{"gene":"PTPRC","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1985,"finding":"The leukocyte-common antigen (T200/L-CA) spans the lipid bilayer with an extracellular N-terminal domain and a large cytoplasmic domain of ~80,000 Mr (~700 amino acids), with an internal homology between two halves of the cytoplasmic domain, as determined from cDNA clones.","method":"cDNA cloning and peptide sequence analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — direct cDNA sequencing combined with peptide data establishing membrane topology","pmids":["3158393"],"is_preprint":false},{"year":1987,"finding":"Human T200/CD45 exists in at least three structural variants generated by cell-type-specific alternative splicing of exons encoding serine/threonine-rich O-glycosylated inserts in the extracellular domain; the cytoplasmic domain of 707 amino acids is shared by all variants.","method":"cDNA cloning and characterization of genomic intron-exon structure","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — multiple overlapping cDNA clones sequenced with genomic structural analysis","pmids":["2956090"],"is_preprint":false},{"year":1987,"finding":"Mouse T200 (CD45) B-cell isoform (B220) contains a 139-amino-acid insert in the amino-terminal region relative to the T-cell form, generated by alternative mRNA splicing, as shown by cDNA sequencing and RNA blotting.","method":"cDNA sequencing, RNA blot analysis, genomic clone analysis of intron-exon structure","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — cDNA sequencing plus genomic structure demonstrating alternative splicing mechanism","pmids":["2955416"],"is_preprint":false},{"year":1987,"finding":"Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens (CD45), providing the molecular basis for the isoform diversity observed across hematopoietic cell types.","method":"cDNA cloning, genomic DNA analysis, Northern blot with exon-specific probes","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 — exon-specific probes on genomic clone plus multiple cDNA classes characterized","pmids":["2824653"],"is_preprint":false},{"year":1988,"finding":"CD45 (leukocyte common antigen) possesses intrinsic protein tyrosine phosphatase (PTPase) activity, demonstrated by co-precipitation of PTPase activity with anti-CD45 antibody from spleen extracts and enzymatic activity in a highly purified CD45 preparation.","method":"Immunoprecipitation of PTPase activity with mAb 9.4, affinity-purified CD45 enzymatic assay, sucrose density gradient co-sedimentation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal biochemical methods demonstrating intrinsic enzymatic activity of purified protein","pmids":["2853967"],"is_preprint":false},{"year":1988,"finding":"Sequence homology between PTPase 1B and the tandem cytoplasmic domains of CD45 established that CD45 is a putative receptor-linked protein tyrosine phosphatase, predicting its enzymatic function before biochemical confirmation.","method":"Amino acid sequence analysis and homology comparison","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — sequence identity analysis leading to functional prediction later confirmed biochemically","pmids":["2845400"],"is_preprint":false},{"year":1989,"finding":"CD45 (L-CA) is required for antigen-induced T cell proliferation; T cell clones lacking L-CA failed to proliferate in response to antigen or cross-linked CD3, but retained IL-2 responsiveness; an L-CA+ revertant restored antigen-induced proliferation.","method":"Generation of L-CA-negative T cell clones by mutagenesis, functional proliferation assays, revertant analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with defined cellular phenotype and revertant rescue","pmids":["2550143"],"is_preprint":false},{"year":1990,"finding":"The first of the two intracellular phosphatase-like domains of CD45 (LCA) has catalytic PTPase activity, requiring a critical cysteine residue; the second domain lacks detectable catalytic activity but influences substrate specificity.","method":"Deletion and point mutations in cytoplasmic domains of LCA expressed in cells, in vitro PTPase assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with mutagenesis establishing catalytic mechanism","pmids":["1695146"],"is_preprint":false},{"year":1990,"finding":"CD45 (T200) is physically associated with CD2 on the surface of mouse T lymphocytes, as demonstrated by co-immunoprecipitation with anti-CD2 antibody from thymocyte, splenocyte, and T-cell tumor lysates; the complex is non-covalent and disrupted by high salt or SDS.","method":"Co-immunoprecipitation, biochemical fractionation (Triton X-114), modulation experiments","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 3 — single lab co-IP with supporting modulation data but no reconstitution","pmids":["1980615"],"is_preprint":false},{"year":1990,"finding":"CD45 is physically associated with CD2 on the surface of human T lymphocytes, demonstrated by chemical cross-linking; anti-CD45 antibodies are co-mitogenic with CD2 but not CD3 antibodies, suggesting a functional link between the CD45 phosphatase and CD2-mediated signaling.","method":"Chemical cross-linking, co-mitogenesis functional assays","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 — chemical crosslinking plus functional co-stimulation assays; single lab","pmids":["1970422"],"is_preprint":false},{"year":1991,"finding":"CD45 co-precipitates with membrane IgM-associated signaling proteins on B cells; antibody-mediated loss of CD45 from the surface correlates with loss of mIgM-induced Ca2+ mobilization; CD45 dephosphorylates mIg-associated proteins, indicating CD45 regulates B cell antigen receptor signal transduction by modulating phosphorylation of receptor subunits.","method":"Co-immunoprecipitation, surface modulation experiments, Ca2+ mobilization assays, in vitro dephosphorylation assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including functional Ca2+ signaling, co-IP, and dephosphorylation assay","pmids":["1648262"],"is_preprint":false},{"year":1991,"finding":"CD26 (dipeptidyl peptidase IV) is co-associated with CD45 on human T lymphocytes; anti-CD26 antibody co-modulates CD45 from the T cell surface and precipitates CD45 from T cell lysates; this association correlates with enhanced CD3ζ tyrosine phosphorylation and increased CD4-associated p56lck activity.","method":"Co-immunoprecipitation, surface modulation, kinase activity assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP with functional correlates, single lab","pmids":["1680916"],"is_preprint":false},{"year":1992,"finding":"CD45 (GP180) binds directly and specifically to fodrin (spectrin-like cytoskeletal protein) and spectrin in vitro (Kd ~1.1 nM for fodrin), mediated by a 48-kDa phosphopeptide of CD45; binding of fodrin/spectrin to CD45 stimulates its PTPase activity 7.5-fold (Vmax increase) without changing Km, indicating cytoskeletal proteins regulate CD45 PTPase activity.","method":"In vitro binding assays, co-isolation biochemistry, enzyme kinetic analysis with purified proteins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro binding with Kd measurement plus enzyme kinetics with purified proteins","pmids":["1400466"],"is_preprint":false},{"year":1999,"finding":"Galectin-1 binds to CD45 on human T cells and induces its redistribution into segregated membrane microdomains that colocalize with CD3 and externalized phosphatidylserine on apoptotic blebs, indicating that spatial redistribution of CD45 is required for galectin-1-induced apoptosis.","method":"Immunofluorescence microscopy, cell surface glycoprotein binding assays, apoptosis assays on T cell lines and human thymocytes","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — direct imaging of CD45 redistribution correlated with functional apoptosis outcome","pmids":["10490978"],"is_preprint":false},{"year":2000,"finding":"CD45 deficiency in a human patient (due to a large deletion at one allele and a splice-site point mutation at the other) results in severe combined immunodeficiency with markedly diminished peripheral T lymphocytes unresponsive to mitogens, demonstrating that CD45 is essential for human T and B lymphocyte function.","method":"Genetic analysis (sequencing), immunological phenotyping of patient cells","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — human loss-of-function genetic analysis with defined immune phenotype","pmids":["10700239"],"is_preprint":false},{"year":2000,"finding":"A point mutation in PTPRC exon 4 interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells, associated with development of multiple sclerosis in multiple independent case-control and family studies.","method":"Genetic association studies, splicing analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 — splicing mechanism demonstrated with genetic association evidence across multiple cohorts","pmids":["11101853"],"is_preprint":false},{"year":2001,"finding":"CD45 functions as a JAK phosphatase: targeted disruption of cd45 leads to enhanced JAK and STAT activation by cytokines and interferons; in vitro, CD45 directly dephosphorylates and binds to JAK1, JAK2, JAK3, and TYK2; CD45 negatively regulates IL-3-mediated proliferation, erythropoietin-dependent haematopoiesis, and antiviral responses.","method":"Gene knockout mice, in vitro dephosphorylation assays with purified proteins, cytokine signaling assays, in vivo antiviral experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — KO model plus direct in vitro dephosphorylation of JAKs combined with multiple in vivo functional readouts","pmids":["11201744"],"is_preprint":false},{"year":2002,"finding":"A novel point mutation in PTPRC exon 4 (position 59 C→A) causes an amino acid substitution (H→Q) and interferes with alternative splicing, resulting in surface expression of a structurally altered CD45 molecule with aberrant isoform expression on memory T cells and monocytes.","method":"DNA sequencing, microsatellite linkage analysis, flow cytometry for isoform expression","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and splicing analysis in a family with defined CD45 isoform expression phenotype","pmids":["12073144"],"is_preprint":false},{"year":2003,"finding":"A polymorphism in exon 6 of PTPRC (A138G), causing a Thr47Ala substitution at a potential O- and N-linked glycosylation site, interferes with alternative splicing, resulting in decreased proportion of T cells expressing CD45 isoforms containing exon A, B, and C, with enrichment of CD45R0+ cells; this variant is present at 23.7% frequency in the Japanese population.","method":"Genotyping, flow cytometry for CD45 isoform expression, RT-PCR splicing analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — direct link between coding variant, splicing, and isoform expression phenotype","pmids":["12716971"],"is_preprint":false},{"year":2016,"finding":"The extracellular region of CD45 is structurally rigid and extends beyond the distance spanned by TCR-ligand complexes; sites of TCR-ligand engagement sterically exclude CD45. Spontaneous 'close contacts' between T cells and supported lipid bilayers cause CD45 and kinase segregation at submicron scale, initiating TCR signaling even in the absence of TCR ligands.","method":"Crystal structure of CD45 extracellular domain, biophysical measurements, TIRF microscopy of close contacts, signaling assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with biophysical and functional imaging demonstrating steric exclusion mechanism","pmids":["26998761"],"is_preprint":false},{"year":2021,"finding":"CD45 plays a crucial role in CD22-mediated inhibition of BCR ligation-induced signaling; however, SHP-1 (PTPN6) rather than CD45 is essential for ligand-mediated regulation of CD22, as disruption of CD22 ligand binding enhanced CD22 phosphorylation in CD45-/- but not SHP-1 loss-of-function mouse B cells; CD22 is identified as a substrate of SHP-1.","method":"CD45 knockout mouse B cells, SHP-1 loss-of-function mutant B cells, phosphorylation assays, BCR signaling assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO and loss-of-function genetics with defined signaling readout distinguishing CD45 from SHP-1 roles","pmids":["33990399"],"is_preprint":false},{"year":1985,"finding":"CD45 (T200/gp180) in mouse T-lymphoma cells is physically linked to the cytoskeletal protein fodrin; the gp180-fodrin complex co-isolates as a 1:1 molar ratio stable complex (sedimentation coefficient ~20S), and fodrin accumulates beneath gp180 patches/caps after ligand-induced receptor rearrangement.","method":"Immunobinding assay, Triton X-114 extraction, sucrose gradient centrifugation, double-label immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical methods showing CD45-fodrin complex with localization data","pmids":["3874872"],"is_preprint":false},{"year":1988,"finding":"T200 (CD45) and Mo1 (CD11b) are stored in tertiary (specific) intracellular granules of resting human neutrophils and translocate to the plasma membrane upon degranulation stimuli (fMLP, calcium ionophore), as demonstrated by fractionation and flow cytometry; at least 50% of total T200 resides intracellularly.","method":"Subcellular fractionation, immunoprecipitation of radiolabeled membrane proteins, flow cytometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — subcellular fractionation with functional degranulation readout replicated across multiple stimuli","pmids":["2838485"],"is_preprint":false}],"current_model":"PTPRC (CD45) is a hematopoietic-specific transmembrane receptor protein tyrosine phosphatase whose extracellular domain undergoes cell-type-specific alternative splicing to generate multiple isoforms; its first cytoplasmic phosphatase domain is catalytically active (requiring a critical cysteine) while the second domain modulates substrate specificity; CD45 dephosphorylates and regulates Src-family kinases (e.g., Lck, Fyn) and JAK kinases to control T and B cell antigen receptor signaling and cytokine receptor signaling, and its steric exclusion from TCR-ligand close contacts drives local kinase/phosphatase segregation that initiates TCR signaling; CD45 also physically associates with CD2, CD26, fodrin/spectrin, and the BCR complex, and is stored in intracellular granules in neutrophils for regulated surface mobilization."},"narrative":{"teleology":[{"year":1985,"claim":"Establishing that CD45 is a single-pass transmembrane glycoprotein with a large (~700 aa) cytoplasmic domain containing an internal tandem duplication resolved a longstanding question about the structural architecture of the leukocyte common antigen.","evidence":"cDNA cloning and peptide sequence analysis from mouse spleen","pmids":["3158393"],"confidence":"High","gaps":["No enzymatic function yet demonstrated","Role of duplicated cytoplasmic domains unknown"]},{"year":1987,"claim":"Demonstrating that at least five CD45 mRNA species arise from differential usage of three alternatively spliced exons encoding O-glycosylated extracellular inserts explained the long-observed heterogeneity of CD45 isoforms across leukocyte lineages.","evidence":"cDNA cloning, genomic intron-exon analysis, and Northern blotting with exon-specific probes in human and mouse hematopoietic cells","pmids":["2956090","2955416","2824653"],"confidence":"High","gaps":["Functional significance of individual isoforms unresolved","Splicing regulatory mechanism unknown"]},{"year":1988,"claim":"Identification of intrinsic protein tyrosine phosphatase activity in purified CD45, combined with sequence homology to PTP1B, established CD45 as the first receptor-type tyrosine phosphatase and provided a biochemical function for the cytoplasmic domain.","evidence":"Co-immunoprecipitation of PTPase activity with anti-CD45 mAb, enzymatic assays on affinity-purified CD45, and sequence homology analysis","pmids":["2853967","2845400"],"confidence":"High","gaps":["Physiological substrates not yet identified","Relative roles of the two phosphatase domains unresolved"]},{"year":1989,"claim":"Loss-of-function analysis using CD45-negative T cell clones and a CD45-positive revertant demonstrated that CD45 phosphatase activity is required for antigen- and CD3-induced T cell activation, while IL-2 responsiveness is CD45-independent.","evidence":"Mutagenized T cell clones, proliferation assays with antigen and anti-CD3, revertant rescue","pmids":["2550143"],"confidence":"High","gaps":["Proximal signaling substrate(s) in TCR pathway not identified","Role in B cell receptor signaling not yet tested"]},{"year":1990,"claim":"Dissection of the tandem phosphatase domains showed that only the membrane-proximal (D1) domain has catalytic PTPase activity, dependent on a critical cysteine, while the membrane-distal (D2) domain influences substrate specificity, resolving the functional division of labor within the cytoplasmic region.","evidence":"Deletion and point mutagenesis of CD45 cytoplasmic domains expressed in cells, in vitro PTPase assays","pmids":["1695146"],"confidence":"High","gaps":["Structural basis of D2 modulation of substrate specificity unknown","No crystal structure of cytoplasmic domains"]},{"year":1990,"claim":"Physical association of CD45 with CD2 on T lymphocytes, demonstrated by both co-immunoprecipitation and chemical cross-linking, revealed that CD45 operates within surface signaling complexes rather than as an isolated enzyme.","evidence":"Co-immunoprecipitation from thymocytes/splenocytes and chemical cross-linking on human T cells, co-mitogenesis assays","pmids":["1980615","1970422"],"confidence":"Medium","gaps":["Direct binding interface not mapped","Stoichiometry and dynamics of the CD45–CD2 complex in situ unknown"]},{"year":1991,"claim":"Co-precipitation of CD45 with membrane IgM-associated proteins and dependence of mIgM-induced calcium mobilization on CD45 surface expression extended the functional requirement for CD45 beyond T cells to B cell antigen receptor signaling.","evidence":"Co-IP, surface modulation, calcium mobilization, and in vitro dephosphorylation in B cell lines","pmids":["1648262"],"confidence":"High","gaps":["Specific BCR-proximal substrate of CD45 not identified","Relative contributions of CD45 vs. SHP-1 to BCR inhibition unclear"]},{"year":1992,"claim":"Demonstration that fodrin/spectrin binds CD45 with nanomolar affinity and stimulates its PTPase activity 7.5-fold established a mechanism by which the cortical cytoskeleton directly regulates CD45 enzymatic output.","evidence":"In vitro binding assays with purified proteins, Kd measurement (~1.1 nM), enzyme kinetic analysis (Vmax increase)","pmids":["1400466"],"confidence":"High","gaps":["In vivo relevance of cytoskeletal activation of CD45 not confirmed","Binding site on CD45 not mapped"]},{"year":2000,"claim":"Identification of compound loss-of-function PTPRC mutations causing severe combined immunodeficiency in a human patient proved that CD45 is non-redundant for human T and B lymphocyte development and function.","evidence":"Genetic sequencing of patient alleles (large deletion and splice-site mutation), immunological phenotyping","pmids":["10700239"],"confidence":"High","gaps":["Precise stage of thymic developmental block in humans not defined","Whether partial CD45 function produces milder immunodeficiency unknown"]},{"year":2000,"claim":"A coding polymorphism in PTPRC exon 4 that disrupts alternative splicing and alters isoform expression on T cells was associated with susceptibility to multiple sclerosis, linking CD45 isoform regulation to autoimmune disease risk.","evidence":"Genetic association in multiple case-control and family cohorts, splicing analysis","pmids":["11101853"],"confidence":"Medium","gaps":["Causal mechanism by which altered isoform ratio promotes autoimmunity not established","Association not replicated uniformly across all populations"]},{"year":2001,"claim":"CD45 knockout mice revealed that CD45 functions as a direct JAK phosphatase, negatively regulating JAK/STAT-mediated cytokine and interferon signaling, expanding the substrate repertoire of CD45 beyond Src-family kinases.","evidence":"cd45-/- mice, in vitro dephosphorylation of JAK1/2/3 and TYK2 with purified proteins, cytokine signaling and antiviral response assays","pmids":["11201744"],"confidence":"High","gaps":["Whether CD45 targets individual JAKs with differential selectivity in specific cell types unclear","No structural basis for JAK recognition"]},{"year":2016,"claim":"Crystal structure of the CD45 extracellular domain revealed a rigid rod-like architecture taller than TCR–pMHC complexes, providing the structural basis for the kinetic segregation model in which CD45 is sterically excluded from close contacts to initiate TCR signaling.","evidence":"X-ray crystallography of CD45 ectodomain, biophysical measurements, TIRF microscopy of close contacts on supported lipid bilayers, signaling assays","pmids":["26998761"],"confidence":"High","gaps":["Whether isoform-specific ectodomain lengths tune the segregation threshold is untested","In vivo measurement of CD45 exclusion dynamics at immunological synapses limited"]},{"year":2021,"claim":"Dissecting CD45 and SHP-1 contributions to CD22-mediated BCR inhibition showed that CD45 is required for CD22-dependent suppression of BCR signaling but that SHP-1, not CD45, mediates ligand-dependent CD22 dephosphorylation, refining the signaling hierarchy downstream of CD22.","evidence":"CD45 KO and SHP-1 loss-of-function mouse B cells, BCR signaling and CD22 phosphorylation assays","pmids":["33990399"],"confidence":"High","gaps":["Direct substrate relationship between CD45 and CD22 not established","Whether CD45 acts upstream of SHP-1 recruitment to CD22 is unresolved"]},{"year":null,"claim":"Key open questions include the structural basis by which the catalytically inactive D2 domain modulates substrate specificity, how isoform-specific ectodomain lengths differentially tune signaling thresholds in vivo, and the in vivo relevance of cytoskeletal (fodrin/spectrin) regulation of CD45 phosphatase activity.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No co-crystal structure of D1–D2 with a physiological substrate","Isoform-specific knock-in models with defined signaling readouts lacking","Fodrin–CD45 interaction not validated in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4,5,7,10,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[6,16,20]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,9,11,13,22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[22]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[12,21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,10,14,16,19,20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,16,19,20]}],"complexes":[],"partners":["CD2","LCK","JAK1","JAK2","JAK3","TYK2","SPTAN1","DPP4"],"other_free_text":[]},"mechanistic_narrative":"PTPRC (CD45) is a hematopoietic-restricted transmembrane receptor-type protein tyrosine phosphatase that serves as a master regulator of lymphocyte antigen receptor and cytokine receptor signaling. Its extracellular domain undergoes cell-type-specific alternative splicing of three exons to generate multiple isoforms differing in O-glycosylated inserts, while its conserved cytoplasmic region contains tandem phosphatase-homology domains of which the membrane-proximal domain is catalytically active via a critical cysteine and the distal domain modulates substrate specificity [PMID:2956090, PMID:1695146]. CD45 dephosphorylates Src-family kinases (e.g., Lck) to regulate T cell receptor signaling and directly dephosphorylates JAK1–3 and TYK2 to negatively regulate cytokine and interferon responses; its large, rigid extracellular domain is sterically excluded from TCR–ligand close contacts, creating local kinase/phosphatase segregation that initiates TCR triggering [PMID:11201744, PMID:26998761]. Loss-of-function mutations in PTPRC cause severe combined immunodeficiency in humans, and coding polymorphisms that alter exon splicing are associated with aberrant isoform expression and susceptibility to multiple sclerosis [PMID:10700239, PMID:11101853]."},"prefetch_data":{"uniprot":{"accession":"P08575","full_name":"Receptor-type tyrosine-protein phosphatase C","aliases":["Leukocyte common antigen","L-CA","T200"],"length_aa":1306,"mass_kda":147.5,"function":"Protein tyrosine-protein phosphatase required for T-cell activation through the antigen receptor (PubMed:35767951). Acts as a positive regulator of T-cell coactivation upon binding to DPP4. The first PTPase domain has enzymatic activity, while the second one seems to affect the substrate specificity of the first one. Upon T-cell activation, recruits and dephosphorylates SKAP1 and FYN. Dephosphorylates LYN, and thereby modulates LYN activity (By similarity). Interacts with CLEC10A at antigen presenting cell-T cell contact; CLEC10A on immature dendritic cells recognizes Tn antigen-carrying PTPRC/CD45 receptor on effector T cells and modulates T cell activation threshold to limit autoreactivity (Microbial infection) Acts as a receptor for human cytomegalovirus protein UL11 and mediates binding of UL11 to T-cells, leading to reduced induction of tyrosine phosphorylation of multiple signaling proteins upon T-cell receptor stimulation and impaired T-cell proliferation","subcellular_location":"Cell membrane; Membrane raft; Synapse","url":"https://www.uniprot.org/uniprotkb/P08575/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRC","classification":"Not Classified","n_dependent_lines":15,"n_total_lines":383,"dependency_fraction":0.0391644908616188},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRC","total_profiled":1310},"omim":[{"mim_id":"621186","title":"PHOSPHATIDYLETHANOLAMINE-BINDING PROTEIN 1 PSEUDOGENE 3; PEBP1P3","url":"https://www.omim.org/entry/621186"},{"mim_id":"619924","title":"IMMUNODEFICIENCY 105, SEVERE COMBINED; IMD105","url":"https://www.omim.org/entry/619924"},{"mim_id":"614826","title":"NYSTAGMUS 7, CONGENITAL, AUTOSOMAL DOMINANT; NYS7","url":"https://www.omim.org/entry/614826"},{"mim_id":"613593","title":"BUTYROPHILIN, SUBFAMILY 3, MEMBER A1; BTN3A1","url":"https://www.omim.org/entry/613593"},{"mim_id":"611208","title":"HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEIN L-LIKE; HNRNPLL","url":"https://www.omim.org/entry/611208"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":273.8}],"url":"https://www.proteinatlas.org/search/PTPRC"},"hgnc":{"alias_symbol":["LCA","T200","GP180","LY5","B220","CD45R"],"prev_symbol":["CD45"]},"alphafold":{"accession":"P08575","domains":[{"cath_id":"-","chopping":"229-300","consensus_level":"medium","plddt":85.0111,"start":229,"end":300},{"cath_id":"2.60.40.10","chopping":"304-387","consensus_level":"medium","plddt":89.3243,"start":304,"end":387},{"cath_id":"2.60.40.10","chopping":"397-480","consensus_level":"medium","plddt":90.08,"start":397,"end":480},{"cath_id":"2.60.40.10","chopping":"489-575","consensus_level":"medium","plddt":90.4813,"start":489,"end":575},{"cath_id":"3.90.190.10","chopping":"635-918","consensus_level":"medium","plddt":94.2512,"start":635,"end":918},{"cath_id":"3.90.190.10","chopping":"948-991_1015-1150_1162-1231","consensus_level":"medium","plddt":90.1466,"start":948,"end":1231}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08575","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08575-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08575-F1-predicted_aligned_error_v6.png","plddt_mean":76.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRC","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRC"},"sequence":{"accession":"P08575","fasta_url":"https://rest.uniprot.org/uniprotkb/P08575.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08575/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08575"}},"corpus_meta":[{"pmid":"6970340","id":"PMC_6970340","title":"B220: a B cell-specific member of th T200 glycoprotein family.","date":"1981","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/6970340","citation_count":639,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11602645","id":"PMC_11602645","title":"CD11c(+)B220(+)Gr-1(+) cells in mouse lymph nodes and spleen display characteristics of plasmacytoid dendritic cells.","date":"2001","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11602645","citation_count":509,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2956090","id":"PMC_2956090","title":"Structural variants of human T200 glycoprotein (leukocyte-common antigen).","date":"1987","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2956090","citation_count":291,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34039664","id":"PMC_34039664","title":"Protein tyrosine phosphatase receptor type C (PTPRC or CD45).","date":"2021","source":"Journal of clinical 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the N-terminal region extracellular and residues 369-1073 intracellular, as determined from cDNA clones and peptide data.\",\n      \"method\": \"cDNA cloning, protein sequencing, topology analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — primary structural determination from cDNA with peptide validation, foundational paper\",\n      \"pmids\": [\"3158393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Human T200 (PTPRC/CD45) structural variants arise by cell-type-specific alternative splicing of the 5' region, generating isoforms differing by inserts of 47 or 161 amino acids rich in serine/threonine (O-linked oligosaccharide sites), while sharing a conserved 707-amino-acid cytoplasmic domain.\",\n      \"method\": \"cDNA cloning, sequencing, RNA blotting\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA sequencing plus Northern blot, replicated across species\",\n      \"pmids\": [\"2956090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Mouse T200 (PTPRC) isoforms are generated by alternative mRNA splicing; B cells and cytotoxic T-cell clones express T200 mRNAs containing all or part of a 139-amino-acid insert in the amino-terminal region, whereas T-helper clones and thymocytes do not, establishing cell-type-specific isoform expression.\",\n      \"method\": \"cDNA sequencing, RNA blot analysis, genomic intron-exon structure analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA and genomic cloning with RNA blotting, replicated in multiple cell types\",\n      \"pmids\": [\"2955416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD45 (T200/PTPRC) is a membrane-associated protein tyrosine phosphatase (PTPase), establishing its enzymatic identity as a phosphotyrosine phosphatase on the leukocyte surface.\",\n      \"method\": \"Enzymatic assay (PTPase activity measurement)\",\n      \"journal\": \"Immunology today\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — enzymatic activity directly demonstrated, widely replicated\",\n      \"pmids\": [\"2553046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"T200 (PTPRC) on T lymphocytes associates with the cytoskeletal protein fodrin; after ligand-induced receptor patching/capping, T200 co-isolates with fodrin in a stable complex (sedimentation ~20S, 1:1 molar ratio) linked through fodrin to actin microfilaments.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, sucrose gradient centrifugation, isoelectric focusing\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-isolation with multiple biochemical methods in one study\",\n      \"pmids\": [\"3874872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD45 (PTPRC/GP180) PTPase activity is directly stimulated by binding to fodrin or spectrin; the 48-kDa phosphopeptide of CD45 contains the fodrin/spectrin-binding domain, and binding increases Vmax 7.5-fold (fodrin) and 3.2-fold (spectrin) without changing Km.\",\n      \"method\": \"In vitro binding assay (Kd ~1.1 nM for fodrin), enzyme kinetics, high-salt dissociation, co-isolation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro binding and enzyme kinetic analysis with mechanistic dissection\",\n      \"pmids\": [\"1400466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"T200 (PTPRC/CD45) is stored in intracellular tertiary (specific) granules in resting human neutrophils and mobilizes to the plasma membrane upon activation/degranulation stimuli, regulating early neutrophil activation events.\",\n      \"method\": \"Flow cytometry, subcellular fractionation, immunoprecipitation of radiolabeled membrane proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular fractionation with functional implication, multiple methods\",\n      \"pmids\": [\"2838485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Anti-CD45 (T200) monoclonal antibodies can provide a second costimulatory signal for T cell proliferation, inducing IL-2 production and replacing monocytes in monocyte-depleted cultures activated by Sepharose-bound CD3; this effect is CD4-specific and does not involve PKC.\",\n      \"method\": \"T cell proliferation assay, IL-2 production measurement, monocyte depletion\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional antibody blocking/stimulation, single lab\",\n      \"pmids\": [\"2960536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD45 (T200/PTPRC) associates non-covalently with CD2 on mouse T lymphocytes; the complex is destroyed by high salt or boiling in SDS, is not generated during cell lysis, and the complexed T200 is enriched in the detergent phase of Triton X-114 partitioning.\",\n      \"method\": \"Co-immunoprecipitation, Triton X-114 phase partitioning, modulation studies\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with multiple biochemical characterizations, single lab\",\n      \"pmids\": [\"1980615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The CD45R (B220) isoform of PTPRC on activated B cells bears IL-2-modulated terminal β-(1-3)-N-acetylgalactosaminyl residues; the ~220-kDa T200 species is the glycoprotein responsible for elevated PNA/SBA lectin binding induced by IL-2 in activated B lymphocytes.\",\n      \"method\": \"Lectin binding assay, immunodepletion, SDS-PAGE, anti-Thy-1 depletion\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — immunodepletion plus biochemical characterization, single lab\",\n      \"pmids\": [\"2956329\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A point mutation in exon 4 of PTPRC (C77G) in the heterozygous state interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells, associated with development of multiple sclerosis.\",\n      \"method\": \"DNA sequencing, mRNA splicing analysis, case-control genetic studies, family linkage analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing mechanism directly demonstrated, replicated in multiple cohorts\",\n      \"pmids\": [\"11101853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A novel point mutation in PTPRC exon 4 (position 59 C→A, H→Q amino acid change) interferes with alternative splicing and causes surface expression of a structurally altered CD45 molecule with CD45RA expressed on memory T cells and monocytes.\",\n      \"method\": \"DNA sequencing, microsatellite linkage analysis, flow cytometry, splicing analysis\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing interference directly demonstrated with genotype-phenotype validation\",\n      \"pmids\": [\"12073144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A polymorphism in exon 6 of PTPRC (A138G, Thr47Ala) interferes with alternative splicing, resulting in decreased proportions of T cells expressing the A, B, and C CD45 isoforms and increased CD45R0+ cells; the affected residue is a potential O- and N-linked glycosylation site.\",\n      \"method\": \"DNA sequencing, PCR, flow cytometry, population genetics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing interference and phenotypic consequence demonstrated, population-level validation\",\n      \"pmids\": [\"12716971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"T200 glycoprotein (PTPRC) on NK effector cells mediates binding to YAC-1 tumor targets through poly-N-acetyllactosamine structures; reconstituted liposomes containing tomato-lectin-enriched T200 inhibit effector-target conjugate formation, and this is abrogated by anti-Ly-5 mAb or endo-beta-galactosidase treatment.\",\n      \"method\": \"Lectin affinity chromatography, liposome reconstitution, conjugate formation assay, enzymatic treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution experiment with enzymatic controls demonstrating carbohydrate-dependent mechanism\",\n      \"pmids\": [\"2965731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Lupus IgG VH4.34 autoantibodies target a B220-specific glycoform of CD45 (PTPRC), specifically an N-linked N-acetyllactosamine determinant on the 220-kDa CD45 isoform that is sterically masked by sialic acid on B220+ memory B cells but exposed on naive B cells.\",\n      \"method\": \"Biochemical studies (immunoprecipitation, flow cytometry), VH4.34 Ab depletion, glycosylation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical characterization of glycoform-specific epitope with depletion controls\",\n      \"pmids\": [\"15034044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD45 (PTPRC) plays a crucial role in CD22-mediated inhibition of BCR-induced signaling, but SHP-1 (not CD45) is the essential phosphatase for ligand-mediated regulation of CD22; in CD45-/- B cells, disruption of CD22 ligand binding still enhances CD22 phosphorylation (a SHP-1-dependent process), demonstrating CD45's role is modulatory rather than the direct writer/eraser of CD22 phosphorylation.\",\n      \"method\": \"CD45 knockout mouse B cells, loss-of-function SHP-1 mutant, BCR signaling assays, phosphorylation analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined signaling phenotype, epistasis established\",\n      \"pmids\": [\"33990399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The CD45R (B220) isoform of PTPRC on B220+ T cells from lpr mice shows constitutively increased phosphoinositide turnover (elevated PI incorporation, inositol phosphate production, and diacylglycerol formation) in the absence of stimulation, linked to defective transmembrane signaling in these cells.\",\n      \"method\": \"Radioisotope incorporation assays ([3H]myoinositol, [3H]arachidonic acid), phospholipase C activity assay, intracellular Ca2+ measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, correlative biochemical measurements in a disease model cell\",\n      \"pmids\": [\"1692067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"Anti-CD45R (B220) monoclonal antibodies inhibit IL-4-mediated B cell proliferation and differentiation at an early phase, with the epitope mapped to the first alternatively spliced exon of the CD45 gene; this inhibition is specific to IL-4 signaling in B cells (not IL-2 or IL-5 responses, and not thymocyte responses to IL-4).\",\n      \"method\": \"Proliferation and differentiation assays, cross-inhibition, immunoblotting, CD45 gene transfectants for epitope mapping\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epitope mapped to specific exon using transfectants, functional specificity demonstrated\",\n      \"pmids\": [\"1703782\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRC (CD45) is a transmembrane protein tyrosine phosphatase whose large cytoplasmic domain harbors intrinsic PTPase activity that is stimulated by direct binding to cytoskeletal proteins (fodrin/spectrin); its extracellular domain undergoes complex cell-type-specific alternative splicing (controlled by exons 4, 5, and 6) generating isoforms with distinct glycosylation patterns, and CD45 functions as an essential regulator of antigen receptor signaling in T and B lymphocytes, modulates NK cell cytotoxicity via poly-N-acetyllactosamine structures, and can be mobilized from intracellular granules to the plasma membrane during neutrophil activation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1985,\n      \"finding\": \"The leukocyte-common antigen (T200/L-CA) spans the lipid bilayer with an extracellular N-terminal domain and a large cytoplasmic domain of ~80,000 Mr (~700 amino acids), with an internal homology between two halves of the cytoplasmic domain, as determined from cDNA clones.\",\n      \"method\": \"cDNA cloning and peptide sequence analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct cDNA sequencing combined with peptide data establishing membrane topology\",\n      \"pmids\": [\"3158393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Human T200/CD45 exists in at least three structural variants generated by cell-type-specific alternative splicing of exons encoding serine/threonine-rich O-glycosylated inserts in the extracellular domain; the cytoplasmic domain of 707 amino acids is shared by all variants.\",\n      \"method\": \"cDNA cloning and characterization of genomic intron-exon structure\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple overlapping cDNA clones sequenced with genomic structural analysis\",\n      \"pmids\": [\"2956090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Mouse T200 (CD45) B-cell isoform (B220) contains a 139-amino-acid insert in the amino-terminal region relative to the T-cell form, generated by alternative mRNA splicing, as shown by cDNA sequencing and RNA blotting.\",\n      \"method\": \"cDNA sequencing, RNA blot analysis, genomic clone analysis of intron-exon structure\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cDNA sequencing plus genomic structure demonstrating alternative splicing mechanism\",\n      \"pmids\": [\"2955416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Differential usage of three exons generates at least five different mRNAs encoding human leukocyte common antigens (CD45), providing the molecular basis for the isoform diversity observed across hematopoietic cell types.\",\n      \"method\": \"cDNA cloning, genomic DNA analysis, Northern blot with exon-specific probes\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — exon-specific probes on genomic clone plus multiple cDNA classes characterized\",\n      \"pmids\": [\"2824653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CD45 (leukocyte common antigen) possesses intrinsic protein tyrosine phosphatase (PTPase) activity, demonstrated by co-precipitation of PTPase activity with anti-CD45 antibody from spleen extracts and enzymatic activity in a highly purified CD45 preparation.\",\n      \"method\": \"Immunoprecipitation of PTPase activity with mAb 9.4, affinity-purified CD45 enzymatic assay, sucrose density gradient co-sedimentation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal biochemical methods demonstrating intrinsic enzymatic activity of purified protein\",\n      \"pmids\": [\"2853967\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"Sequence homology between PTPase 1B and the tandem cytoplasmic domains of CD45 established that CD45 is a putative receptor-linked protein tyrosine phosphatase, predicting its enzymatic function before biochemical confirmation.\",\n      \"method\": \"Amino acid sequence analysis and homology comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — sequence identity analysis leading to functional prediction later confirmed biochemically\",\n      \"pmids\": [\"2845400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"CD45 (L-CA) is required for antigen-induced T cell proliferation; T cell clones lacking L-CA failed to proliferate in response to antigen or cross-linked CD3, but retained IL-2 responsiveness; an L-CA+ revertant restored antigen-induced proliferation.\",\n      \"method\": \"Generation of L-CA-negative T cell clones by mutagenesis, functional proliferation assays, revertant analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with defined cellular phenotype and revertant rescue\",\n      \"pmids\": [\"2550143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The first of the two intracellular phosphatase-like domains of CD45 (LCA) has catalytic PTPase activity, requiring a critical cysteine residue; the second domain lacks detectable catalytic activity but influences substrate specificity.\",\n      \"method\": \"Deletion and point mutations in cytoplasmic domains of LCA expressed in cells, in vitro PTPase assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with mutagenesis establishing catalytic mechanism\",\n      \"pmids\": [\"1695146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD45 (T200) is physically associated with CD2 on the surface of mouse T lymphocytes, as demonstrated by co-immunoprecipitation with anti-CD2 antibody from thymocyte, splenocyte, and T-cell tumor lysates; the complex is non-covalent and disrupted by high salt or SDS.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation (Triton X-114), modulation experiments\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab co-IP with supporting modulation data but no reconstitution\",\n      \"pmids\": [\"1980615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD45 is physically associated with CD2 on the surface of human T lymphocytes, demonstrated by chemical cross-linking; anti-CD45 antibodies are co-mitogenic with CD2 but not CD3 antibodies, suggesting a functional link between the CD45 phosphatase and CD2-mediated signaling.\",\n      \"method\": \"Chemical cross-linking, co-mitogenesis functional assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — chemical crosslinking plus functional co-stimulation assays; single lab\",\n      \"pmids\": [\"1970422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD45 co-precipitates with membrane IgM-associated signaling proteins on B cells; antibody-mediated loss of CD45 from the surface correlates with loss of mIgM-induced Ca2+ mobilization; CD45 dephosphorylates mIg-associated proteins, indicating CD45 regulates B cell antigen receptor signal transduction by modulating phosphorylation of receptor subunits.\",\n      \"method\": \"Co-immunoprecipitation, surface modulation experiments, Ca2+ mobilization assays, in vitro dephosphorylation assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including functional Ca2+ signaling, co-IP, and dephosphorylation assay\",\n      \"pmids\": [\"1648262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD26 (dipeptidyl peptidase IV) is co-associated with CD45 on human T lymphocytes; anti-CD26 antibody co-modulates CD45 from the T cell surface and precipitates CD45 from T cell lysates; this association correlates with enhanced CD3ζ tyrosine phosphorylation and increased CD4-associated p56lck activity.\",\n      \"method\": \"Co-immunoprecipitation, surface modulation, kinase activity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP with functional correlates, single lab\",\n      \"pmids\": [\"1680916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD45 (GP180) binds directly and specifically to fodrin (spectrin-like cytoskeletal protein) and spectrin in vitro (Kd ~1.1 nM for fodrin), mediated by a 48-kDa phosphopeptide of CD45; binding of fodrin/spectrin to CD45 stimulates its PTPase activity 7.5-fold (Vmax increase) without changing Km, indicating cytoskeletal proteins regulate CD45 PTPase activity.\",\n      \"method\": \"In vitro binding assays, co-isolation biochemistry, enzyme kinetic analysis with purified proteins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro binding with Kd measurement plus enzyme kinetics with purified proteins\",\n      \"pmids\": [\"1400466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Galectin-1 binds to CD45 on human T cells and induces its redistribution into segregated membrane microdomains that colocalize with CD3 and externalized phosphatidylserine on apoptotic blebs, indicating that spatial redistribution of CD45 is required for galectin-1-induced apoptosis.\",\n      \"method\": \"Immunofluorescence microscopy, cell surface glycoprotein binding assays, apoptosis assays on T cell lines and human thymocytes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct imaging of CD45 redistribution correlated with functional apoptosis outcome\",\n      \"pmids\": [\"10490978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD45 deficiency in a human patient (due to a large deletion at one allele and a splice-site point mutation at the other) results in severe combined immunodeficiency with markedly diminished peripheral T lymphocytes unresponsive to mitogens, demonstrating that CD45 is essential for human T and B lymphocyte function.\",\n      \"method\": \"Genetic analysis (sequencing), immunological phenotyping of patient cells\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function genetic analysis with defined immune phenotype\",\n      \"pmids\": [\"10700239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A point mutation in PTPRC exon 4 interferes with mRNA splicing and results in altered expression of CD45 isoforms on immune cells, associated with development of multiple sclerosis in multiple independent case-control and family studies.\",\n      \"method\": \"Genetic association studies, splicing analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — splicing mechanism demonstrated with genetic association evidence across multiple cohorts\",\n      \"pmids\": [\"11101853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD45 functions as a JAK phosphatase: targeted disruption of cd45 leads to enhanced JAK and STAT activation by cytokines and interferons; in vitro, CD45 directly dephosphorylates and binds to JAK1, JAK2, JAK3, and TYK2; CD45 negatively regulates IL-3-mediated proliferation, erythropoietin-dependent haematopoiesis, and antiviral responses.\",\n      \"method\": \"Gene knockout mice, in vitro dephosphorylation assays with purified proteins, cytokine signaling assays, in vivo antiviral experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO model plus direct in vitro dephosphorylation of JAKs combined with multiple in vivo functional readouts\",\n      \"pmids\": [\"11201744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A novel point mutation in PTPRC exon 4 (position 59 C→A) causes an amino acid substitution (H→Q) and interferes with alternative splicing, resulting in surface expression of a structurally altered CD45 molecule with aberrant isoform expression on memory T cells and monocytes.\",\n      \"method\": \"DNA sequencing, microsatellite linkage analysis, flow cytometry for isoform expression\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and splicing analysis in a family with defined CD45 isoform expression phenotype\",\n      \"pmids\": [\"12073144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A polymorphism in exon 6 of PTPRC (A138G), causing a Thr47Ala substitution at a potential O- and N-linked glycosylation site, interferes with alternative splicing, resulting in decreased proportion of T cells expressing CD45 isoforms containing exon A, B, and C, with enrichment of CD45R0+ cells; this variant is present at 23.7% frequency in the Japanese population.\",\n      \"method\": \"Genotyping, flow cytometry for CD45 isoform expression, RT-PCR splicing analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct link between coding variant, splicing, and isoform expression phenotype\",\n      \"pmids\": [\"12716971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The extracellular region of CD45 is structurally rigid and extends beyond the distance spanned by TCR-ligand complexes; sites of TCR-ligand engagement sterically exclude CD45. Spontaneous 'close contacts' between T cells and supported lipid bilayers cause CD45 and kinase segregation at submicron scale, initiating TCR signaling even in the absence of TCR ligands.\",\n      \"method\": \"Crystal structure of CD45 extracellular domain, biophysical measurements, TIRF microscopy of close contacts, signaling assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with biophysical and functional imaging demonstrating steric exclusion mechanism\",\n      \"pmids\": [\"26998761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD45 plays a crucial role in CD22-mediated inhibition of BCR ligation-induced signaling; however, SHP-1 (PTPN6) rather than CD45 is essential for ligand-mediated regulation of CD22, as disruption of CD22 ligand binding enhanced CD22 phosphorylation in CD45-/- but not SHP-1 loss-of-function mouse B cells; CD22 is identified as a substrate of SHP-1.\",\n      \"method\": \"CD45 knockout mouse B cells, SHP-1 loss-of-function mutant B cells, phosphorylation assays, BCR signaling assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO and loss-of-function genetics with defined signaling readout distinguishing CD45 from SHP-1 roles\",\n      \"pmids\": [\"33990399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1985,\n      \"finding\": \"CD45 (T200/gp180) in mouse T-lymphoma cells is physically linked to the cytoskeletal protein fodrin; the gp180-fodrin complex co-isolates as a 1:1 molar ratio stable complex (sedimentation coefficient ~20S), and fodrin accumulates beneath gp180 patches/caps after ligand-induced receptor rearrangement.\",\n      \"method\": \"Immunobinding assay, Triton X-114 extraction, sucrose gradient centrifugation, double-label immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods showing CD45-fodrin complex with localization data\",\n      \"pmids\": [\"3874872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"T200 (CD45) and Mo1 (CD11b) are stored in tertiary (specific) intracellular granules of resting human neutrophils and translocate to the plasma membrane upon degranulation stimuli (fMLP, calcium ionophore), as demonstrated by fractionation and flow cytometry; at least 50% of total T200 resides intracellularly.\",\n      \"method\": \"Subcellular fractionation, immunoprecipitation of radiolabeled membrane proteins, flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — subcellular fractionation with functional degranulation readout replicated across multiple stimuli\",\n      \"pmids\": [\"2838485\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRC (CD45) is a hematopoietic-specific transmembrane receptor protein tyrosine phosphatase whose extracellular domain undergoes cell-type-specific alternative splicing to generate multiple isoforms; its first cytoplasmic phosphatase domain is catalytically active (requiring a critical cysteine) while the second domain modulates substrate specificity; CD45 dephosphorylates and regulates Src-family kinases (e.g., Lck, Fyn) and JAK kinases to control T and B cell antigen receptor signaling and cytokine receptor signaling, and its steric exclusion from TCR-ligand close contacts drives local kinase/phosphatase segregation that initiates TCR signaling; CD45 also physically associates with CD2, CD26, fodrin/spectrin, and the BCR complex, and is stored in intracellular granules in neutrophils for regulated surface mobilization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTPRC (CD45) is a transmembrane receptor-type protein tyrosine phosphatase expressed on all nucleated hematopoietic cells that serves as a central regulator of antigen receptor signaling in lymphocytes and modulates activation in other leukocyte lineages. Its large cytoplasmic domain harbors intrinsic PTPase activity that is directly stimulated (up to 7.5-fold increase in Vmax) by binding the cytoskeletal linker protein fodrin/spectrin, coupling phosphatase function to cortical actin organization [PMID:1400466, PMID:3874872]. The extracellular domain undergoes cell-type-specific alternative splicing of exons 4, 5, and 6, generating isoforms (CD45RA, CD45RB, CD45RO, B220) with distinct O-linked and N-linked glycosylation patterns that influence ligand interactions, NK cell target recognition via poly-N-acetyllactosamine structures, and IL-4-dependent B cell signaling [PMID:2956090, PMID:2955416, PMID:2965731, PMID:1703782]. Point mutations in the alternatively spliced exons that disrupt normal splicing regulation alter CD45 isoform ratios on immune cells and have been linked to susceptibility to multiple sclerosis [PMID:11101853, PMID:12073144].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Determination of the transmembrane topology and domain architecture of PTPRC established that it possesses an unusually large cytoplasmic tail (~707 aa), setting the stage for identifying its enzymatic function.\",\n      \"evidence\": \"cDNA cloning, protein sequencing, and topology analysis of T200 from T lymphocytes\",\n      \"pmids\": [\"3158393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic activity yet assigned to the cytoplasmic domain\", \"Extracellular domain function unknown\"]\n    },\n    {\n      \"year\": 1985,\n      \"claim\": \"Discovery that T200/CD45 physically associates with the cytoskeletal protein fodrin via its cytoplasmic domain revealed a direct link between this surface glycoprotein and the actin cytoskeleton.\",\n      \"evidence\": \"Co-immunoprecipitation, sucrose gradient sedimentation, and immunofluorescence after receptor capping on T lymphocytes\",\n      \"pmids\": [\"3874872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the fodrin interaction unknown\", \"Whether association is constitutive or regulated unclear\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Identification of cell-type-specific alternative splicing of the 5′ extracellular region explained the heterogeneity of CD45 isoforms (T200 variants) across lymphocyte subsets and resolved how a single gene generates multiple surface glycoprotein species.\",\n      \"evidence\": \"cDNA cloning and RNA blotting in human T cells, B cells, and thymocytes across two independent studies (human and mouse)\",\n      \"pmids\": [\"2956090\", \"2955416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cis-regulatory elements controlling exon inclusion not identified\", \"Functional significance of different isoforms unclear\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"The finding that poly-N-acetyllactosamine glycans on CD45 mediate NK cell binding to tumor targets established a direct adhesion/recognition function for the extracellular domain, independent of its phosphatase activity.\",\n      \"evidence\": \"Liposome reconstitution of lectin-enriched T200, conjugate formation assays with enzymatic and antibody controls on NK-YAC-1 system\",\n      \"pmids\": [\"2965731\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Counter-receptor on target cells not identified\", \"Whether this glycan-dependent adhesion occurs in vivo unconfirmed\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Discovery that CD45 resides in intracellular specific granules of resting neutrophils and translocates to the plasma membrane upon activation revealed a regulated mobilization mechanism for this phosphatase in innate immune cells.\",\n      \"evidence\": \"Subcellular fractionation, flow cytometry, and immunoprecipitation of radiolabeled neutrophil membrane proteins\",\n      \"pmids\": [\"2838485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals triggering granule mobilization not defined\", \"Whether phosphatase activity is required for neutrophil activation not tested\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Demonstration that CD45 possesses intrinsic protein tyrosine phosphatase activity unified its structural identity as a transmembrane PTPase and explained its requirement in lymphocyte signaling.\",\n      \"evidence\": \"Direct enzymatic PTPase activity assay on purified CD45\",\n      \"pmids\": [\"2553046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrates not identified\", \"Whether both tandem PTP domains are catalytically active unknown\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Multiple studies established isoform-specific functional roles: CD45 associates with CD2 on T cells, provides costimulatory signals for T cell activation, and the B220 isoform-specific exon is required for IL-4-mediated B cell responses, demonstrating that alternatively spliced domains have distinct signaling functions.\",\n      \"evidence\": \"Co-immunoprecipitation of CD45–CD2 complexes; anti-CD45 costimulation of T cell proliferation; anti-B220 blockade of IL-4 signaling with epitope mapping via CD45 gene transfectants\",\n      \"pmids\": [\"1980615\", \"2960536\", \"1703782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis for isoform-specific signaling not resolved\", \"CD2–CD45 interaction not confirmed by reciprocal methods\", \"Whether costimulatory function requires phosphatase activity untested\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"In vitro reconstitution showed that fodrin/spectrin binding directly stimulates CD45 PTPase catalytic activity (7.5-fold Vmax increase), establishing a mechanistic link between cytoskeletal association and enzymatic regulation.\",\n      \"evidence\": \"Purified protein binding assays (Kd ~1.1 nM), enzyme kinetics with fodrin/spectrin, domain mapping to 48-kDa phosphopeptide\",\n      \"pmids\": [\"1400466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of allosteric activation unknown\", \"In vivo relevance of fodrin-stimulated activity not demonstrated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that a C77G point mutation in PTPRC exon 4 disrupts alternative splicing and alters isoform expression, with association to multiple sclerosis, provided the first genetic evidence that splicing regulation of CD45 is disease-relevant in humans.\",\n      \"evidence\": \"DNA sequencing, mRNA splicing analysis, case-control and family linkage studies\",\n      \"pmids\": [\"11101853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism linking altered isoforms to disease pathogenesis not established\", \"Replications in other populations inconsistent\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of additional exon 4 and exon 6 mutations that disrupt CD45 splicing broadened the genetic evidence that cis-acting sequences in the alternatively spliced exons control isoform expression and glycosylation, with functional consequences for T cell phenotype.\",\n      \"evidence\": \"DNA sequencing, flow cytometry, splicing analysis in patient cells and population cohorts\",\n      \"pmids\": [\"12073144\", \"12716971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-acting splicing factors that recognize these cis elements not identified\", \"Whether glycosylation changes are causative or correlative unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Genetic dissection in CD45-knockout B cells established that CD45 phosphatase activity is required for full CD22-mediated BCR inhibition but is not the direct phosphatase acting on CD22 (SHP-1 fills that role), clarifying an epistatic relationship between CD45 and SHP-1 in BCR signaling.\",\n      \"evidence\": \"CD45 knockout mouse B cells, SHP-1 loss-of-function mutant, BCR signaling and CD22 phosphorylation assays\",\n      \"pmids\": [\"33990399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrates of CD45 in BCR signaling pathway still not comprehensively mapped\", \"Whether CD45 acts upstream of Lyn or other Src-family kinases in this context not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for fodrin-mediated allosteric activation of CD45 PTPase activity, the identity of the trans-acting splicing regulators controlling exon inclusion, and a comprehensive map of direct in vivo CD45 substrates across leukocyte lineages remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the fodrin–CD45 activation complex\", \"Trans-acting splicing factors controlling CD45 exon inclusion unidentified\", \"Comprehensive in vivo substrate identification lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 15]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0168256\", \"supporting_discovery_ids\": [3, 7, 15, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 15, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SPTAN1\",\n      \"SPTBN1\",\n      \"CD2\",\n      \"PTPN6\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"PTPRC (CD45) is a hematopoietic-restricted transmembrane receptor-type protein tyrosine phosphatase that serves as a master regulator of lymphocyte antigen receptor and cytokine receptor signaling. Its extracellular domain undergoes cell-type-specific alternative splicing of three exons to generate multiple isoforms differing in O-glycosylated inserts, while its conserved cytoplasmic region contains tandem phosphatase-homology domains of which the membrane-proximal domain is catalytically active via a critical cysteine and the distal domain modulates substrate specificity [PMID:2956090, PMID:1695146]. CD45 dephosphorylates Src-family kinases (e.g., Lck) to regulate T cell receptor signaling and directly dephosphorylates JAK1–3 and TYK2 to negatively regulate cytokine and interferon responses; its large, rigid extracellular domain is sterically excluded from TCR–ligand close contacts, creating local kinase/phosphatase segregation that initiates TCR triggering [PMID:11201744, PMID:26998761]. Loss-of-function mutations in PTPRC cause severe combined immunodeficiency in humans, and coding polymorphisms that alter exon splicing are associated with aberrant isoform expression and susceptibility to multiple sclerosis [PMID:10700239, PMID:11101853].\",\n  \"teleology\": [\n    {\n      \"year\": 1985,\n      \"claim\": \"Establishing that CD45 is a single-pass transmembrane glycoprotein with a large (~700 aa) cytoplasmic domain containing an internal tandem duplication resolved a longstanding question about the structural architecture of the leukocyte common antigen.\",\n      \"evidence\": \"cDNA cloning and peptide sequence analysis from mouse spleen\",\n      \"pmids\": [\"3158393\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No enzymatic function yet demonstrated\", \"Role of duplicated cytoplasmic domains unknown\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Demonstrating that at least five CD45 mRNA species arise from differential usage of three alternatively spliced exons encoding O-glycosylated extracellular inserts explained the long-observed heterogeneity of CD45 isoforms across leukocyte lineages.\",\n      \"evidence\": \"cDNA cloning, genomic intron-exon analysis, and Northern blotting with exon-specific probes in human and mouse hematopoietic cells\",\n      \"pmids\": [\"2956090\", \"2955416\", \"2824653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of individual isoforms unresolved\", \"Splicing regulatory mechanism unknown\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Identification of intrinsic protein tyrosine phosphatase activity in purified CD45, combined with sequence homology to PTP1B, established CD45 as the first receptor-type tyrosine phosphatase and provided a biochemical function for the cytoplasmic domain.\",\n      \"evidence\": \"Co-immunoprecipitation of PTPase activity with anti-CD45 mAb, enzymatic assays on affinity-purified CD45, and sequence homology analysis\",\n      \"pmids\": [\"2853967\", \"2845400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not yet identified\", \"Relative roles of the two phosphatase domains unresolved\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Loss-of-function analysis using CD45-negative T cell clones and a CD45-positive revertant demonstrated that CD45 phosphatase activity is required for antigen- and CD3-induced T cell activation, while IL-2 responsiveness is CD45-independent.\",\n      \"evidence\": \"Mutagenized T cell clones, proliferation assays with antigen and anti-CD3, revertant rescue\",\n      \"pmids\": [\"2550143\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal signaling substrate(s) in TCR pathway not identified\", \"Role in B cell receptor signaling not yet tested\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Dissection of the tandem phosphatase domains showed that only the membrane-proximal (D1) domain has catalytic PTPase activity, dependent on a critical cysteine, while the membrane-distal (D2) domain influences substrate specificity, resolving the functional division of labor within the cytoplasmic region.\",\n      \"evidence\": \"Deletion and point mutagenesis of CD45 cytoplasmic domains expressed in cells, in vitro PTPase assays\",\n      \"pmids\": [\"1695146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of D2 modulation of substrate specificity unknown\", \"No crystal structure of cytoplasmic domains\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Physical association of CD45 with CD2 on T lymphocytes, demonstrated by both co-immunoprecipitation and chemical cross-linking, revealed that CD45 operates within surface signaling complexes rather than as an isolated enzyme.\",\n      \"evidence\": \"Co-immunoprecipitation from thymocytes/splenocytes and chemical cross-linking on human T cells, co-mitogenesis assays\",\n      \"pmids\": [\"1980615\", \"1970422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"Stoichiometry and dynamics of the CD45–CD2 complex in situ unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Co-precipitation of CD45 with membrane IgM-associated proteins and dependence of mIgM-induced calcium mobilization on CD45 surface expression extended the functional requirement for CD45 beyond T cells to B cell antigen receptor signaling.\",\n      \"evidence\": \"Co-IP, surface modulation, calcium mobilization, and in vitro dephosphorylation in B cell lines\",\n      \"pmids\": [\"1648262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific BCR-proximal substrate of CD45 not identified\", \"Relative contributions of CD45 vs. SHP-1 to BCR inhibition unclear\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Demonstration that fodrin/spectrin binds CD45 with nanomolar affinity and stimulates its PTPase activity 7.5-fold established a mechanism by which the cortical cytoskeleton directly regulates CD45 enzymatic output.\",\n      \"evidence\": \"In vitro binding assays with purified proteins, Kd measurement (~1.1 nM), enzyme kinetic analysis (Vmax increase)\",\n      \"pmids\": [\"1400466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of cytoskeletal activation of CD45 not confirmed\", \"Binding site on CD45 not mapped\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of compound loss-of-function PTPRC mutations causing severe combined immunodeficiency in a human patient proved that CD45 is non-redundant for human T and B lymphocyte development and function.\",\n      \"evidence\": \"Genetic sequencing of patient alleles (large deletion and splice-site mutation), immunological phenotyping\",\n      \"pmids\": [\"10700239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise stage of thymic developmental block in humans not defined\", \"Whether partial CD45 function produces milder immunodeficiency unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"A coding polymorphism in PTPRC exon 4 that disrupts alternative splicing and alters isoform expression on T cells was associated with susceptibility to multiple sclerosis, linking CD45 isoform regulation to autoimmune disease risk.\",\n      \"evidence\": \"Genetic association in multiple case-control and family cohorts, splicing analysis\",\n      \"pmids\": [\"11101853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism by which altered isoform ratio promotes autoimmunity not established\", \"Association not replicated uniformly across all populations\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"CD45 knockout mice revealed that CD45 functions as a direct JAK phosphatase, negatively regulating JAK/STAT-mediated cytokine and interferon signaling, expanding the substrate repertoire of CD45 beyond Src-family kinases.\",\n      \"evidence\": \"cd45-/- mice, in vitro dephosphorylation of JAK1/2/3 and TYK2 with purified proteins, cytokine signaling and antiviral response assays\",\n      \"pmids\": [\"11201744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD45 targets individual JAKs with differential selectivity in specific cell types unclear\", \"No structural basis for JAK recognition\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Crystal structure of the CD45 extracellular domain revealed a rigid rod-like architecture taller than TCR–pMHC complexes, providing the structural basis for the kinetic segregation model in which CD45 is sterically excluded from close contacts to initiate TCR signaling.\",\n      \"evidence\": \"X-ray crystallography of CD45 ectodomain, biophysical measurements, TIRF microscopy of close contacts on supported lipid bilayers, signaling assays\",\n      \"pmids\": [\"26998761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether isoform-specific ectodomain lengths tune the segregation threshold is untested\", \"In vivo measurement of CD45 exclusion dynamics at immunological synapses limited\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Dissecting CD45 and SHP-1 contributions to CD22-mediated BCR inhibition showed that CD45 is required for CD22-dependent suppression of BCR signaling but that SHP-1, not CD45, mediates ligand-dependent CD22 dephosphorylation, refining the signaling hierarchy downstream of CD22.\",\n      \"evidence\": \"CD45 KO and SHP-1 loss-of-function mouse B cells, BCR signaling and CD22 phosphorylation assays\",\n      \"pmids\": [\"33990399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate relationship between CD45 and CD22 not established\", \"Whether CD45 acts upstream of SHP-1 recruitment to CD22 is unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis by which the catalytically inactive D2 domain modulates substrate specificity, how isoform-specific ectodomain lengths differentially tune signaling thresholds in vivo, and the in vivo relevance of cytoskeletal (fodrin/spectrin) regulation of CD45 phosphatase activity.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No co-crystal structure of D1–D2 with a physiological substrate\", \"Isoform-specific knock-in models with defined signaling readouts lacking\", \"Fodrin–CD45 interaction not validated in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4, 5, 7, 10, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [6, 16, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 9, 11, 13, 22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [12, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 10, 14, 16, 19, 20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 16, 19, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CD2\",\n      \"LCK\",\n      \"JAK1\",\n      \"JAK2\",\n      \"JAK3\",\n      \"TYK2\",\n      \"SPTAN1\",\n      \"DPP4\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}