experiments indicates that CD45 plays a pivotal role in antigen-stimulated proliferation of T lymphocytes and in thymic development [10].
• CD45: an emerging role as a protein tyrosine phosphatase required for lymphocyte activation and development [10].
• CD45 is one of the most abundant leukocyte cell surface glycoproteins and is expressed exclusively upon cells of the hematopoietic system [10].

Chemical compound and disease context of PTPRC

• In this study, we investigate the role of the C-->G mutation in position 77 of exon 4 of the protein tyrosine phosphatase receptor-type C (PTPRC) gene, coding for the CD45 molecule, for the development of multiple sclerosis (MS) in an Italian continental population [11].
• We have found that a greater induction in HIV-1 long terminal repeat-driven gene expression was observed upon PMA/ionomycin (Iono) stimulation of a CD45-deficient cell line (J45.01) in comparison to the parental Jurkat cells [12].
• Further elucidation of downstream signaling events revealed that CD45 modulates HIV-1 gp120-induced apoptosis by regulating Fas ligand induction and activation of the phosphoinositide 3-kinase/Akt pathway [13].
• The cytoplasmic domains of two human transmembrane protein tyrosine phosphatases (PTPases), LAR and CD45, have been expressed in Escherichia coli, purified to near-homogeneity, and compared for catalytic efficiency toward several phosphotyrosine-containing peptide substrates [14].
• Establishment of a CD45-positive immature plasma cell line from an aggressive multiple myeloma with high serum lactate dehydrogenase [15].

Biological context of PTPRC

• Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed [16].
• The PTPRC mutated genotype has been recently described as associated with MS in three different case-control studies carried out in German MS patients, whereas similar studies performed in the US and Swedish populations failed to demonstrate such an association [11].
• This finding suggests a role, in at least a group of patients, for the PTPRC mutation in genetic susceptibility to MS [11].
• Here we describe a novel polymorphism in exon 4 (A54G) of the gene encoding CD45 (PTPRC) that results in an amino acid substitution of Thr-19 to Ala in exon 4 [17].
• Protein tyrosine phosphatase receptor type C polypeptide (PTPRC) on human chromosome band 1q31-->q32 localizes with marker D1S413(1) on a 610-kb yeast artificial chromosome [18].

Anatomical context of PTPRC

• CD45, encoded by PTPRC in humans, is the most abundantly expressed protein on the surface of many lymphocytes [19].
• CD45, a protein-tyrosine phophatase receptor type C (PTPRC), is essential for both thymic selection and peripheral activation of T and B cells [20].
• Association of CD2 and CD45 on human T lymphocytes [21].
• In this article, Ed Clark and Jeff Ledbetter discuss recent findings in the emerging area of leukocyte cell surface enzymology with emphasis on CD45, a membrane-associated protein tyrosine phosphatase (PTPase)2,3 [22].
• These transmembrane proteins are selectively sorted in microvesicles because CD28 and CD45, which are highly expressed at the plasma membrane, are not found [23].

Associations of PTPRC with chemical compounds

• The first of these sialoglycoproteins to be identified was the receptor-linked phosphotyrosine phosphatase CD45, which is required for antigen/CD3-induced T-cell activation [24].
• The enzymatically inactive CD45 C828S mutant protein, in which the cysteine residue at the catalytic center was changed to a serine residue, bound tightly to the phosphorylated CD3 zeta chain [25].
• To this end, we searched for high-affinity substrates of the CD45 PTPase among the tyrosine-phosphorylated T-cell proteins by using purified glutathione S-transferase-CD45 fusion molecules [25].
• Pretreatment of T-cells with the lipid raft inhibitor, methyl-beta-cyclodextrin, blocked the association between CXCR4 and CD45 and markedly abolished CXCL12-induced chemotaxis [26].
• The kinetics of association between CD4 or CD8 and CD45 was measured by fluorescence resonance energy transfer and confirmed by immunoprecipitation of dithiobis succinimidylpropionate or disuccinimidyl suberate cross-linked 125I-labeled resting or activated T cells [27].

Physical interactions of PTPRC

• Moreover, we show that CD26 directly binds to the cytoplasmic domain of CD45 [28].
• Receptor tyrosine phosphatase, CD45 binds galectin-1 but does not mediate its apoptotic signal in T cell lines [29].
• In contrast, the increase in [Ca2+]i induced by formation of homoaggregates of CD4 was strongly amplified when CD4 was coupled to CD45 [30].
• We compared the effect of CD45 ligation on signal transduction mediated by the binding of IL2 or anti-CD3 to these two receptors [31].
• Our results confirm and extend previous observations that CD22 is a sialic acid-binding lectin which interacts with CD45 and other glycoproteins capable of presenting alpha 2,6-linked sialic acid in a manner that promotes high affinity binding [32].

Enzymatic interactions of PTPRC

• We also showed that phosphorylated JAK1 and JAK3 were directly dephosphorylated by recombinant CD45 in vitro [33].
• Ezrin was constitutively tyrosine phosphorylated in wild-type and CD45-deficient Jurkat T cells, but not in Lck-deficient cells [34].
• Specific interaction of the CD45 protein-tyrosine phosphatase with tyrosine-phosphorylated CD3 zeta chain [25].
• In contrast, CD45 ligation did not alter the pattern of tyrosine-phosphorylated proteins in "resting" T-cell blasts responding to IL2, except for a mobility shift of a 55 kDa protein and increased phosphorylation of a 112 kDa substrate [31].
• In addition, phospholipase Cgamma1 (PLCgamma1) and PLCgamma2 were tyrosine phosphorylated upon Ag stimulation in CD45- cells, despite much reduced inositol trisphosphate production and lack of calcium mobilization [35].

Regulatory relationships of PTPRC

• In Jurkat T cells, betaI spectrin peptides suppress surface recruitment of CD45 and CD3 and abrogate T cell activation [36].
• In addition, the intracytoplasmic amino acids adjacent to the transmembrane region of LPAP may influence its binding to CD45 [37].
• Furthermore, we show that the association is increased during T cell activation and that triggering CD45 molecules through discrete epitopes induces the down-modulation of CD100 molecules at the cell surface [38].
• Anti-CD45 triggering of CD45 significantly inhibited interleukin-4 + anti-CD40-induced switch recombination in a switch recombination vector assay in stably transfected Ramos 2G6 human B cells, as well as Ig epsilon germ-line transcription and Smu-Sepsilon switch recombination in primary human B cells [33].
• We observed a significant reduction in CXCL12-induced chemotaxis in the CD45-negative Jurkat cell line (J45.01) as compared with the CD45-positive control (JE6.1) cells [26].

Other interactions of PTPRC

• Using chemical crosslinking techniques, we now show that CD45 is linked to CD2 on the surface of human T lymphocytes [21].
• The spectrin-ankyrin skeleton controls CD45 surface display and interleukin-2 production [36].
• Regulation of CD45 engagement by the B-cell receptor CD22 [24].
• Importantly, aggregation of CD26 by anti-CD26 mAb crosslinking also causes coaggregation of CD45 into rafts [28].
• By contrast, the CD45 antigens possess protein-tyrosine phosphatase activity within their intracellular domains and are postulated to function by virtue of a regulatory interaction with CD4/CD8:p56lck and its potential substrates [39].

Analytical, diagnostic and therapeutic context of PTPRC

• By immunoprecipitation of surface-labeled CD45 molecules from MN thymocytes, a proportion of the CD45 is in fact of low molecular mass but does not include epitopes recognized by CD45R0, nor by CD45RB mAb specific for the p190 [40].
• This effect of CD45 was associated with inhibition of a rise in intracellular calcium following TcR/CD3 ligation [41].
• These data suggest that the CD45RB and CD45RA isoforms of the LCA may be appropriate targets for in vivo immunotherapy [42].
• The relationship of cell shedding to leukocytes (CD45), macrophages (CD68) and blood vessels (CD34) were studied by immunohistochemistry [43].
• We examined the CD45 isoforms expressed in the various human thymocytes' subsets defined by CD3, CD4, and CD8 expressions using RT-PCR and 4-color flow cytometry [44].

References