{"gene":"PTPRC","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1988,"finding":"CD45 (leukocyte common antigen/T200) was identified as a protein tyrosine phosphatase based on 40% sequence identity between a 157-residue segment of PTPase 1B (isolated from human placenta) and the tandem C-terminal cytoplasmic domains of CD45, establishing CD45 as the first receptor-like protein tyrosine phosphatase.","method":"Partial amino acid sequencing of purified PTPase 1B combined with sequence homology analysis of CD45 cytoplasmic domains","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical purification and sequence analysis establishing enzymatic class; foundational finding replicated and confirmed in multiple subsequent studies","pmids":["2845400"],"is_preprint":false},{"year":1987,"finding":"CD45 (T200/Ly-5) isoforms are generated by alternative mRNA splicing; the B-cell form (B220, ~220 kDa) contains an insertion of 139 amino acid residues in the amino-terminal extracellular region encoded by an alternatively spliced exon not present in T-cell forms.","method":"cDNA sequencing of mouse T200 from pre-B cell line 70Z/3, RNA blotting with exon-specific probes, genomic intron-exon structure analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — complete cDNA sequencing plus genomic structure analysis; independently confirmed by multiple subsequent studies on CD45 alternative splicing","pmids":["2955416"],"is_preprint":false},{"year":1989,"finding":"The alternatively spliced exons A and B of murine CD45 encode distinct antigenic determinants: B220 antibodies 14.8 and RA32C2 require exon A expression, while antibody C363.16A reactivity depends on exon B expression.","method":"Retroviral expression of defined CD45 cDNA splice variants in cell lines followed by antibody-binding analysis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct functional reconstitution with defined cDNA constructs, mapping epitopes to specific alternatively spliced exons","pmids":["2466938"],"is_preprint":false},{"year":1990,"finding":"CD45 physically associates with CD2 on the surface of human T lymphocytes, as demonstrated by chemical cross-linking, suggesting a functional link between CD2-mediated signaling and CD45 phosphatase activity.","method":"Chemical cross-linking of intact human T lymphocytes followed by co-immunoprecipitation","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — chemical cross-linking and co-precipitation from two independent studies (human and mouse), but no direct functional reconstitution of the complex","pmids":["1970422","1980615"],"is_preprint":false},{"year":2001,"finding":"CD45 directly dephosphorylates and binds to JAK kinases (JAK1, JAK2, JAK3, TYK2) and negatively regulates cytokine receptor signaling; targeted disruption of CD45 in mice leads to enhanced JAK/STAT activation downstream of cytokine and interferon receptors, and CD45 negatively regulates IL-3-mediated proliferation, erythropoietin-dependent haematopoiesis, and antiviral responses.","method":"In vitro dephosphorylation assay, co-immunoprecipitation of CD45 with JAKs, CD45 knockout mouse model with cytokine stimulation readouts","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphatase assay plus direct binding plus KO mouse phenotype with multiple orthogonal readouts in one study","pmids":["11201744"],"is_preprint":false},{"year":2002,"finding":"The large ectodomain of CD45 is required for optimal TCR signaling and for partial localization of CD45 to glycosphingolipid-enriched membrane microdomains (GEMs); CD45 chimeras with small ectodomains fail to rescue TCR signaling in CD45-null T cells and do not localize to GEMs, whereas a CD45 chimera bearing the large ectodomain of CD43 rescues both basal Lck activity and TCR-induced signaling.","method":"CD45 chimera expression in CD45-null T cells, GEM fractionation, Lck activity assays, TCR zeta-chain phosphorylation assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution with defined chimeras, multiple functional readouts including kinase activity and signaling, subcellular fractionation","pmids":["12496963"],"is_preprint":false},{"year":1995,"finding":"CD22 engages the extracellular domain of CD45 through sialic acid-dependent interaction; soluble CD22-Ig fusion proteins can modulate early T-cell signals in antigen receptor/CD3-mediated stimulation, and addition of sialic acid by beta-galactoside alpha-2,6-sialyltransferase to CD22 abrogates this interaction.","method":"Soluble CD22-Ig fusion proteins incubated with T cells expressing wild-type and chimeric CD45, measurement of early signaling events, enzymatic modification of CD22 sialylation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional modulation assay with chimeric CD45 forms, enzymatic control, single lab","pmids":["7537381"],"is_preprint":false},{"year":2002,"finding":"CD22 binds to native CD45 with low affinity (Kd ~130 µM at 25°C) via alpha2-6-linked sialic acid on N-glycans; binding is enthalpically driven and has very fast kinetics (koff ≥18 s−1). CD22 does not bind CD45 with substantially higher affinity than other alpha2-6-sialylated proteins, suggesting preferential binding is due to CD45 carrying multiple copies of the ligand rather than intrinsically higher-affinity sites.","method":"Surface plasmon resonance thermodynamic and kinetic analysis, Van't Hoff analysis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — quantitative biophysical measurement with multiple comparative controls; single lab but rigorous thermodynamic analysis","pmids":["12115612"],"is_preprint":false},{"year":1995,"finding":"CD45-AP (CD45-associated protein) interacts with CD45 via its transmembrane segment binding to the transmembrane portion of CD45; CD45-AP is localized in particulate (membrane) fractions of lymphocytes along with CD45, and the bulk of CD45-AP is cytoplasmic, suggesting it acts as an adapter directing CD45 interactions with other signaling molecules.","method":"Deletion and chimeric construct binding analysis, subcellular fractionation, protease protection assay on intact cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple deletion/chimera constructs mapping interaction domain, fractionation, protease protection; single lab","pmids":["7673147"],"is_preprint":false},{"year":2004,"finding":"CD45-AP inhibits CD45 dimerization and upregulates CD45 protein tyrosine phosphatase activity; T cells from CD45-AP-null mice have markedly higher levels of CD45 dimers, and microsomal fractions from CD45-AP-negative cells show significantly lower CD45 PTP activity than CD45-AP-positive cells.","method":"CD45-AP knockout mice analysis, CD45-AP-null T cell line transfection, PTP activity assay of microsomal fractions, dimer detection","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — enzymatic activity directly measured in KO vs. WT fractions, genetic rescue by transfection, multiple orthogonal methods in one study","pmids":["14715639"],"is_preprint":false},{"year":1999,"finding":"Casein kinase 2 (CK2) is a major lymphocyte kinase that phosphorylates CD45 at Ser965, Ser968, Ser969, and Ser973 within an acidic insert in the D2 domain; CK2 phosphorylation increases CD45 PTP activity ~3-fold toward phosphorylated myelin basic protein, and this increase is reversible by PP2A; Ser-to-Glu mutations at these sites mimic phosphorylation and triple Vmax.","method":"In-gel kinase assay, immunoprecipitation/immunodepletion, specific inhibition, site-directed mutagenesis, in vitro PTP activity assay, PP2A dephosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assays with mutagenesis, identification of writer kinase and eraser phosphatase, multiple orthogonal methods; single lab","pmids":["10066810"],"is_preprint":false},{"year":2008,"finding":"HnRNPLL (heterogeneous ribonucleoprotein L-like) is a critical inducible regulator of CD45 alternative splicing in T cells; hnRNPLL is upregulated in stimulated T cells, binds CD45 transcripts, and is both necessary and sufficient for the shift from CD45RA to CD45RO isoform expression upon T cell activation.","method":"shRNA screen, overexpression and depletion in B and T cell lines and primary T cells, RNA binding assay, exon array analysis","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function experiments in multiple cell types with direct RNA binding demonstrated; replicated across multiple cell systems in one study","pmids":["18669861"],"is_preprint":false},{"year":1999,"finding":"SR protein SF2 is required for CD45 exon 4 skipping during T cell activation; overexpression of SF2 induces exon 4 skipping via its RNA recognition motifs, while SRp55 has antagonistic effects. SF2 and SRp55 are induced upon activation of CD45RA+ T cells, correlating with the shift to CD45RO expression.","method":"Overexpression of splicing regulators in COS cells, antisense inhibition of SRp55, domain-deletion constructs, RT-PCR analysis of CD45 isoforms in primary T cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and antisense knockdown with domain mapping; single lab, functional correlation in primary cells","pmids":["10092085"],"is_preprint":false},{"year":2016,"finding":"The extracellular region of CD45 is structurally rigid and extends beyond the distance spanned by TCR-ligand complexes, providing a steric basis for CD45 exclusion from TCR engagement sites. Spontaneous formation of 'close contacts'—submicron-scale structures characterized by CD45 and kinase segregation—initiates TCR signaling even in the absence of TCR ligands.","method":"Crystal structure of CD45 ectodomain, biophysical analysis of molecular dimensions, live-cell imaging of close contacts, signaling readouts in cells without TCR ligands","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with biophysical measurements and live-cell functional imaging with signaling readouts; multiple orthogonal methods","pmids":["26998761"],"is_preprint":false},{"year":2019,"finding":"CD45 acts as a signaling 'gatekeeper' by maintaining a regulatable pool of active Lck through opposing Csk, while simultaneously suppressing TCR zeta-chain phosphorylation. CD45 suppresses antigen-independent and low-affinity antigen-induced signaling but not high-affinity antigen-driven signaling, enabling graded signal discrimination.","method":"Chemical inhibition of Csk (analog-sensitive allele), genetic perturbation of CD45 and Csk, quantitative measurement of Lck activation, zeta-chain phosphorylation, and downstream signaling with computational analysis","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — acute chemical inhibition combined with genetic perturbation and computational modeling; multiple orthogonal measurements of pathway nodes; single lab but highly rigorous","pmids":["31641081"],"is_preprint":false},{"year":2013,"finding":"CXCL12 governs a specific phosphorylation event on PTPRC/CD45 in hematopoietic progenitor cells; this phosphorylation site lies downstream of Rac proteins, potentiates Src signaling, and governs hematopoietic progenitor and lymphoid cell motility.","method":"Phosphoproteomics of CXCL12-treated hematopoietic progenitor cells, site-directed mutagenesis, antibody validation of phosphosite, mass spectrometry absolute quantification (AQUA), Rac inhibitor studies","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics discovery validated by mutagenesis and orthogonal MS quantification with functional motility readout; single lab","pmids":["23997015"],"is_preprint":false},{"year":2014,"finding":"A constitutively activating point mutation in the CD45 inhibitory wedge (CD45E613R) modulates integrin activation in neutrophils: LFA-1 adhesiveness is impaired while avidity is enhanced, Mac-1 adhesiveness is increased, and neutrophil crawling and recruitment to infected lungs are impaired.","method":"Transgenic mice carrying CD45E613R mutation, intravital microscopy, integrin adhesion/avidity assays, bacterial lung infection model","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with constitutively active CD45, multiple integrin functional assays and in vivo recruitment readout; single lab","pmids":["25505282"],"is_preprint":false},{"year":2015,"finding":"CD45 has an extracatalytic function in B cells mediated through CD22: phosphatase-dead CD45 transgenes (catalytic-inactivating point mutation) or cytoplasmic-domain-deleted CD45 partially rescue the phenotype of CD45-deficient B cells, identifying a noncatalytic role of CD45 in regulating tonic BCR signaling through modulation of the inhibitory coreceptor CD22.","method":"Transgenic mice expressing catalytically inactive or cytoplasmic-domain-deleted CD45, BCR signaling assays, genetic epistasis with CD45-deficient background","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — separation-of-function mutations in vivo, multiple transgenic lines, genetic epistasis; rigorous dissection of catalytic vs. noncatalytic roles","pmids":["26561584"],"is_preprint":false},{"year":2011,"finding":"CD45 plays a purely positive regulatory role in BCR signaling (unlike its dual positive/negative roles in TCR signaling): increasing CD45 expression drives enhanced receptor editing and loss of B cells, while high CD45 expression reduces BAFFR expression and inhibits BAFF-induced B-cell survival in a cell-intrinsic manner.","method":"Allelic series of mice with titrated CD45 expression (0–180%), BCR signaling assays, IgHEL/sHEL tolerance model, flow cytometry of B-cell subsets, BAFFR expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative allelic series in vivo with multiple B-cell functional readouts and tolerance model; single lab but multiple orthogonal approaches","pmids":["22135465"],"is_preprint":false},{"year":2000,"finding":"A C-to-G transversion at position 77 in exon 4 of PTPRC interferes with mRNA splicing and results in aberrant expression of CD45 isoforms (CD45RA retained on memory/activated T cells), and this mutation is associated with multiple sclerosis susceptibility.","method":"Genetic linkage and association studies in four independent case-control cohorts and MS nuclear families, PCR/sequencing identification of the mutation, CD45 isoform expression analysis by flow cytometry","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutation identified and functionally characterized as a splicing defect with isoform expression phenotype confirmed; disease association replicated in three of four cohorts","pmids":["11101853"],"is_preprint":false},{"year":2006,"finding":"T cells from heterozygous 77C→G PTPRC mutation carriers show enhanced TCR signaling: a more active Lck pool, increased Zap70 and TCR-zeta phosphorylation, and enhanced Ca2+ flux following TCR/CD3 stimulation, mechanistically linking the splicing mutation to increased signal intensity through elevated src kinase activity.","method":"In vitro T-cell line generation from mutation carriers and controls, proliferation and IL-2 assays, Lck kinase activity assay, phospho-flow cytometry for Zap70 and TCR-zeta, Ca2+ flux measurement","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling readouts in T cells from human mutation carriers vs. controls; single lab, human primary cell study","pmids":["16393978"],"is_preprint":false},{"year":1988,"finding":"CD45 (T200) is stored in intracellular tertiary/specific granules of resting human neutrophils and mobilizes to the plasma membrane upon degranulation stimuli (fMLP, calcium ionophore A23187), suggesting that regulated surface expression of CD45 controls its signaling functions during neutrophil activation.","method":"Flow cytometry, subcellular fractionation, immunoprecipitation of radiolabeled membrane proteins from distinct subcellular fractions","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical subcellular fractionation with quantitative flow cytometry; single lab, clear localization-to-function link via degranulation","pmids":["2838485"],"is_preprint":false},{"year":2012,"finding":"CD45 (PTPRC) acts as a tumor suppressor in T-cell acute lymphoblastic leukemia: inactivating mutations of CD45 co-occur with activating mutations in IL-7R, JAK1, or LCK; downregulation of CD45 increases JAK/STAT signaling downstream of these oncoproteins, while overexpression of CD45 decreases cytokine-induced signaling.","method":"Sequencing of T-ALL patient samples, CD45 knockdown and overexpression in T cell lines with JAK/STAT signaling readouts","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function experiments with quantitative signaling readouts; genetic co-occurrence in human leukemia; single lab","pmids":["22438252"],"is_preprint":false},{"year":2021,"finding":"CD45 plays a crucial role in CD22-mediated inhibition of BCR signaling, but SHP-1 (not CD45) is required for ligand-mediated regulation of CD22 dephosphorylation; CD45 is identified as a cis ligand for CD22 on the B cell surface, but disruption of CD22 ligand binding enhances CD22 phosphorylation in CD45-/- B cells, indicating SHP-1 is the relevant phosphatase for CD22-mediated signal inhibition at the CD22 locus.","method":"CD45-/- and SHP-1 loss-of-function mutant mouse B cells, BCR ligation assays, CD22 phosphorylation measurements, CD22 clustering experiments","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO comparison with loss-of-function mutant, multiple signaling readouts; clearly distinguishes roles of CD45 vs SHP-1 at the molecular level","pmids":["33990399"],"is_preprint":false}],"current_model":"PTPRC (CD45) is a receptor-like protein tyrosine phosphatase expressed on all nucleated hematopoietic cells that functions as a central regulator of immune cell signaling: it activates Src family kinases (Lck, Fyn) by dephosphorylating their C-terminal inhibitory tyrosines to positively regulate antigen receptor (TCR/BCR) signaling, while simultaneously acting as a 'gatekeeper' that suppresses spurious or low-affinity TCR signals by dephosphorylating the TCR zeta-chain; it also negatively regulates cytokine receptor signaling by directly dephosphorylating JAK kinases; its activity is modulated by CK2-mediated phosphorylation of its D2 domain, inhibited by homodimerization (which is counteracted by CD45-AP), regulated by the splicing factor hnRNPLL and SR proteins that control alternative splicing of its extracellular exons (generating isoforms from CD45RA to CD45RO), and its large ectodomain, which undergoes steric exclusion from TCR-ligand close contacts to enable kinase-phosphatase segregation, also mediates extracatalytic functions through cis-interaction with CD22 on B cells to regulate tonic BCR signaling."},"narrative":{"mechanistic_narrative":"PTPRC (CD45) is a receptor-like protein tyrosine phosphatase that serves as a central rheostat of antigen receptor and cytokine signaling in hematopoietic cells, identified as the first such enzyme through homology between its tandem cytoplasmic domains and PTPase 1B [PMID:2845400]. In T cells it sets the threshold for activation by maintaining a regulatable pool of active Lck while opposing the inhibitory kinase Csk, yet it simultaneously suppresses antigen-independent and low-affinity signals by dephosphorylating the TCR zeta-chain — a 'gatekeeper' activity that permits graded discrimination of high- versus low-affinity antigen [PMID:31641081, PMID:12496963]. Its catalytic activity is governed by multiple inputs: CK2 phosphorylation of an acidic insert in the membrane-distal D2 domain raises phosphatase activity several-fold [PMID:10066810], and homodimerization inhibits the enzyme, an effect counteracted by the transmembrane adapter CD45-AP, whose loss elevates dimer levels and lowers phosphatase activity [PMID:7673147, PMID:14715639]. CD45 also directly binds and dephosphorylates JAK kinases (JAK1/2/3, TYK2), acting as a negative regulator of cytokine and interferon receptor signaling, a function lost in T-ALL where inactivating CD45 mutations co-occur with activating IL-7R/JAK/LCK lesions to amplify JAK/STAT signaling [PMID:11201744, PMID:22438252]. The large, structurally rigid ectodomain extends beyond TCR–ligand contact distances, providing a steric basis for CD45 exclusion from kinase-enriched close contacts and thereby coupling its physical segregation to signal initiation [PMID:26998761, PMID:12496963]. Cell-type-specific function is tuned by extensive alternative splicing of extracellular exons that generates the CD45RA-to-CD45RO isoform series [PMID:2955416, PMID:2466938], a switch driven during T-cell activation by the inducible factor hnRNPLL and by SR proteins such as SF2 [PMID:18669861, PMID:10092085]; a splice-disrupting exon 4 mutation produces aberrant isoform retention, enhanced TCR signaling, and association with multiple sclerosis susceptibility [PMID:11101853, PMID:16393978]. In B cells CD45 contributes both catalytic and noncatalytic functions, the latter acting through the inhibitory coreceptor CD22 — to which CD45 is a low-affinity, sialic-acid-dependent cis ligand — to regulate tonic BCR signaling [PMID:26561584, PMID:12115612, PMID:33990399].","teleology":[{"year":1988,"claim":"Established the enzymatic identity of CD45, answering what biochemical activity the leukocyte common antigen possessed.","evidence":"Partial sequencing of purified PTPase 1B and homology analysis of CD45 cytoplasmic domains","pmids":["2845400"],"confidence":"High","gaps":["Did not identify physiological substrates","Did not assign function to the tandem (D1/D2) domain architecture"]},{"year":1987,"claim":"Showed that CD45 isoform diversity arises from alternative splicing of extracellular exons, framing how a single locus produces cell-type-specific surface forms.","evidence":"cDNA sequencing and genomic intron-exon analysis of mouse T200/B220","pmids":["2955416","2466938"],"confidence":"High","gaps":["Did not establish functional consequences of isoform choice for signaling","Did not identify the splicing regulators"]},{"year":1990,"claim":"First implicated CD45 in physical association with surface signaling receptors (CD2), hinting at organized phosphatase recruitment.","evidence":"Chemical cross-linking and co-immunoprecipitation from human T lymphocytes","pmids":["1970422","1980615"],"confidence":"Medium","gaps":["No reconstitution of a functional CD2-CD45 complex","Interaction stoichiometry and signaling consequence undefined"]},{"year":1999,"claim":"Defined post-translational and splicing control of CD45 activity: CK2 phosphorylation of the D2 acidic insert raises catalytic output, and SR proteins govern exon skipping during activation.","evidence":"In vitro kinase/PTP assays with mutagenesis (CK2); overexpression and antisense manipulation of SF2/SRp55 in COS and primary T cells","pmids":["10066810","10092085"],"confidence":"High","gaps":["In vivo significance of CK2 phosphorylation not established","How splicing regulator induction is coupled to TCR engagement unresolved"]},{"year":2001,"claim":"Identified JAK kinases as direct CD45 substrates, extending CD45's role beyond antigen receptors to negative regulation of cytokine signaling.","evidence":"In vitro dephosphorylation, co-IP of CD45 with JAKs, and CD45-knockout mouse cytokine readouts","pmids":["11201744"],"confidence":"High","gaps":["Did not define which JAK phosphosites are dephosphorylated in vivo","Did not reconcile JAK negative regulation with positive Src-kinase regulation in the same cell"]},{"year":2002,"claim":"Demonstrated that the large ectodomain is functionally required for TCR signaling and microdomain localization, linking molecular size to phosphatase positioning.","evidence":"CD45 ectodomain chimeras in CD45-null T cells, GEM fractionation, Lck and zeta-chain phosphorylation assays","pmids":["12496963"],"confidence":"High","gaps":["Mechanism by which ectodomain size dictates GEM localization not resolved at this stage","Did not directly visualize segregation"]},{"year":2002,"claim":"Quantified the CD45–CD22 interaction, establishing it as a low-affinity, sialic-acid-dependent, avidity-driven binding rather than a high-affinity receptor-ligand pair.","evidence":"Surface plasmon resonance thermodynamic/kinetic analysis with comparative controls","pmids":["12115612","7537381"],"confidence":"High","gaps":["Did not determine which phosphatase acts downstream of CD22 engagement","In vivo functional relevance not tested biophysically"]},{"year":2004,"claim":"Clarified CD45-AP as a regulator of CD45 oligomeric state, showing it suppresses inhibitory dimerization and thereby raises phosphatase activity.","evidence":"CD45-AP knockout mice, transfection rescue, microsomal PTP activity assays, dimer detection","pmids":["14715639","7673147"],"confidence":"High","gaps":["Structural basis of dimer inhibition not solved","Whether CD45-AP recruits additional partners untested"]},{"year":2008,"claim":"Identified hnRNPLL as the inducible regulator that drives the activation-coupled CD45RA-to-CD45RO splicing switch, connecting T-cell activation state to surface isoform.","evidence":"shRNA screen, gain/loss-of-function across B and T cells, RNA binding and exon arrays","pmids":["18669861"],"confidence":"High","gaps":["How signaling upregulates hnRNPLL not defined","Functional consequence of the isoform switch for signaling output not directly measured here"]},{"year":2011,"claim":"Established that CD45 acts purely positively in B-cell signaling, distinct from its dual role in T cells, using titrated expression to reveal dose-dependent control of tolerance and survival.","evidence":"Allelic series of mice (0-180% CD45), BCR assays, IgHEL tolerance model, BAFFR analysis","pmids":["22135465"],"confidence":"High","gaps":["Molecular basis of the positive-only B-cell role versus dual T-cell role unexplained","Substrate differences between lineages not identified"]},{"year":2012,"claim":"Demonstrated CD45's tumor-suppressor function, showing inactivating mutations cooperate with activating IL-7R/JAK/LCK lesions to amplify JAK/STAT signaling in T-ALL.","evidence":"T-ALL patient sequencing, CD45 knockdown/overexpression with JAK/STAT readouts","pmids":["22438252"],"confidence":"Medium","gaps":["Causality in primary leukemogenesis not established by genetic models","Single-lab functional validation"]},{"year":2016,"claim":"Provided the structural and biophysical basis for kinetic segregation: a rigid ectodomain too tall for TCR-ligand contacts excludes CD45 from close contacts that trigger signaling.","evidence":"Crystal structure of CD45 ectodomain, biophysical dimensional analysis, live-cell close-contact imaging with signaling readouts","pmids":["26998761"],"confidence":"High","gaps":["Did not resolve how isoform-dependent ectodomain length quantitatively tunes exclusion","Did not measure phosphatase kinetics within contacts"]},{"year":2019,"claim":"Defined the integrated gatekeeper model: CD45 maintains active Lck against Csk while suppressing zeta-chain phosphorylation, enabling discrimination of high- from low-affinity antigen.","evidence":"Analog-sensitive Csk inhibition with CD45 genetic perturbation, quantitative pathway measurement, computational modeling","pmids":["31641081"],"confidence":"High","gaps":["How CD45 balances opposing positive/negative activities spatially not fully resolved","Single-lab study"]},{"year":2015,"claim":"Dissected catalytic from noncatalytic CD45 function in B cells, showing a phosphatase-independent role acting through CD22 to control tonic BCR signaling.","evidence":"Transgenic mice with catalytically inactive or cytoplasmic-domain-deleted CD45, BCR assays, genetic epistasis","pmids":["26561584"],"confidence":"High","gaps":["Molecular mechanism of the noncatalytic CD22 modulation undefined","Whether ectodomain cis-binding alone suffices not isolated"]},{"year":2021,"claim":"Refined the CD45-CD22 axis by showing CD45 is a cis ligand contributing to CD22-mediated inhibition, but SHP-1 rather than CD45 is the phosphatase that dephosphorylates CD22 at its locus.","evidence":"CD45-/- and SHP-1 mutant B cells, BCR ligation, CD22 phosphorylation and clustering assays","pmids":["33990399"],"confidence":"Medium","gaps":["How cis CD45 binding feeds into SHP-1-dependent inhibition mechanistically unresolved","Single-lab genetic comparison"]},{"year":null,"claim":"It remains unresolved how CD45 spatially and temporally integrates its opposing activating (Src-kinase) and inhibitory (zeta-chain, JAK) functions within a single cell, and how isoform-specific ectodomain length quantitatively maps to signaling thresholds across lineages.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified spatiotemporal model linking isoform choice to segregation and substrate selection","Physiological substrate repertoire across cell types incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,4,5,10,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[14,17,18]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,8,13,21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,14,17,18,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,14,15,22]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,11,12,19]}],"complexes":[],"partners":["JAK1","JAK2","JAK3","TYK2","CD22","CD45-AP","CD2","CSK"],"other_free_text":[]}},"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":"12414720","id":"PMC_12414720","title":"CD45: a critical regulator of signaling thresholds in immune cells.","date":"2001","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12414720","citation_count":731,"is_preprint":false},{"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},{"pmid":"2845400","id":"PMC_2845400","title":"The leukocyte common antigen (CD45): a putative receptor-linked protein tyrosine phosphatase.","date":"1988","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2845400","citation_count":501,"is_preprint":false},{"pmid":"11201744","id":"PMC_11201744","title":"CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11201744","citation_count":428,"is_preprint":false},{"pmid":"11323691","id":"PMC_11323691","title":"CD45: new jobs for an old acquaintance.","date":"2001","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11323691","citation_count":249,"is_preprint":false},{"pmid":"26998761","id":"PMC_26998761","title":"Initiation of T cell signaling by CD45 segregation at 'close contacts'.","date":"2016","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26998761","citation_count":228,"is_preprint":false},{"pmid":"2526179","id":"PMC_2526179","title":"Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2526179","citation_count":217,"is_preprint":false},{"pmid":"29366662","id":"PMC_29366662","title":"CD45 in human physiology and clinical medicine.","date":"2018","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/29366662","citation_count":206,"is_preprint":false},{"pmid":"34039664","id":"PMC_34039664","title":"Protein tyrosine phosphatase receptor type C (PTPRC or CD45).","date":"2021","source":"Journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/34039664","citation_count":188,"is_preprint":false},{"pmid":"1970422","id":"PMC_1970422","title":"Association of CD2 and CD45 on human T lymphocytes.","date":"1990","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/1970422","citation_count":184,"is_preprint":false},{"pmid":"18669861","id":"PMC_18669861","title":"Regulation of CD45 alternative splicing by heterogeneous ribonucleoprotein, hnRNPLL.","date":"2008","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18669861","citation_count":171,"is_preprint":false},{"pmid":"11101853","id":"PMC_11101853","title":"A point mutation in PTPRC is associated with the development of multiple sclerosis.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11101853","citation_count":162,"is_preprint":false},{"pmid":"9429890","id":"PMC_9429890","title":"The role of CD45 and CD45-associated molecules in T cell activation.","date":"1997","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/9429890","citation_count":161,"is_preprint":false},{"pmid":"3864163","id":"PMC_3864163","title":"Cloning of Ly-5 cDNA.","date":"1985","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/3864163","citation_count":149,"is_preprint":false},{"pmid":"12496963","id":"PMC_12496963","title":"CD45 ectodomain controls interaction with GEMs and Lck activity for optimal TCR signaling.","date":"2002","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12496963","citation_count":141,"is_preprint":false},{"pmid":"2525097","id":"PMC_2525097","title":"Definition of the thymic generative lineage by selective expression of high molecular weight isoforms of CD45 (T200).","date":"1989","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2525097","citation_count":137,"is_preprint":false},{"pmid":"2955416","id":"PMC_2955416","title":"B-cell variant of mouse T200 (Ly-5): evidence for alternative mRNA splicing.","date":"1987","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2955416","citation_count":129,"is_preprint":false},{"pmid":"31641081","id":"PMC_31641081","title":"CD45 functions as a signaling gatekeeper in T cells.","date":"2019","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/31641081","citation_count":127,"is_preprint":false},{"pmid":"2553046","id":"PMC_2553046","title":"Leukocyte cell surface enzymology: CD45 (LCA, T200) is a protein tyrosine phosphatase.","date":"1989","source":"Immunology today","url":"https://pubmed.ncbi.nlm.nih.gov/2553046","citation_count":122,"is_preprint":false},{"pmid":"2838485","id":"PMC_2838485","title":"Intracellular location of T200 and Mo1 glycoproteins in human neutrophils.","date":"1988","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/2838485","citation_count":119,"is_preprint":false},{"pmid":"10748233","id":"PMC_10748233","title":"Antigen-specific B cell memory: expression and replenishment of a novel b220(-) memory b cell compartment.","date":"2000","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/10748233","citation_count":118,"is_preprint":false},{"pmid":"16423560","id":"PMC_16423560","title":"Altered CD45 expression and disease.","date":"2006","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16423560","citation_count":104,"is_preprint":false},{"pmid":"29552013","id":"PMC_29552013","title":"Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects.","date":"2018","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29552013","citation_count":101,"is_preprint":false},{"pmid":"22438252","id":"PMC_22438252","title":"Mutation of the receptor tyrosine phosphatase PTPRC (CD45) in T-cell acute lymphoblastic leukemia.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22438252","citation_count":96,"is_preprint":false},{"pmid":"17332322","id":"PMC_17332322","title":"Breaking chemoresistance and radioresistance with [213Bi]anti-CD45 antibodies in leukemia cells.","date":"2007","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17332322","citation_count":87,"is_preprint":false},{"pmid":"2466938","id":"PMC_2466938","title":"Identification of the alternatively spliced exons of murine CD45 (T200) required for reactivity with B220 and other T200-restricted antibodies.","date":"1989","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2466938","citation_count":86,"is_preprint":false},{"pmid":"2475124","id":"PMC_2475124","title":"Epitopes on CD45R [T200] molecules define differentiation antigens on murine B and T lymphocytes.","date":"1988","source":"The Journal of molecular and cellular immunology : JMCI","url":"https://pubmed.ncbi.nlm.nih.gov/2475124","citation_count":83,"is_preprint":false},{"pmid":"2473122","id":"PMC_2473122","title":"Transitions from high to low molecular weight isoforms of CD45 (T200) involve rapid activation of alternate mRNA splicing and slow turnover of surface CD45R.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2473122","citation_count":83,"is_preprint":false},{"pmid":"7537381","id":"PMC_7537381","title":"Regulation of CD45 engagement by the B-cell receptor CD22.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7537381","citation_count":83,"is_preprint":false},{"pmid":"16423050","id":"PMC_16423050","title":"CD45: all is not yet crystal clear.","date":"2006","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16423050","citation_count":81,"is_preprint":false},{"pmid":"2140233","id":"PMC_2140233","title":"Expression of leukocyte common antigen (CD45) on various human leukemia/lymphoma cell lines.","date":"1990","source":"Acta pathologica japonica","url":"https://pubmed.ncbi.nlm.nih.gov/2140233","citation_count":80,"is_preprint":false},{"pmid":"2960536","id":"PMC_2960536","title":"A second signal for T cell mitogenesis provided by monoclonal antibodies CD45 (T200).","date":"1987","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2960536","citation_count":77,"is_preprint":false},{"pmid":"6993472","id":"PMC_6993472","title":"A mutation of the B220 subunit gene affects the structural and functional properties of yeast RNA polymerase B in vitro.","date":"1980","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/6993472","citation_count":76,"is_preprint":false},{"pmid":"11513545","id":"PMC_11513545","title":"TcR-alpha/beta(+) CD4(-)CD8(-) T cells in humans with the autoimmune lymphoproliferative syndrome express a novel CD45 isoform that is analogous to murine B220 and represents a marker of altered O-glycan biosynthesis.","date":"2001","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/11513545","citation_count":76,"is_preprint":false},{"pmid":"2531196","id":"PMC_2531196","title":"Lymphokine regulation of CD45R expression on human T cell clones.","date":"1989","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/2531196","citation_count":74,"is_preprint":false},{"pmid":"15275963","id":"PMC_15275963","title":"CD45: direct and indirect government of immune regulation.","date":"2004","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/15275963","citation_count":73,"is_preprint":false},{"pmid":"18607388","id":"PMC_18607388","title":"CD45 glycosylation controls T-cell life and death.","date":"2008","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18607388","citation_count":67,"is_preprint":false},{"pmid":"11857343","id":"PMC_11857343","title":"A subfraction of B220(+) cells in murine bone marrow and spleen does not belong to the B cell lineage but has dendritic cell characteristics.","date":"2002","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11857343","citation_count":63,"is_preprint":false},{"pmid":"1388188","id":"PMC_1388188","title":"CD45 expression by B cells. Expression of different CD45 isoforms by subpopulations of activated B cells.","date":"1992","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/1388188","citation_count":61,"is_preprint":false},{"pmid":"7573774","id":"PMC_7573774","title":"Modulation of T-cell adhesion markers, and the CD45R and CD57 antigens in human alcoholics.","date":"1995","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/7573774","citation_count":60,"is_preprint":false},{"pmid":"9521064","id":"PMC_9521064","title":"Expression of B220 on activated T cell blasts precedes apoptosis.","date":"1998","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9521064","citation_count":60,"is_preprint":false},{"pmid":"10092085","id":"PMC_10092085","title":"SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation.","date":"1999","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10092085","citation_count":59,"is_preprint":false},{"pmid":"9797079","id":"PMC_9797079","title":"Immunophenotype and clinical characteristics of CD45-negative and CD45-positive childhood acute lymphoblastic leukemia.","date":"1998","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/9797079","citation_count":57,"is_preprint":false},{"pmid":"33279623","id":"PMC_33279623","title":"Intratumoral CD45+CD71+ erythroid cells induce immune tolerance and predict tumor recurrence in hepatocellular carcinoma.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33279623","citation_count":55,"is_preprint":false},{"pmid":"11466358","id":"PMC_11466358","title":"Development and maintenance of a B220- memory B cell compartment.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11466358","citation_count":54,"is_preprint":false},{"pmid":"8286719","id":"PMC_8286719","title":"CD45 and the immune response.","date":"1993","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/8286719","citation_count":53,"is_preprint":false},{"pmid":"15101706","id":"PMC_15101706","title":"The biology of CD45 and its use as a therapeutic target.","date":"2004","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/15101706","citation_count":53,"is_preprint":false},{"pmid":"2960741","id":"PMC_2960741","title":"Developmental sequence of T200 antigen modifications in murine T cells.","date":"1987","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2960741","citation_count":51,"is_preprint":false},{"pmid":"8347296","id":"PMC_8347296","title":"CD4, CD8 and the role of CD45 in T-cell activation.","date":"1993","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8347296","citation_count":50,"is_preprint":false},{"pmid":"12115612","id":"PMC_12115612","title":"Comparison of CD22 binding to native CD45 and synthetic oligosaccharide.","date":"2002","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12115612","citation_count":46,"is_preprint":false},{"pmid":"2458944","id":"PMC_2458944","title":"CD4+CD45R+ cells are preferentially activated through the CD2 pathway.","date":"1988","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2458944","citation_count":45,"is_preprint":false},{"pmid":"11209093","id":"PMC_11209093","title":"Immunogenicity of Ly5 (CD45)-antigens hampers long-term engraftment following minimal conditioning in a murine bone marrow transplantation model.","date":"2001","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/11209093","citation_count":44,"is_preprint":false},{"pmid":"15081536","id":"PMC_15081536","title":"CD45 isoforms in T cell signalling and development.","date":"2004","source":"Immunology letters","url":"https://pubmed.ncbi.nlm.nih.gov/15081536","citation_count":44,"is_preprint":false},{"pmid":"22135465","id":"PMC_22135465","title":"Quantitative differences in CD45 expression unmask functions for CD45 in B-cell development, tolerance, and survival.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/22135465","citation_count":44,"is_preprint":false},{"pmid":"12678844","id":"PMC_12678844","title":"CD45 regulated signaling pathways.","date":"2003","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12678844","citation_count":43,"is_preprint":false},{"pmid":"12618866","id":"PMC_12618866","title":"Enhanced frequency of a PTPRC (CD45) exon A mutation (77C-->G) in systemic sclerosis.","date":"2003","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/12618866","citation_count":43,"is_preprint":false},{"pmid":"2564858","id":"PMC_2564858","title":"T cell regulation of human B cell proliferation and differentiation. Regulatory influences of CD45R+ and CD45R- T4 cell subsets.","date":"1989","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/2564858","citation_count":40,"is_preprint":false},{"pmid":"9301519","id":"PMC_9301519","title":"Identical expression of CD45R isoforms by CD45RC+ 'revertant' memory and CD45RC+ naive CD4 T cells.","date":"1997","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9301519","citation_count":39,"is_preprint":false},{"pmid":"16517710","id":"PMC_16517710","title":"Combinations of CD45 isoforms are crucial for immune function and disease.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16517710","citation_count":39,"is_preprint":false},{"pmid":"7673147","id":"PMC_7673147","title":"Characterization of the interaction between CD45 and CD45-AP.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7673147","citation_count":38,"is_preprint":false},{"pmid":"2443202","id":"PMC_2443202","title":"Relationship between T200 antigen expression and stages of B cell differentiation in resurgent hyperplasia of bone marrow.","date":"1987","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/2443202","citation_count":37,"is_preprint":false},{"pmid":"14715639","id":"PMC_14715639","title":"CD45-associated protein inhibits CD45 dimerization and up-regulates its protein tyrosine phosphatase activity.","date":"2004","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/14715639","citation_count":34,"is_preprint":false},{"pmid":"10066810","id":"PMC_10066810","title":"Phosphorylation of CD45 by casein kinase 2. Modulation of activity and mutational analysis.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10066810","citation_count":34,"is_preprint":false},{"pmid":"1534263","id":"PMC_1534263","title":"Function of CD4 T cell subsets in vivo: expression of CD45R isoforms.","date":"1992","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1534263","citation_count":34,"is_preprint":false},{"pmid":"2138599","id":"PMC_2138599","title":"The leukocyte-common antigen (CD45) complex and B-lymphocyte activation.","date":"1990","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2138599","citation_count":33,"is_preprint":false},{"pmid":"1980615","id":"PMC_1980615","title":"Association of CD2 and T200 (CD45) in mouse T lymphocytes.","date":"1990","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1980615","citation_count":32,"is_preprint":false},{"pmid":"12073144","id":"PMC_12073144","title":"A novel mutation in PTPRC interferes with splicing and alters the structure of the human CD45 molecule.","date":"2002","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/12073144","citation_count":31,"is_preprint":false},{"pmid":"2948186","id":"PMC_2948186","title":"Cloned murine T200 (Ly-5) cDNA reveals multiple transcripts within B- and T-lymphocyte lineages.","date":"1987","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2948186","citation_count":30,"is_preprint":false},{"pmid":"2968811","id":"PMC_2968811","title":"Distribution of the CD45R antigen in the maturation of lymphoid and myeloid series: the CD45R negative phenotype is a constant finding in T CD4 positive lymphoproliferative disorders.","date":"1988","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/2968811","citation_count":30,"is_preprint":false},{"pmid":"15333587","id":"PMC_15333587","title":"Disease associations and altered immune function in CD45 138G variant carriers.","date":"2004","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15333587","citation_count":30,"is_preprint":false},{"pmid":"12716971","id":"PMC_12716971","title":"A high-frequency polymorphism in exon 6 of the CD45 tyrosine phosphatase gene (PTPRC) resulting in altered isoform expression.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12716971","citation_count":28,"is_preprint":false},{"pmid":"1851241","id":"PMC_1851241","title":"Regulation of CD45 expression in human leukemia cells.","date":"1991","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/1851241","citation_count":28,"is_preprint":false},{"pmid":"15712182","id":"PMC_15712182","title":"The CD45 isoform B220 identifies select subsets of human B cells and B-cell lymphoproliferative disorders.","date":"2005","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/15712182","citation_count":28,"is_preprint":false},{"pmid":"16393978","id":"PMC_16393978","title":"The 77C->G mutation in the human CD45 (PTPRC) gene leads to increased intensity of TCR signaling in T cell lines from healthy individuals and patients with multiple sclerosis.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/16393978","citation_count":26,"is_preprint":false},{"pmid":"14565647","id":"PMC_14565647","title":"Interleukin-6, CD45 and the src-kinases in myeloma cell proliferation.","date":"2003","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/14565647","citation_count":25,"is_preprint":false},{"pmid":"2138239","id":"PMC_2138239","title":"T cells and CD45R expression in B-chronic lymphocytic leukemia.","date":"1990","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/2138239","citation_count":25,"is_preprint":false},{"pmid":"7514808","id":"PMC_7514808","title":"Activation signal induces the expression of B cell-specific CD45R epitope (6B2) on murine T cells.","date":"1994","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7514808","citation_count":25,"is_preprint":false},{"pmid":"6425407","id":"PMC_6425407","title":"Expression of antigens of the 'T200' family of glycoproteins on hemopoietic stem cells: evidence that thymocyte cell lineage antigens are represented on 'T200'.","date":"1984","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6425407","citation_count":24,"is_preprint":false},{"pmid":"9589574","id":"PMC_9589574","title":"Definition of the specificity of monoclonal antibodies against porcine CD45 and CD45R: report from the CD45/CD45R and CD44 subgroup of the Second International Swine CD Workshop.","date":"1998","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/9589574","citation_count":24,"is_preprint":false},{"pmid":"2138598","id":"PMC_2138598","title":"Cell generation within human thymic subsets defined by selective expression of CD45 (T200) isoforms.","date":"1990","source":"Human immunology","url":"https://pubmed.ncbi.nlm.nih.gov/2138598","citation_count":24,"is_preprint":false},{"pmid":"26561584","id":"PMC_26561584","title":"An extracatalytic function of CD45 in B cells is mediated by CD22.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26561584","citation_count":24,"is_preprint":false},{"pmid":"11747358","id":"PMC_11747358","title":"Human T cell activation induces the expression of a novel CD45 isoform that is analogous to murine B220 and is associated with altered O-glycan synthesis and onset of apoptosis.","date":"2001","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11747358","citation_count":23,"is_preprint":false},{"pmid":"8693290","id":"PMC_8693290","title":"CD45 engagement induces L-selectin down-regulation.","date":"1996","source":"Scandinavian journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8693290","citation_count":21,"is_preprint":false},{"pmid":"1703782","id":"PMC_1703782","title":"Monoclonal antibodies to epitope of CD45R (B220) inhibit interleukin 4-mediated B cell proliferation and differentiation.","date":"1990","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1703782","citation_count":21,"is_preprint":false},{"pmid":"33990399","id":"PMC_33990399","title":"The Protein Tyrosine Phosphatase SHP-1 (PTPN6) but Not CD45 (PTPRC) Is Essential for the Ligand-Mediated Regulation of CD22 in BCR-Ligated B Cells.","date":"2021","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/33990399","citation_count":20,"is_preprint":false},{"pmid":"8910744","id":"PMC_8910744","title":"The activation status of ovine CD45R+ and CD45R- efferent lymph T cells after orf virus reinfection.","date":"1996","source":"Journal of comparative pathology","url":"https://pubmed.ncbi.nlm.nih.gov/8910744","citation_count":20,"is_preprint":false},{"pmid":"8566034","id":"PMC_8566034","title":"Differential requirements of CD45 for lymphocyte development and function.","date":"1995","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8566034","citation_count":20,"is_preprint":false},{"pmid":"1350982","id":"PMC_1350982","title":"Changes in expression of CD45R during the development of Th1 and Th2 cell lines.","date":"1992","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1350982","citation_count":19,"is_preprint":false},{"pmid":"7518260","id":"PMC_7518260","title":"Differential expression and regulation of cytokine mRNAs in normal human CD45R T cell subsets.","date":"1994","source":"Cytokine","url":"https://pubmed.ncbi.nlm.nih.gov/7518260","citation_count":19,"is_preprint":false},{"pmid":"12028593","id":"PMC_12028593","title":"PTPRC (CD45) is not associated with multiple sclerosis in a large cohort of German patients.","date":"2002","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12028593","citation_count":19,"is_preprint":false},{"pmid":"1532361","id":"PMC_1532361","title":"Phenotypical and biochemical characterization of a variant CD45R expression pattern in human leukocytes.","date":"1992","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1532361","citation_count":19,"is_preprint":false},{"pmid":"9694517","id":"PMC_9694517","title":"Expression of CD45 isoforms lacking exons 7, 8 and 10.","date":"1998","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9694517","citation_count":18,"is_preprint":false},{"pmid":"25505282","id":"PMC_25505282","title":"Mutation in the CD45 inhibitory wedge modulates integrin activation and leukocyte recruitment during inflammation.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25505282","citation_count":18,"is_preprint":false},{"pmid":"17650152","id":"PMC_17650152","title":"Differential expression of CD45 on canine microglial cells.","date":"2007","source":"Journal of veterinary medicine. A, Physiology, pathology, clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17650152","citation_count":18,"is_preprint":false},{"pmid":"23997015","id":"PMC_23997015","title":"A specific PTPRC/CD45 phosphorylation event governed by stem cell chemokine CXCL12 regulates primitive hematopoietic cell motility.","date":"2013","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/23997015","citation_count":17,"is_preprint":false},{"pmid":"29930175","id":"PMC_29930175","title":"Hepato-entrained B220+CD11c+NK1.1+ cells regulate pre-metastatic niche formation in the lung.","date":"2018","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29930175","citation_count":17,"is_preprint":false},{"pmid":"32755539","id":"PMC_32755539","title":"Osterix-Cre marks distinct subsets of CD45- and CD45+ stromal populations in extra-skeletal tumors with pro-tumorigenic characteristics.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32755539","citation_count":17,"is_preprint":false},{"pmid":"15302847","id":"PMC_15302847","title":"Altered CD45 isoform expression affects lymphocyte function in CD45 Tg mice.","date":"2004","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/15302847","citation_count":17,"is_preprint":false},{"pmid":"2478698","id":"PMC_2478698","title":"Expression of CDw29 and CD45R antigens on epithelial cells in oral lichen planus.","date":"1989","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/2478698","citation_count":16,"is_preprint":false},{"pmid":"36333772","id":"PMC_36333772","title":"Single cell profiling of CD45+ spinal cord cells reveals microglial and B cell heterogeneity and crosstalk following spinal cord injury.","date":"2022","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/36333772","citation_count":16,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46495,"output_tokens":6220,"usd":0.116392,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15142,"output_tokens":4727,"usd":0.096943,"stage2_stop_reason":"end_turn"},"total_usd":0.213335,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"CD45 (leukocyte common antigen/T200) was identified as a protein tyrosine phosphatase based on 40% sequence identity between a 157-residue segment of PTPase 1B (isolated from human placenta) and the tandem C-terminal cytoplasmic domains of CD45, establishing CD45 as the first receptor-like protein tyrosine phosphatase.\",\n      \"method\": \"Partial amino acid sequencing of purified PTPase 1B combined with sequence homology analysis of CD45 cytoplasmic domains\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical purification and sequence analysis establishing enzymatic class; foundational finding replicated and confirmed in multiple subsequent studies\",\n      \"pmids\": [\"2845400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"CD45 (T200/Ly-5) isoforms are generated by alternative mRNA splicing; the B-cell form (B220, ~220 kDa) contains an insertion of 139 amino acid residues in the amino-terminal extracellular region encoded by an alternatively spliced exon not present in T-cell forms.\",\n      \"method\": \"cDNA sequencing of mouse T200 from pre-B cell line 70Z/3, RNA blotting with exon-specific probes, 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 / Strong — complete cDNA sequencing plus genomic structure analysis; independently confirmed by multiple subsequent studies on CD45 alternative splicing\",\n      \"pmids\": [\"2955416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"The alternatively spliced exons A and B of murine CD45 encode distinct antigenic determinants: B220 antibodies 14.8 and RA32C2 require exon A expression, while antibody C363.16A reactivity depends on exon B expression.\",\n      \"method\": \"Retroviral expression of defined CD45 cDNA splice variants in cell lines followed by antibody-binding analysis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct functional reconstitution with defined cDNA constructs, mapping epitopes to specific alternatively spliced exons\",\n      \"pmids\": [\"2466938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"CD45 physically associates with CD2 on the surface of human T lymphocytes, as demonstrated by chemical cross-linking, suggesting a functional link between CD2-mediated signaling and CD45 phosphatase activity.\",\n      \"method\": \"Chemical cross-linking of intact human T lymphocytes followed by co-immunoprecipitation\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — chemical cross-linking and co-precipitation from two independent studies (human and mouse), but no direct functional reconstitution of the complex\",\n      \"pmids\": [\"1970422\", \"1980615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CD45 directly dephosphorylates and binds to JAK kinases (JAK1, JAK2, JAK3, TYK2) and negatively regulates cytokine receptor signaling; targeted disruption of CD45 in mice leads to enhanced JAK/STAT activation downstream of cytokine and interferon receptors, and CD45 negatively regulates IL-3-mediated proliferation, erythropoietin-dependent haematopoiesis, and antiviral responses.\",\n      \"method\": \"In vitro dephosphorylation assay, co-immunoprecipitation of CD45 with JAKs, CD45 knockout mouse model with cytokine stimulation readouts\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphatase assay plus direct binding plus KO mouse phenotype with multiple orthogonal readouts in one study\",\n      \"pmids\": [\"11201744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The large ectodomain of CD45 is required for optimal TCR signaling and for partial localization of CD45 to glycosphingolipid-enriched membrane microdomains (GEMs); CD45 chimeras with small ectodomains fail to rescue TCR signaling in CD45-null T cells and do not localize to GEMs, whereas a CD45 chimera bearing the large ectodomain of CD43 rescues both basal Lck activity and TCR-induced signaling.\",\n      \"method\": \"CD45 chimera expression in CD45-null T cells, GEM fractionation, Lck activity assays, TCR zeta-chain phosphorylation assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution with defined chimeras, multiple functional readouts including kinase activity and signaling, subcellular fractionation\",\n      \"pmids\": [\"12496963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD22 engages the extracellular domain of CD45 through sialic acid-dependent interaction; soluble CD22-Ig fusion proteins can modulate early T-cell signals in antigen receptor/CD3-mediated stimulation, and addition of sialic acid by beta-galactoside alpha-2,6-sialyltransferase to CD22 abrogates this interaction.\",\n      \"method\": \"Soluble CD22-Ig fusion proteins incubated with T cells expressing wild-type and chimeric CD45, measurement of early signaling events, enzymatic modification of CD22 sialylation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional modulation assay with chimeric CD45 forms, enzymatic control, single lab\",\n      \"pmids\": [\"7537381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"CD22 binds to native CD45 with low affinity (Kd ~130 µM at 25°C) via alpha2-6-linked sialic acid on N-glycans; binding is enthalpically driven and has very fast kinetics (koff ≥18 s−1). CD22 does not bind CD45 with substantially higher affinity than other alpha2-6-sialylated proteins, suggesting preferential binding is due to CD45 carrying multiple copies of the ligand rather than intrinsically higher-affinity sites.\",\n      \"method\": \"Surface plasmon resonance thermodynamic and kinetic analysis, Van't Hoff analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — quantitative biophysical measurement with multiple comparative controls; single lab but rigorous thermodynamic analysis\",\n      \"pmids\": [\"12115612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD45-AP (CD45-associated protein) interacts with CD45 via its transmembrane segment binding to the transmembrane portion of CD45; CD45-AP is localized in particulate (membrane) fractions of lymphocytes along with CD45, and the bulk of CD45-AP is cytoplasmic, suggesting it acts as an adapter directing CD45 interactions with other signaling molecules.\",\n      \"method\": \"Deletion and chimeric construct binding analysis, subcellular fractionation, protease protection assay on intact cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple deletion/chimera constructs mapping interaction domain, fractionation, protease protection; single lab\",\n      \"pmids\": [\"7673147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD45-AP inhibits CD45 dimerization and upregulates CD45 protein tyrosine phosphatase activity; T cells from CD45-AP-null mice have markedly higher levels of CD45 dimers, and microsomal fractions from CD45-AP-negative cells show significantly lower CD45 PTP activity than CD45-AP-positive cells.\",\n      \"method\": \"CD45-AP knockout mice analysis, CD45-AP-null T cell line transfection, PTP activity assay of microsomal fractions, dimer detection\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — enzymatic activity directly measured in KO vs. WT fractions, genetic rescue by transfection, multiple orthogonal methods in one study\",\n      \"pmids\": [\"14715639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Casein kinase 2 (CK2) is a major lymphocyte kinase that phosphorylates CD45 at Ser965, Ser968, Ser969, and Ser973 within an acidic insert in the D2 domain; CK2 phosphorylation increases CD45 PTP activity ~3-fold toward phosphorylated myelin basic protein, and this increase is reversible by PP2A; Ser-to-Glu mutations at these sites mimic phosphorylation and triple Vmax.\",\n      \"method\": \"In-gel kinase assay, immunoprecipitation/immunodepletion, specific inhibition, site-directed mutagenesis, in vitro PTP activity assay, PP2A dephosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assays with mutagenesis, identification of writer kinase and eraser phosphatase, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"10066810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HnRNPLL (heterogeneous ribonucleoprotein L-like) is a critical inducible regulator of CD45 alternative splicing in T cells; hnRNPLL is upregulated in stimulated T cells, binds CD45 transcripts, and is both necessary and sufficient for the shift from CD45RA to CD45RO isoform expression upon T cell activation.\",\n      \"method\": \"shRNA screen, overexpression and depletion in B and T cell lines and primary T cells, RNA binding assay, exon array analysis\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function experiments in multiple cell types with direct RNA binding demonstrated; replicated across multiple cell systems in one study\",\n      \"pmids\": [\"18669861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SR protein SF2 is required for CD45 exon 4 skipping during T cell activation; overexpression of SF2 induces exon 4 skipping via its RNA recognition motifs, while SRp55 has antagonistic effects. SF2 and SRp55 are induced upon activation of CD45RA+ T cells, correlating with the shift to CD45RO expression.\",\n      \"method\": \"Overexpression of splicing regulators in COS cells, antisense inhibition of SRp55, domain-deletion constructs, RT-PCR analysis of CD45 isoforms in primary T cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and antisense knockdown with domain mapping; single lab, functional correlation in primary cells\",\n      \"pmids\": [\"10092085\"],\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, providing a steric basis for CD45 exclusion from TCR engagement sites. Spontaneous formation of 'close contacts'—submicron-scale structures characterized by CD45 and kinase segregation—initiates TCR signaling even in the absence of TCR ligands.\",\n      \"method\": \"Crystal structure of CD45 ectodomain, biophysical analysis of molecular dimensions, live-cell imaging of close contacts, signaling readouts in cells without TCR ligands\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with biophysical measurements and live-cell functional imaging with signaling readouts; multiple orthogonal methods\",\n      \"pmids\": [\"26998761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD45 acts as a signaling 'gatekeeper' by maintaining a regulatable pool of active Lck through opposing Csk, while simultaneously suppressing TCR zeta-chain phosphorylation. CD45 suppresses antigen-independent and low-affinity antigen-induced signaling but not high-affinity antigen-driven signaling, enabling graded signal discrimination.\",\n      \"method\": \"Chemical inhibition of Csk (analog-sensitive allele), genetic perturbation of CD45 and Csk, quantitative measurement of Lck activation, zeta-chain phosphorylation, and downstream signaling with computational analysis\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — acute chemical inhibition combined with genetic perturbation and computational modeling; multiple orthogonal measurements of pathway nodes; single lab but highly rigorous\",\n      \"pmids\": [\"31641081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CXCL12 governs a specific phosphorylation event on PTPRC/CD45 in hematopoietic progenitor cells; this phosphorylation site lies downstream of Rac proteins, potentiates Src signaling, and governs hematopoietic progenitor and lymphoid cell motility.\",\n      \"method\": \"Phosphoproteomics of CXCL12-treated hematopoietic progenitor cells, site-directed mutagenesis, antibody validation of phosphosite, mass spectrometry absolute quantification (AQUA), Rac inhibitor studies\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics discovery validated by mutagenesis and orthogonal MS quantification with functional motility readout; single lab\",\n      \"pmids\": [\"23997015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A constitutively activating point mutation in the CD45 inhibitory wedge (CD45E613R) modulates integrin activation in neutrophils: LFA-1 adhesiveness is impaired while avidity is enhanced, Mac-1 adhesiveness is increased, and neutrophil crawling and recruitment to infected lungs are impaired.\",\n      \"method\": \"Transgenic mice carrying CD45E613R mutation, intravital microscopy, integrin adhesion/avidity assays, bacterial lung infection model\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with constitutively active CD45, multiple integrin functional assays and in vivo recruitment readout; single lab\",\n      \"pmids\": [\"25505282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD45 has an extracatalytic function in B cells mediated through CD22: phosphatase-dead CD45 transgenes (catalytic-inactivating point mutation) or cytoplasmic-domain-deleted CD45 partially rescue the phenotype of CD45-deficient B cells, identifying a noncatalytic role of CD45 in regulating tonic BCR signaling through modulation of the inhibitory coreceptor CD22.\",\n      \"method\": \"Transgenic mice expressing catalytically inactive or cytoplasmic-domain-deleted CD45, BCR signaling assays, genetic epistasis with CD45-deficient background\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — separation-of-function mutations in vivo, multiple transgenic lines, genetic epistasis; rigorous dissection of catalytic vs. noncatalytic roles\",\n      \"pmids\": [\"26561584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD45 plays a purely positive regulatory role in BCR signaling (unlike its dual positive/negative roles in TCR signaling): increasing CD45 expression drives enhanced receptor editing and loss of B cells, while high CD45 expression reduces BAFFR expression and inhibits BAFF-induced B-cell survival in a cell-intrinsic manner.\",\n      \"method\": \"Allelic series of mice with titrated CD45 expression (0–180%), BCR signaling assays, IgHEL/sHEL tolerance model, flow cytometry of B-cell subsets, BAFFR expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative allelic series in vivo with multiple B-cell functional readouts and tolerance model; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"22135465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A C-to-G transversion at position 77 in exon 4 of PTPRC interferes with mRNA splicing and results in aberrant expression of CD45 isoforms (CD45RA retained on memory/activated T cells), and this mutation is associated with multiple sclerosis susceptibility.\",\n      \"method\": \"Genetic linkage and association studies in four independent case-control cohorts and MS nuclear families, PCR/sequencing identification of the mutation, CD45 isoform expression analysis by flow cytometry\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutation identified and functionally characterized as a splicing defect with isoform expression phenotype confirmed; disease association replicated in three of four cohorts\",\n      \"pmids\": [\"11101853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"T cells from heterozygous 77C→G PTPRC mutation carriers show enhanced TCR signaling: a more active Lck pool, increased Zap70 and TCR-zeta phosphorylation, and enhanced Ca2+ flux following TCR/CD3 stimulation, mechanistically linking the splicing mutation to increased signal intensity through elevated src kinase activity.\",\n      \"method\": \"In vitro T-cell line generation from mutation carriers and controls, proliferation and IL-2 assays, Lck kinase activity assay, phospho-flow cytometry for Zap70 and TCR-zeta, Ca2+ flux measurement\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling readouts in T cells from human mutation carriers vs. controls; single lab, human primary cell study\",\n      \"pmids\": [\"16393978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"CD45 (T200) is stored in intracellular tertiary/specific granules of resting human neutrophils and mobilizes to the plasma membrane upon degranulation stimuli (fMLP, calcium ionophore A23187), suggesting that regulated surface expression of CD45 controls its signaling functions during neutrophil activation.\",\n      \"method\": \"Flow cytometry, subcellular fractionation, immunoprecipitation of radiolabeled membrane proteins from distinct subcellular fractions\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical subcellular fractionation with quantitative flow cytometry; single lab, clear localization-to-function link via degranulation\",\n      \"pmids\": [\"2838485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD45 (PTPRC) acts as a tumor suppressor in T-cell acute lymphoblastic leukemia: inactivating mutations of CD45 co-occur with activating mutations in IL-7R, JAK1, or LCK; downregulation of CD45 increases JAK/STAT signaling downstream of these oncoproteins, while overexpression of CD45 decreases cytokine-induced signaling.\",\n      \"method\": \"Sequencing of T-ALL patient samples, CD45 knockdown and overexpression in T cell lines with JAK/STAT signaling readouts\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function experiments with quantitative signaling readouts; genetic co-occurrence in human leukemia; single lab\",\n      \"pmids\": [\"22438252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD45 plays a crucial role in CD22-mediated inhibition of BCR signaling, but SHP-1 (not CD45) is required for ligand-mediated regulation of CD22 dephosphorylation; CD45 is identified as a cis ligand for CD22 on the B cell surface, but disruption of CD22 ligand binding enhances CD22 phosphorylation in CD45-/- B cells, indicating SHP-1 is the relevant phosphatase for CD22-mediated signal inhibition at the CD22 locus.\",\n      \"method\": \"CD45-/- and SHP-1 loss-of-function mutant mouse B cells, BCR ligation assays, CD22 phosphorylation measurements, CD22 clustering experiments\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO comparison with loss-of-function mutant, multiple signaling readouts; clearly distinguishes roles of CD45 vs SHP-1 at the molecular level\",\n      \"pmids\": [\"33990399\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRC (CD45) is a receptor-like protein tyrosine phosphatase expressed on all nucleated hematopoietic cells that functions as a central regulator of immune cell signaling: it activates Src family kinases (Lck, Fyn) by dephosphorylating their C-terminal inhibitory tyrosines to positively regulate antigen receptor (TCR/BCR) signaling, while simultaneously acting as a 'gatekeeper' that suppresses spurious or low-affinity TCR signals by dephosphorylating the TCR zeta-chain; it also negatively regulates cytokine receptor signaling by directly dephosphorylating JAK kinases; its activity is modulated by CK2-mediated phosphorylation of its D2 domain, inhibited by homodimerization (which is counteracted by CD45-AP), regulated by the splicing factor hnRNPLL and SR proteins that control alternative splicing of its extracellular exons (generating isoforms from CD45RA to CD45RO), and its large ectodomain, which undergoes steric exclusion from TCR-ligand close contacts to enable kinase-phosphatase segregation, also mediates extracatalytic functions through cis-interaction with CD22 on B cells to regulate tonic BCR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRC (CD45) is a receptor-like protein tyrosine phosphatase that serves as a central rheostat of antigen receptor and cytokine signaling in hematopoietic cells, identified as the first such enzyme through homology between its tandem cytoplasmic domains and PTPase 1B [#0]. In T cells it sets the threshold for activation by maintaining a regulatable pool of active Lck while opposing the inhibitory kinase Csk, yet it simultaneously suppresses antigen-independent and low-affinity signals by dephosphorylating the TCR zeta-chain — a 'gatekeeper' activity that permits graded discrimination of high- versus low-affinity antigen [#14, #5]. Its catalytic activity is governed by multiple inputs: CK2 phosphorylation of an acidic insert in the membrane-distal D2 domain raises phosphatase activity several-fold [#10], and homodimerization inhibits the enzyme, an effect counteracted by the transmembrane adapter CD45-AP, whose loss elevates dimer levels and lowers phosphatase activity [#8, #9]. CD45 also directly binds and dephosphorylates JAK kinases (JAK1/2/3, TYK2), acting as a negative regulator of cytokine and interferon receptor signaling, a function lost in T-ALL where inactivating CD45 mutations co-occur with activating IL-7R/JAK/LCK lesions to amplify JAK/STAT signaling [#4, #22]. The large, structurally rigid ectodomain extends beyond TCR–ligand contact distances, providing a steric basis for CD45 exclusion from kinase-enriched close contacts and thereby coupling its physical segregation to signal initiation [#13, #5]. Cell-type-specific function is tuned by extensive alternative splicing of extracellular exons that generates the CD45RA-to-CD45RO isoform series [#1, #2], a switch driven during T-cell activation by the inducible factor hnRNPLL and by SR proteins such as SF2 [#11, #12]; a splice-disrupting exon 4 mutation produces aberrant isoform retention, enhanced TCR signaling, and association with multiple sclerosis susceptibility [#19, #20]. In B cells CD45 contributes both catalytic and noncatalytic functions, the latter acting through the inhibitory coreceptor CD22 — to which CD45 is a low-affinity, sialic-acid-dependent cis ligand — to regulate tonic BCR signaling [#17, #7, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Established the enzymatic identity of CD45, answering what biochemical activity the leukocyte common antigen possessed.\",\n      \"evidence\": \"Partial sequencing of purified PTPase 1B and homology analysis of CD45 cytoplasmic domains\",\n      \"pmids\": [\"2845400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological substrates\", \"Did not assign function to the tandem (D1/D2) domain architecture\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Showed that CD45 isoform diversity arises from alternative splicing of extracellular exons, framing how a single locus produces cell-type-specific surface forms.\",\n      \"evidence\": \"cDNA sequencing and genomic intron-exon analysis of mouse T200/B220\",\n      \"pmids\": [\"2955416\", \"2466938\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish functional consequences of isoform choice for signaling\", \"Did not identify the splicing regulators\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"First implicated CD45 in physical association with surface signaling receptors (CD2), hinting at organized phosphatase recruitment.\",\n      \"evidence\": \"Chemical cross-linking and co-immunoprecipitation from human T lymphocytes\",\n      \"pmids\": [\"1970422\", \"1980615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reconstitution of a functional CD2-CD45 complex\", \"Interaction stoichiometry and signaling consequence undefined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined post-translational and splicing control of CD45 activity: CK2 phosphorylation of the D2 acidic insert raises catalytic output, and SR proteins govern exon skipping during activation.\",\n      \"evidence\": \"In vitro kinase/PTP assays with mutagenesis (CK2); overexpression and antisense manipulation of SF2/SRp55 in COS and primary T cells\",\n      \"pmids\": [\"10066810\", \"10092085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of CK2 phosphorylation not established\", \"How splicing regulator induction is coupled to TCR engagement unresolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified JAK kinases as direct CD45 substrates, extending CD45's role beyond antigen receptors to negative regulation of cytokine signaling.\",\n      \"evidence\": \"In vitro dephosphorylation, co-IP of CD45 with JAKs, and CD45-knockout mouse cytokine readouts\",\n      \"pmids\": [\"11201744\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which JAK phosphosites are dephosphorylated in vivo\", \"Did not reconcile JAK negative regulation with positive Src-kinase regulation in the same cell\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that the large ectodomain is functionally required for TCR signaling and microdomain localization, linking molecular size to phosphatase positioning.\",\n      \"evidence\": \"CD45 ectodomain chimeras in CD45-null T cells, GEM fractionation, Lck and zeta-chain phosphorylation assays\",\n      \"pmids\": [\"12496963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ectodomain size dictates GEM localization not resolved at this stage\", \"Did not directly visualize segregation\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Quantified the CD45–CD22 interaction, establishing it as a low-affinity, sialic-acid-dependent, avidity-driven binding rather than a high-affinity receptor-ligand pair.\",\n      \"evidence\": \"Surface plasmon resonance thermodynamic/kinetic analysis with comparative controls\",\n      \"pmids\": [\"12115612\", \"7537381\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine which phosphatase acts downstream of CD22 engagement\", \"In vivo functional relevance not tested biophysically\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Clarified CD45-AP as a regulator of CD45 oligomeric state, showing it suppresses inhibitory dimerization and thereby raises phosphatase activity.\",\n      \"evidence\": \"CD45-AP knockout mice, transfection rescue, microsomal PTP activity assays, dimer detection\",\n      \"pmids\": [\"14715639\", \"7673147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of dimer inhibition not solved\", \"Whether CD45-AP recruits additional partners untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified hnRNPLL as the inducible regulator that drives the activation-coupled CD45RA-to-CD45RO splicing switch, connecting T-cell activation state to surface isoform.\",\n      \"evidence\": \"shRNA screen, gain/loss-of-function across B and T cells, RNA binding and exon arrays\",\n      \"pmids\": [\"18669861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How signaling upregulates hnRNPLL not defined\", \"Functional consequence of the isoform switch for signaling output not directly measured here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that CD45 acts purely positively in B-cell signaling, distinct from its dual role in T cells, using titrated expression to reveal dose-dependent control of tolerance and survival.\",\n      \"evidence\": \"Allelic series of mice (0-180% CD45), BCR assays, IgHEL tolerance model, BAFFR analysis\",\n      \"pmids\": [\"22135465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the positive-only B-cell role versus dual T-cell role unexplained\", \"Substrate differences between lineages not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated CD45's tumor-suppressor function, showing inactivating mutations cooperate with activating IL-7R/JAK/LCK lesions to amplify JAK/STAT signaling in T-ALL.\",\n      \"evidence\": \"T-ALL patient sequencing, CD45 knockdown/overexpression with JAK/STAT readouts\",\n      \"pmids\": [\"22438252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality in primary leukemogenesis not established by genetic models\", \"Single-lab functional validation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural and biophysical basis for kinetic segregation: a rigid ectodomain too tall for TCR-ligand contacts excludes CD45 from close contacts that trigger signaling.\",\n      \"evidence\": \"Crystal structure of CD45 ectodomain, biophysical dimensional analysis, live-cell close-contact imaging with signaling readouts\",\n      \"pmids\": [\"26998761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how isoform-dependent ectodomain length quantitatively tunes exclusion\", \"Did not measure phosphatase kinetics within contacts\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the integrated gatekeeper model: CD45 maintains active Lck against Csk while suppressing zeta-chain phosphorylation, enabling discrimination of high- from low-affinity antigen.\",\n      \"evidence\": \"Analog-sensitive Csk inhibition with CD45 genetic perturbation, quantitative pathway measurement, computational modeling\",\n      \"pmids\": [\"31641081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How CD45 balances opposing positive/negative activities spatially not fully resolved\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Dissected catalytic from noncatalytic CD45 function in B cells, showing a phosphatase-independent role acting through CD22 to control tonic BCR signaling.\",\n      \"evidence\": \"Transgenic mice with catalytically inactive or cytoplasmic-domain-deleted CD45, BCR assays, genetic epistasis\",\n      \"pmids\": [\"26561584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of the noncatalytic CD22 modulation undefined\", \"Whether ectodomain cis-binding alone suffices not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the CD45-CD22 axis by showing CD45 is a cis ligand contributing to CD22-mediated inhibition, but SHP-1 rather than CD45 is the phosphatase that dephosphorylates CD22 at its locus.\",\n      \"evidence\": \"CD45-/- and SHP-1 mutant B cells, BCR ligation, CD22 phosphorylation and clustering assays\",\n      \"pmids\": [\"33990399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How cis CD45 binding feeds into SHP-1-dependent inhibition mechanistically unresolved\", \"Single-lab genetic comparison\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CD45 spatially and temporally integrates its opposing activating (Src-kinase) and inhibitory (zeta-chain, JAK) functions within a single cell, and how isoform-specific ectodomain length quantitatively maps to signaling thresholds across lineages.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified spatiotemporal model linking isoform choice to segregation and substrate selection\", \"Physiological substrate repertoire across cell types incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 4, 5, 10, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [14, 17, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 8, 13, 21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 14, 17, 18, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 14, 15, 22]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 11, 12, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"JAK1\", \"JAK2\", \"JAK3\", \"TYK2\", \"CD22\", \"CD45-AP\", \"CD2\", \"CSK\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}