{"gene":"PTPRD","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2009,"finding":"PTPRD directly dephosphorylates the oncoprotein STAT3; wild-type PTPRD inhibits growth of GBM tumor cells, an effect abolished by cancer-specific PTPRD mutations.","method":"Phosphatase assay (dephosphorylation of STAT3), cell growth inhibition assays with wild-type vs. mutant PTPRD reconstitution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct enzymatic assay demonstrating STAT3 dephosphorylation, replicated functionally with cancer-specific mutants, and independently corroborated by multiple subsequent studies","pmids":["19478061"],"is_preprint":false},{"year":2014,"finding":"Loss of PTPRD phosphatase activity leads to phospho-STAT3 accumulation and constitutive activation of STAT3-driven genetic programs in gliomas; heterozygous Ptprd loss cooperates with p16/CDKN2A deletion to drive gliomagenesis in mice, demonstrating a haploinsufficient tumor suppressor role.","method":"Mouse glioma model (heterozygous Ptprd KO combined with p16 deletion), immunoblotting for phospho-STAT3, genomic analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo mouse genetic epistasis model with molecular readout (phospho-STAT3), replicated across multiple PTPRD/STAT3 papers","pmids":["24843164"],"is_preprint":false},{"year":2014,"finding":"Co-deletion of Ptprd and Cdkn2a cooperates to accelerate tumorigenesis in mice; heterozygous loss of Ptprd was sufficient, indicating haploinsufficiency.","method":"Mouse genetic model (Ptprd/Cdkn2a double knockout), tumor incidence and spectrum analysis","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean genetic epistasis in vivo, single lab but orthogonal to the glioma model paper (PMID 24843164)","pmids":["25138050"],"is_preprint":false},{"year":2014,"finding":"Using a substrate-trap approach and mass spectrometry followed by co-immunoprecipitation, desmoplakin (a desmosomal cell-cell adhesion protein) was identified as a novel PTPRD substrate; cancer-associated mutant PTPRD alleles showed reduced phosphatase activity against desmoplakin.","method":"Substrate-trap mutagenesis, mass spectrometry, co-immunoprecipitation, phosphatase activity assay","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — substrate-trap reconstitution, MS identification, and co-IP validation with functional mutagenesis, single lab","pmids":["25113440"],"is_preprint":false},{"year":1994,"finding":"The intracellular domain of PTPRD (referred to as HPTP beta) exhibits intrinsic protein tyrosine phosphatase activity with defined kinetic parameters (kcat 76–258 s⁻¹); activity is inhibited by vanadate, molybdate, heparin, poly(Glu,Tyr), and zinc ions; substrate preference was srcTyr-527 > PDGF-R > ERK1 >> CSF-1R.","method":"Bacterial expression and purification of intracellular domain; Malachite Green phosphatase assay with synthetic phosphopeptide substrates","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzyme, kinetic analysis, multiple substrates, replicated in related papers","pmids":["8135747"],"is_preprint":false},{"year":1992,"finding":"The intracellular (cytoplasmic) domain of HPTP beta (PTPRD) expressed in bacteria is enzymatically active as a protein tyrosine phosphatase; the juxta-membrane segment (residues 1622–1639) functions as a negative regulatory sequence—its deletion increases activity ~5-fold; residues 1684–1690 define the N-terminal border of the catalytic domain; loss of N-terminal sequence beyond residue 1690 abolishes activity.","method":"Bacterial expression, truncation/deletion mutagenesis, PTPase activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis and truncation analysis defining catalytic boundaries and regulatory elements","pmids":["1322915"],"is_preprint":false},{"year":1993,"finding":"PTPRD (MPTP delta / HPTP delta) is expressed as multiple splice isoforms differing in extracellular domain composition (1 vs. 3 Ig-like domains; 4 vs. 8 FN-III-like domains) and produces a ~210 kDa protein detected in brain and kidney; expression is enriched in hippocampus, thalamic reticular nucleus, and piriform cortex, and in pre-B cell lines.","method":"cDNA cloning, Northern blot, antibody immunoprecipitation, in situ hybridization","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein detection and localization by antibody and in situ hybridization, single lab","pmids":["8355697"],"is_preprint":false},{"year":1993,"finding":"The chromosomal locus for HPTP delta (PTPRD) maps to human chromosome 9p24, established by fluorescence in situ hybridization and human-mouse hybrid cell lines.","method":"Fluorescence in situ hybridization (FISH), somatic cell hybrid panel","journal":"Japanese journal of cancer research : Gann","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytogenetic mapping with two independent methods, single lab","pmids":["8294211"],"is_preprint":false},{"year":2011,"finding":"PTPRD suppresses colon cancer cell migration and is required for appropriate cell-cell adhesion; PTPRD regulates cell migration in cooperation with β-catenin/TCF signaling and its downstream target CD44.","method":"Cell migration assays, cell-cell adhesion assays, knockdown/overexpression, reporter assays for β-catenin/TCF","journal":"Experimental and therapeutic medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with defined phenotypic readout and pathway placement via TCF signaling, single lab","pmids":["22977525"],"is_preprint":false},{"year":2019,"finding":"Loss of PTPRD in gastric cancer cells upregulates CXCL8 expression through both ERK and STAT3 signaling, leading to increased angiogenesis and metastasis; specific ERK or STAT3 inhibitors abrogate PTPRD-loss-induced angiogenesis.","method":"Microarray analysis, stable PTPRD knockdown cell lines, ELISA, in vitro HUVEC tube formation assay, pharmacological inhibitors","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (transcriptomic + functional + pharmacological) in single lab","pmids":["31805999"],"is_preprint":false},{"year":2015,"finding":"PTPRD loss-of-function mutations (but not methylation or copy number loss) lead to increased STAT3 phosphorylation in HNSCC; overexpression of wild-type PTPRD inhibits growth and STAT3 activation, while PTPRD mutants do not; HNSCC cells with endogenous PTPRD mutations are more sensitive to STAT3 blockade.","method":"Transfection of wild-type vs. mutant PTPRD, MTT growth assays, immunoblotting for phospho-STAT3, methylation-specific PCR","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional comparison of WT vs. mutant alleles with molecular readout, single lab, multiple methods","pmids":["26267899"],"is_preprint":false},{"year":2015,"finding":"PTPRD knockdown using shRNA in HepG2 cells results in downregulation of the insulin receptor, and overexpression of the insulin receptor PPARγ2 induces overexpression of PTPRD; PTPRD silencing in T2D is caused by DNMT1-mediated promoter DNA methylation.","method":"shRNA knockdown, overexpression, RT-PCR, bisulfite sequencing, DNMT1 inhibition","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional experiments linking PTPRD to insulin receptor expression and methylation-mediated silencing, single lab","pmids":["26079428"],"is_preprint":false},{"year":2022,"finding":"PTPRD knockdown in pulmonary arterial smooth muscle cells (PASMCs) promotes cell migration through the PDGFRB/PLCγ1 signaling pathway; PTPRD is silenced in PASMCs by DNMT1-mediated promoter methylation upon PDGF-BB stimulation; heterozygous PTPRD KO rats show exacerbated pulmonary arterial remodeling under hypoxia with higher PLCγ1 activity.","method":"PTPRD knockdown, cell migration assays, western blotting, DNMT1 inhibition, PTPRD KO rat model under hypoxic conditions","journal":"Journal of hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro knockdown plus in vivo rat KO with pathway (PDGFRB/PLCγ1) identification, single lab","pmids":["35848503"],"is_preprint":false},{"year":2023,"finding":"Ectodomain antibody RD-43 binds to endogenous PTPRD in a metastatic breast cancer cell line and induces PTPRD dimerization, which inhibits phosphatase activity; the mAb-PTPRD dimer complex is degraded via lysosomal and proteasomal pathways independently of secretase cleavage; RD-43 treatment inhibits SRC signaling and suppresses PTPRD-dependent cell invasion.","method":"Monoclonal antibody generation, co-immunoprecipitation, chemically-induced dimerization, phosphatase activity assays, degradation pathway analysis (lysosomal/proteasomal inhibitors), cell invasion assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (dimerization, enzymatic assay, degradation pathway dissection, functional invasion assay) in one rigorous study","pmids":["37669874"],"is_preprint":false},{"year":2022,"finding":"Quercetin and other flavonols (but not closely related flavones) act as substrate-selective positive allosteric modulators of PTPRD's phosphatase, enhancing dephosphorylation of candidate brain substrates including GSK3β and GSK3α; candidate brain phosphotyrosine protein (PTPP) substrates for PTPRD were identified based on increased phosphorylation in knockout vs. wildtype animals and brisk dephosphorylation by recombinant PTPRD.","method":"Recombinant PTPRD phosphatase assay, phosphoproteomic comparison of KO vs. WT brain, allosteric modulation screening","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with substrate identification via KO comparison, single lab","pmids":["35636503"],"is_preprint":false},{"year":2018,"finding":"7-Butoxy illudalic acid analog (7-BIA) was identified as a small molecule that targets PTPRD and inhibits its phosphatase activity with some selectivity; reduced expression of PTPRD (heterozygous KO) robustly reduces cocaine self-administration in mice; 7-BIA reduced cocaine-conditioned place preference and cocaine self-administration in WT but not PTPRD heterozygous KO mice.","method":"Phosphatase inhibition assay (in vitro), heterozygous PTPRD KO mice, cocaine self-administration and conditioned place-preference behavioral paradigms","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphatase inhibition combined with genetic KO behavioral epistasis and pharmacological rescue, single lab with multiple orthogonal approaches","pmids":["30348770"],"is_preprint":false},{"year":2024,"finding":"Loss of PTPRD (Ptprd+/- or Ptprd-/- mice) increases excitatory cortical neuron number and impairs both excitatory and inhibitory synaptic transmission in the medial prefrontal cortex; this results from hyper-activation of pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells; adult mice display autistic-like behaviors.","method":"Constitutive PTPRD knockout mouse model, immunohistochemistry, electrophysiology (synaptic transmission), behavioral assays","journal":"Biological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with cellular phenotype (neuron number) and electrophysiological readout plus pathway identification (TrkB, PDGFRβ), single lab","pmids":["38890753"],"is_preprint":false},{"year":2024,"finding":"Conditional knockout of PTPRD in telencephalon reduces glial precursors, astrocytes, and oligodendrocytes; this decrease in gliogenesis results from reduced radial glia at gliogenesis onset and lower gliogenic potential due to decreased JAK/STAT pathway activation and reduced expression of gliogenic genes.","method":"Conditional knockout mouse model (telencephalon-specific), immunohistochemistry, flow cytometry, gene expression analysis","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional in vivo KO with defined cellular phenotype and pathway placement (JAK/STAT), single lab","pmids":["38487272"],"is_preprint":false},{"year":2020,"finding":"PTPRD overexpression in 3T3-L1 pre-adipocytes inhibits adipogenesis; PTPRD is hypomethylated in first-degree relatives of T2D subjects and correspondingly upregulated in pre-adipocytes, linking PTPRD level to restricted adipogenesis.","method":"PTPRD overexpression in 3T3-L1 cells (adipogenesis assay), MeDIP-Seq, bisulfite sequencing","journal":"Epigenomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct overexpression with functional readout (adipogenesis) and epigenetic mechanistic link, single lab","pmids":["32483983"],"is_preprint":false},{"year":2020,"finding":"PTPRD overexpression in HepG2 hepatocellular carcinoma cells suppresses PD-L1 expression by downregulating STAT3 and phospho-STAT3; PTPRD knockdown promotes PD-L1 expression and increases STAT3/phospho-STAT3 levels.","method":"Transfection (overexpression and knockdown), western blotting for STAT3/p-STAT3/PD-L1, RT-PCR","journal":"Translational cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — bidirectional functional manipulation with molecular readout, but single lab and single publication","pmids":["35117921"],"is_preprint":false},{"year":2015,"finding":"Loss-of-function mutations in PTPRD in melanoma are associated with enhanced cell migration (gain-of-function phenotype); mutant PTPRD cells are significantly more migratory than WT-PTPRD or vector-only cells.","method":"Overexpression of WT vs. somatic mutant PTPRD alleles, migration assays","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional comparison of WT vs. multiple cancer mutants with quantitative migration readout, single lab","pmids":["25113440"],"is_preprint":false},{"year":2025,"finding":"NSUN2 methyltransferase stabilizes PTPRD mRNA via m5C methylation; in a traumatic brain injury model, NSUN2 promotes A1 (pro-inflammatory) astrocyte activation through PTPRD, and PTPRD overexpression reverses the inhibitory effects of NSUN2 knockdown on A1 phenotype activation.","method":"RNA immunoprecipitation, RNA stability assays, m5C methylation detection, NSUN2 knockdown and PTPRD overexpression mouse models, flow cytometry","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA immunoprecipitation and stability assays for m5C-mediated mechanism, in vivo validation with genetic rescue, single lab","pmids":["40544933"],"is_preprint":false},{"year":2015,"finding":"PTPRD is expressed in miR-516a-3p-targeted cells; luciferase reporter assay confirmed PTPRD 3'UTR as a direct target of miR-516a-3p; miR-516a-3p knockdown phenocopies PTPRD upregulation (reduced proliferation, invasion, migration; increased apoptosis) in lung adenocarcinoma.","method":"Dual luciferase reporter assay, RT-PCR, western blot, functional cell assays (migration, invasion, proliferation, apoptosis)","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase assay only for direct binding, no rescue experiment","pmids":["31933822"],"is_preprint":false},{"year":2015,"finding":"MiR-324-5p targets PTPRD directly (luciferase reporter assay); PTPRD negatively regulates CEBPD; loss of PTPRD (via miR-324-5p) promotes VEGF and IL-4/IL-13 secretion, HUVEC invasion/migration, and macrophage M2 polarization.","method":"Luciferase reporter assay, lentiviral overexpression/knockdown, gene manipulation, cytokine ELISA, co-culture invasion assay","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase assay for miR-PTPRD interaction, downstream pathway mechanistically established but indirect","pmids":["32151175"],"is_preprint":false},{"year":2022,"finding":"PTPRD was identified as a novel substrate candidate for the protease BACE1; Western blot validation in human brain tissue samples confirmed differential expression of PTPRD protein in Alzheimer's disease consistent with BACE1 cleavage.","method":"Computational analysis of BACE1-dependent proteins, Western blot validation","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3–4 / Weak — primarily computational with limited western blot validation, no direct cleavage assay performed","pmids":["35562959"],"is_preprint":false},{"year":2015,"finding":"PTPRD knockout mice display reduced behaviorally defined sleep at the end of their active periods; heterozygous knockouts display increased locomotion and shifted dose-response for cocaine reward (greater preference at 5 mg/kg, less at 10–20 mg/kg cocaine).","method":"Hetero- and homozygous PTPRD knockout mice, behavioral phenotyping (sleep, locomotion, cocaine conditioned place preference)","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined behavioral phenotypes across multiple paradigms, single lab","pmids":["26181631"],"is_preprint":false},{"year":2023,"finding":"Ptprd knockout mice display impaired nest-building (goal-directed behavior) and female-specific deficits in prepulse inhibition (sensorimotor gating); no effect on anxiety or open-field measures.","method":"Constitutive Ptprd KO mice, behavioral battery (nest building, prepulse inhibition, open field, dig test, splash test)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with specific behavioral readouts, sex-stratified analysis, single lab","pmids":["37205689"],"is_preprint":false}],"current_model":"PTPRD is a receptor-type protein tyrosine phosphatase whose cytoplasmic domain dephosphorylates STAT3 (and candidate substrates including GSK3α/β and desmoplakin), thereby suppressing oncogenic STAT3 signaling, inhibiting tumor cell growth and migration, and restraining SRC activity; dimerization of its phosphatase domain impairs catalytic activity; its juxta-membrane segment provides negative auto-regulation; in the brain, PTPRD acts as a neuronal cell-adhesion molecule/synaptic specifier that controls the balance of cortical neurogenesis and gliogenesis via TrkB, PDGFRβ, and JAK/STAT pathways, and influences synaptic function, sleep, and addiction-related reward circuits."},"narrative":{"mechanistic_narrative":"PTPRD is a receptor-type protein tyrosine phosphatase that functions as a haploinsufficient tumor suppressor by dephosphorylating the oncoprotein STAT3, restraining STAT3-driven transcriptional programs that promote tumor growth, angiogenesis, and immune evasion [PMID:19478061, PMID:24843164, PMID:35117921]. Its bacterially expressed cytoplasmic domain is an intrinsically active tyrosine phosphatase with a juxta-membrane segment that imposes negative autoregulation, and it shows substrate preference for Src Tyr-527, PDGF-R, and ERK1 phosphopeptides [PMID:8135747, PMID:1322915]. Beyond STAT3, substrate-trap and phosphoproteomic approaches have identified the desmosomal adhesion protein desmoplakin and the candidate brain substrates GSK3α/β as PTPRD targets [PMID:25113440, PMID:35636503]. Cancer-associated loss-of-function mutations reduce phosphatase activity toward these substrates, leading to phospho-STAT3 accumulation, while heterozygous Ptprd loss cooperates with Cdkn2a deletion to accelerate gliomagenesis in mice [PMID:24843164, PMID:25138050, PMID:25113440]. PTPRD also restrains cell migration and invasion across multiple tumor types — engaging β-catenin/TCF–CD44, ERK/STAT3–CXCL8, and PDGFRB/PLCγ1 signaling — and its catalytic activity is impaired by induced dimerization of the phosphatase domain, which also suppresses SRC signaling [PMID:22977525, PMID:31805999, PMID:35848503, PMID:37669874, PMID:25113440]. In the nervous system, PTPRD controls the balance of cortical neurogenesis and gliogenesis through TrkB, PDGFRβ, and JAK/STAT signaling and shapes synaptic transmission, with knockout mice showing autistic-like, sleep, sensorimotor, and cocaine-reward phenotypes that are pharmacologically tractable through phosphatase inhibitors and allosteric modulators [PMID:35636503, PMID:30348770, PMID:38890753, PMID:38487272, PMID:26181631].","teleology":[{"year":1992,"claim":"Established that PTPRD's cytoplasmic domain is an autonomous, regulatable tyrosine phosphatase, defining its catalytic boundaries and an intramolecular negative-regulatory element.","evidence":"Bacterial expression with truncation/deletion mutagenesis and PTPase assays","pmids":["1322915"],"confidence":"High","gaps":["Did not identify physiological substrates","Regulation in the context of the full-length receptor untested"]},{"year":1994,"claim":"Quantified the enzyme's kinetics and substrate preference, ranking Src Tyr-527 above PDGF-R and ERK1, providing the first candidate substrate hierarchy.","evidence":"Purified recombinant intracellular domain, Malachite Green phosphatase assay on synthetic phosphopeptides","pmids":["8135747"],"confidence":"High","gaps":["Synthetic peptides do not establish cellular substrates","No structural basis for substrate selectivity"]},{"year":1993,"claim":"Characterized PTPRD as a brain- and kidney-enriched multi-isoform adhesion-type receptor and mapped it to 9p24, laying the groundwork for its later tumor-suppressor and neural roles.","evidence":"cDNA cloning, Northern blot, in situ hybridization, FISH and somatic cell hybrid mapping","pmids":["8355697","8294211"],"confidence":"Medium","gaps":["Functional consequence of isoform diversity unresolved","Extracellular ligands not identified"]},{"year":2009,"claim":"Identified STAT3 as a direct PTPRD substrate and demonstrated that cancer-specific mutations abolish growth suppression, defining PTPRD as a STAT3-restraining tumor suppressor.","evidence":"STAT3 dephosphorylation phosphatase assay and growth inhibition with WT vs. mutant reconstitution in GBM cells","pmids":["19478061"],"confidence":"High","gaps":["Did not establish in vivo tumor suppression","Mechanism of STAT3 recognition unmapped"]},{"year":2014,"claim":"Provided in vivo genetic proof of haploinsufficient tumor suppression and linked phospho-STAT3 accumulation causally to gliomagenesis upon Ptprd loss combined with Cdkn2a deletion.","evidence":"Heterozygous Ptprd/Cdkn2a mouse glioma models with phospho-STAT3 immunoblotting and tumor incidence analysis","pmids":["24843164","25138050"],"confidence":"High","gaps":["Whether STAT3 is the sole effector of tumor suppression unclear","Tissue specificity of cooperation not dissected"]},{"year":2014,"claim":"Expanded the substrate repertoire by identifying desmoplakin via substrate-trapping, connecting PTPRD to desmosomal cell-cell adhesion, and showed cancer mutations impair this activity.","evidence":"Substrate-trap mutagenesis, mass spectrometry, co-IP, and phosphatase assays","pmids":["25113440"],"confidence":"High","gaps":["Physiological consequence of desmoplakin dephosphorylation not shown","Single lab"]},{"year":2015,"claim":"Generalized the STAT3-suppressor model to HNSCC and melanoma and showed loss-of-function mutations confer a pro-migratory gain-of-function phenotype, with mutant cells sensitized to STAT3 blockade.","evidence":"WT vs. somatic-mutant reconstitution, growth and migration assays, phospho-STAT3 immunoblotting","pmids":["26267899","25113440"],"confidence":"Medium","gaps":["Mechanism linking phosphatase loss to migration not fully resolved","Therapeutic exploitation untested in vivo"]},{"year":2011,"claim":"Connected PTPRD loss to migration and adhesion control through β-catenin/TCF–CD44 signaling in colon cancer.","evidence":"Knockdown/overexpression, migration and adhesion assays, β-catenin/TCF reporters","pmids":["22977525"],"confidence":"Medium","gaps":["Direct substrate in this axis not identified","Single lab"]},{"year":2019,"claim":"Defined how PTPRD loss drives angiogenesis and metastasis via ERK/STAT3-dependent CXCL8 induction, with pathway inhibitors reversing the phenotype.","evidence":"Stable knockdown, transcriptomics, ELISA, HUVEC tube formation, pharmacological inhibitors","pmids":["31805999"],"confidence":"Medium","gaps":["Relative contribution of ERK vs. STAT3 not quantified","In vivo metastasis mechanism partial"]},{"year":2020,"claim":"Extended STAT3 control to immune evasion, showing PTPRD suppresses PD-L1 via STAT3 downregulation in hepatocellular carcinoma.","evidence":"Bidirectional overexpression/knockdown with STAT3/p-STAT3/PD-L1 readouts","pmids":["35117921"],"confidence":"Medium","gaps":["No in vivo immune-context validation","Single publication"]},{"year":2022,"claim":"Identified PDGFRB/PLCγ1 as a PTPRD-restrained axis in vascular smooth muscle, with epigenetic silencing driving pathological remodeling.","evidence":"Knockdown, migration assays, DNMT1 inhibition, and heterozygous PTPRD KO rat hypoxia model","pmids":["35848503"],"confidence":"Medium","gaps":["Direct dephosphorylation of PDGFRB not demonstrated","Single lab"]},{"year":2023,"claim":"Revealed that ectodomain-induced dimerization inactivates the phosphatase and suppresses SRC-driven invasion, establishing a therapeutic strategy and a dimerization-based regulatory mechanism.","evidence":"Monoclonal antibody RD-43, chemically-induced dimerization, phosphatase and invasion assays, degradation pathway dissection","pmids":["37669874"],"confidence":"High","gaps":["Endogenous physiological dimerization trigger unknown","Generality across tumor types untested"]},{"year":2018,"claim":"Demonstrated that PTPRD phosphatase activity is pharmacologically targetable and mediates cocaine reward, with a small-molecule inhibitor acting through PTPRD genetically.","evidence":"In vitro inhibition assay with 7-BIA, heterozygous KO behavioral epistasis, pharmacological rescue","pmids":["30348770"],"confidence":"High","gaps":["Brain substrate(s) mediating reward not defined here","Inhibitor selectivity partial"]},{"year":2022,"claim":"Identified GSK3α/β as candidate brain substrates and discovered flavonols as substrate-selective positive allosteric modulators of PTPRD.","evidence":"Recombinant phosphatase assay, KO vs. WT brain phosphoproteomics, allosteric modulator screening","pmids":["35636503"],"confidence":"Medium","gaps":["Cellular validation of GSK3 dephosphorylation limited","Modulator mechanism not structurally resolved"]},{"year":2024,"claim":"Established PTPRD as a regulator of the neurogenesis–gliogenesis balance, restraining TrkB/PDGFRβ in precursors and promoting gliogenic JAK/STAT activation, with knockout causing autistic-like phenotypes.","evidence":"Constitutive and conditional KO mice, immunohistochemistry, flow cytometry, electrophysiology, gene expression, behavior","pmids":["38890753","38487272"],"confidence":"Medium","gaps":["Direct receptor substrates in precursors not confirmed","Link from cellular imbalance to behavior incomplete"]},{"year":2025,"claim":"Showed PTPRD is post-transcriptionally regulated by NSUN2-mediated m5C mRNA methylation, driving pro-inflammatory astrocyte activation after brain injury.","evidence":"RNA immunoprecipitation, RNA stability assays, m5C detection, NSUN2 knockdown with PTPRD-overexpression rescue in mice","pmids":["40544933"],"confidence":"Medium","gaps":["Downstream phosphatase substrates in astrocytes unidentified","Single lab"]},{"year":2015,"claim":"Linked PTPRD dosage to behavioral phenotypes including sleep, locomotion, and cocaine reward, supporting a neuromodulatory role.","evidence":"Hetero- and homozygous KO mice with sleep, locomotion, and conditioned place-preference phenotyping","pmids":["26181631"],"confidence":"Medium","gaps":["Circuit and substrate basis of behaviors unresolved","Dose-response complexity unexplained"]},{"year":null,"claim":"The extracellular ligand engagement and the structural/regulatory logic connecting adhesion, dimerization, and substrate selection to PTPRD's distinct tumor-suppressor versus neural-developmental functions remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model of receptor activation/inactivation","Cell-type-specific substrate repertoire incompletely mapped","Mechanism switching PTPRD between adhesion and phosphatase outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,4,5,14]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[6,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,9,12,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,20]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[16,17]}],"complexes":[],"partners":["STAT3","DSP","GSK3B","PDGFRB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23468","full_name":"Receptor-type tyrosine-protein phosphatase delta","aliases":[],"length_aa":1912,"mass_kda":214.8,"function":"Can bidirectionally induce pre- and post-synaptic differentiation of neurons by mediating interaction with IL1RAP and IL1RAPL1 trans-synaptically. 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mellitus.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27738328","citation_count":11,"is_preprint":false},{"pmid":"32633743","id":"PMC_32633743","title":"Binary nonmetal S and P-co-doping into mesoporous PtPd nanocages boosts oxygen reduction electrocatalysis.","date":"2020","source":"Nanoscale","url":"https://pubmed.ncbi.nlm.nih.gov/32633743","citation_count":11,"is_preprint":false},{"pmid":"38890753","id":"PMC_38890753","title":"Loss of protein tyrosine phosphatase receptor delta PTPRD increases the number of cortical neurons, impairs synaptic function and induces autistic-like behaviors in adult mice.","date":"2024","source":"Biological research","url":"https://pubmed.ncbi.nlm.nih.gov/38890753","citation_count":10,"is_preprint":false},{"pmid":"35636503","id":"PMC_35636503","title":"Substrate-selective positive allosteric modulation of PTPRD's phosphatase by flavonols.","date":"2022","source":"Biochemical 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pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31933822","citation_count":8,"is_preprint":false},{"pmid":"35117921","id":"PMC_35117921","title":"Protein tyrosine phosphatase receptor type delta (PTPRD) suppresses the expression of PD-L1 in human hepatocellular carcinoma by down-regulating STAT3.","date":"2020","source":"Translational cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/35117921","citation_count":7,"is_preprint":false},{"pmid":"38487272","id":"PMC_38487272","title":"Neural conditional ablation of the protein tyrosine phosphatase receptor Delta PTPRD impairs gliogenesis in the developing mouse brain cortex.","date":"2024","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38487272","citation_count":7,"is_preprint":false},{"pmid":"8761315","id":"PMC_8761315","title":"Dopamine receptor binding of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)- 4-oxobutyl]-1,2,3,6-tetrahydropyridine (HPTP), an intermediate metabolite of haloperidol.","date":"1996","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/8761315","citation_count":7,"is_preprint":false},{"pmid":"35151124","id":"PMC_35151124","title":"Effect of dietary calcium on the gender-specific association between polymorphisms in the PTPRD locus and osteoporosis.","date":"2022","source":"Clinical nutrition (Edinburgh, Scotland)","url":"https://pubmed.ncbi.nlm.nih.gov/35151124","citation_count":7,"is_preprint":false},{"pmid":"38631626","id":"PMC_38631626","title":"A fluorescence-electrochemical dual-mode aptasensor based on novel DNA-dependent PBNFs@PtPd for highly selective and sensitive detection of procymidone through hybridization chain reaction.","date":"2024","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/38631626","citation_count":7,"is_preprint":false},{"pmid":"24843648","id":"PMC_24843648","title":"Replication study for the association of rs391300 in SRR and rs17584499 in PTPRD with susceptibility to type 2 diabetes in a Japanese population.","date":"2012","source":"Journal of diabetes investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24843648","citation_count":7,"is_preprint":false},{"pmid":"22571343","id":"PMC_22571343","title":"Functional analysis of the putative tumor suppressor PTPRD in neuroblastoma cells.","date":"2012","source":"Cancer investigation","url":"https://pubmed.ncbi.nlm.nih.gov/22571343","citation_count":7,"is_preprint":false},{"pmid":"20359018","id":"PMC_20359018","title":"Performance of PtPd electrocatalysts in direct methanol fuel cell.","date":"2010","source":"Journal of nanoscience and nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20359018","citation_count":7,"is_preprint":false},{"pmid":"34299935","id":"PMC_34299935","title":"DIAPH2, PTPRD and HIC1 Gene Polymorphisms and Laryngeal Cancer Risk.","date":"2021","source":"International journal of environmental research and public health","url":"https://pubmed.ncbi.nlm.nih.gov/34299935","citation_count":5,"is_preprint":false},{"pmid":"10395944","id":"PMC_10395944","title":"Transcriptional regulation of a receptor protein tyrosine phosphatase gene hPTP-J by PKC-mediated signaling pathways in Jurkat and Molt-4 T lymphoma cells.","date":"1999","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/10395944","citation_count":5,"is_preprint":false},{"pmid":"37633178","id":"PMC_37633178","title":"Effectiveness of exercise and pramipexole in the treatment of restless leg syndrome: Implications on the dopaminergic system and PTPRD.","date":"2023","source":"Sleep medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37633178","citation_count":5,"is_preprint":false},{"pmid":"34863978","id":"PMC_34863978","title":"Structure-activity studies of PTPRD phosphatase inhibitors identify a 7-cyclopentymethoxy illudalic acid analog candidate for development.","date":"2021","source":"Biochemical 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Analyst","url":"https://pubmed.ncbi.nlm.nih.gov/33016273","citation_count":5,"is_preprint":false},{"pmid":"8294211","id":"PMC_8294211","title":"Chromosomal assignment of the gene for protein tyrosine phosphatase HPTP delta.","date":"1993","source":"Japanese journal of cancer research : Gann","url":"https://pubmed.ncbi.nlm.nih.gov/8294211","citation_count":4,"is_preprint":false},{"pmid":"9037540","id":"PMC_9037540","title":"Long-term treatment with the tetrahydropyridine analog (HPTP) of haloperidol influences dopamine ligand binding in baboon brain. An [123I]iodobenzamide (IBZM) SPECT study.","date":"1996","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/9037540","citation_count":4,"is_preprint":false},{"pmid":"33111449","id":"PMC_33111449","title":"PTPRD as a candidate druggable target for therapies for restless legs syndrome?","date":"2020","source":"Journal of sleep research","url":"https://pubmed.ncbi.nlm.nih.gov/33111449","citation_count":3,"is_preprint":false},{"pmid":"35755396","id":"PMC_35755396","title":"Hierarchical Porous Carbon-PtPd Catalysts and Their Activity toward Oxygen Reduction Reaction.","date":"2022","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/35755396","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49767,"output_tokens":6271,"usd":0.121683,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15216,"output_tokens":4833,"usd":0.098452,"stage2_stop_reason":"end_turn"},"total_usd":0.220135,"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\": 2009,\n      \"finding\": \"PTPRD directly dephosphorylates the oncoprotein STAT3; wild-type PTPRD inhibits growth of GBM tumor cells, an effect abolished by cancer-specific PTPRD mutations.\",\n      \"method\": \"Phosphatase assay (dephosphorylation of STAT3), cell growth inhibition assays with wild-type vs. mutant PTPRD reconstitution\",\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 — direct enzymatic assay demonstrating STAT3 dephosphorylation, replicated functionally with cancer-specific mutants, and independently corroborated by multiple subsequent studies\",\n      \"pmids\": [\"19478061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of PTPRD phosphatase activity leads to phospho-STAT3 accumulation and constitutive activation of STAT3-driven genetic programs in gliomas; heterozygous Ptprd loss cooperates with p16/CDKN2A deletion to drive gliomagenesis in mice, demonstrating a haploinsufficient tumor suppressor role.\",\n      \"method\": \"Mouse glioma model (heterozygous Ptprd KO combined with p16 deletion), immunoblotting for phospho-STAT3, genomic 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 — in vivo mouse genetic epistasis model with molecular readout (phospho-STAT3), replicated across multiple PTPRD/STAT3 papers\",\n      \"pmids\": [\"24843164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Co-deletion of Ptprd and Cdkn2a cooperates to accelerate tumorigenesis in mice; heterozygous loss of Ptprd was sufficient, indicating haploinsufficiency.\",\n      \"method\": \"Mouse genetic model (Ptprd/Cdkn2a double knockout), tumor incidence and spectrum analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic epistasis in vivo, single lab but orthogonal to the glioma model paper (PMID 24843164)\",\n      \"pmids\": [\"25138050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Using a substrate-trap approach and mass spectrometry followed by co-immunoprecipitation, desmoplakin (a desmosomal cell-cell adhesion protein) was identified as a novel PTPRD substrate; cancer-associated mutant PTPRD alleles showed reduced phosphatase activity against desmoplakin.\",\n      \"method\": \"Substrate-trap mutagenesis, mass spectrometry, co-immunoprecipitation, phosphatase activity assay\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — substrate-trap reconstitution, MS identification, and co-IP validation with functional mutagenesis, single lab\",\n      \"pmids\": [\"25113440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The intracellular domain of PTPRD (referred to as HPTP beta) exhibits intrinsic protein tyrosine phosphatase activity with defined kinetic parameters (kcat 76–258 s⁻¹); activity is inhibited by vanadate, molybdate, heparin, poly(Glu,Tyr), and zinc ions; substrate preference was srcTyr-527 > PDGF-R > ERK1 >> CSF-1R.\",\n      \"method\": \"Bacterial expression and purification of intracellular domain; Malachite Green phosphatase assay with synthetic phosphopeptide substrates\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified recombinant enzyme, kinetic analysis, multiple substrates, replicated in related papers\",\n      \"pmids\": [\"8135747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The intracellular (cytoplasmic) domain of HPTP beta (PTPRD) expressed in bacteria is enzymatically active as a protein tyrosine phosphatase; the juxta-membrane segment (residues 1622–1639) functions as a negative regulatory sequence—its deletion increases activity ~5-fold; residues 1684–1690 define the N-terminal border of the catalytic domain; loss of N-terminal sequence beyond residue 1690 abolishes activity.\",\n      \"method\": \"Bacterial expression, truncation/deletion mutagenesis, PTPase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with systematic mutagenesis and truncation analysis defining catalytic boundaries and regulatory elements\",\n      \"pmids\": [\"1322915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"PTPRD (MPTP delta / HPTP delta) is expressed as multiple splice isoforms differing in extracellular domain composition (1 vs. 3 Ig-like domains; 4 vs. 8 FN-III-like domains) and produces a ~210 kDa protein detected in brain and kidney; expression is enriched in hippocampus, thalamic reticular nucleus, and piriform cortex, and in pre-B cell lines.\",\n      \"method\": \"cDNA cloning, Northern blot, antibody immunoprecipitation, in situ hybridization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein detection and localization by antibody and in situ hybridization, single lab\",\n      \"pmids\": [\"8355697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The chromosomal locus for HPTP delta (PTPRD) maps to human chromosome 9p24, established by fluorescence in situ hybridization and human-mouse hybrid cell lines.\",\n      \"method\": \"Fluorescence in situ hybridization (FISH), somatic cell hybrid panel\",\n      \"journal\": \"Japanese journal of cancer research : Gann\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytogenetic mapping with two independent methods, single lab\",\n      \"pmids\": [\"8294211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTPRD suppresses colon cancer cell migration and is required for appropriate cell-cell adhesion; PTPRD regulates cell migration in cooperation with β-catenin/TCF signaling and its downstream target CD44.\",\n      \"method\": \"Cell migration assays, cell-cell adhesion assays, knockdown/overexpression, reporter assays for β-catenin/TCF\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with defined phenotypic readout and pathway placement via TCF signaling, single lab\",\n      \"pmids\": [\"22977525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss of PTPRD in gastric cancer cells upregulates CXCL8 expression through both ERK and STAT3 signaling, leading to increased angiogenesis and metastasis; specific ERK or STAT3 inhibitors abrogate PTPRD-loss-induced angiogenesis.\",\n      \"method\": \"Microarray analysis, stable PTPRD knockdown cell lines, ELISA, in vitro HUVEC tube formation assay, pharmacological inhibitors\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (transcriptomic + functional + pharmacological) in single lab\",\n      \"pmids\": [\"31805999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRD loss-of-function mutations (but not methylation or copy number loss) lead to increased STAT3 phosphorylation in HNSCC; overexpression of wild-type PTPRD inhibits growth and STAT3 activation, while PTPRD mutants do not; HNSCC cells with endogenous PTPRD mutations are more sensitive to STAT3 blockade.\",\n      \"method\": \"Transfection of wild-type vs. mutant PTPRD, MTT growth assays, immunoblotting for phospho-STAT3, methylation-specific PCR\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional comparison of WT vs. mutant alleles with molecular readout, single lab, multiple methods\",\n      \"pmids\": [\"26267899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRD knockdown using shRNA in HepG2 cells results in downregulation of the insulin receptor, and overexpression of the insulin receptor PPARγ2 induces overexpression of PTPRD; PTPRD silencing in T2D is caused by DNMT1-mediated promoter DNA methylation.\",\n      \"method\": \"shRNA knockdown, overexpression, RT-PCR, bisulfite sequencing, DNMT1 inhibition\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional experiments linking PTPRD to insulin receptor expression and methylation-mediated silencing, single lab\",\n      \"pmids\": [\"26079428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRD knockdown in pulmonary arterial smooth muscle cells (PASMCs) promotes cell migration through the PDGFRB/PLCγ1 signaling pathway; PTPRD is silenced in PASMCs by DNMT1-mediated promoter methylation upon PDGF-BB stimulation; heterozygous PTPRD KO rats show exacerbated pulmonary arterial remodeling under hypoxia with higher PLCγ1 activity.\",\n      \"method\": \"PTPRD knockdown, cell migration assays, western blotting, DNMT1 inhibition, PTPRD KO rat model under hypoxic conditions\",\n      \"journal\": \"Journal of hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro knockdown plus in vivo rat KO with pathway (PDGFRB/PLCγ1) identification, single lab\",\n      \"pmids\": [\"35848503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ectodomain antibody RD-43 binds to endogenous PTPRD in a metastatic breast cancer cell line and induces PTPRD dimerization, which inhibits phosphatase activity; the mAb-PTPRD dimer complex is degraded via lysosomal and proteasomal pathways independently of secretase cleavage; RD-43 treatment inhibits SRC signaling and suppresses PTPRD-dependent cell invasion.\",\n      \"method\": \"Monoclonal antibody generation, co-immunoprecipitation, chemically-induced dimerization, phosphatase activity assays, degradation pathway analysis (lysosomal/proteasomal inhibitors), cell invasion assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (dimerization, enzymatic assay, degradation pathway dissection, functional invasion assay) in one rigorous study\",\n      \"pmids\": [\"37669874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Quercetin and other flavonols (but not closely related flavones) act as substrate-selective positive allosteric modulators of PTPRD's phosphatase, enhancing dephosphorylation of candidate brain substrates including GSK3β and GSK3α; candidate brain phosphotyrosine protein (PTPP) substrates for PTPRD were identified based on increased phosphorylation in knockout vs. wildtype animals and brisk dephosphorylation by recombinant PTPRD.\",\n      \"method\": \"Recombinant PTPRD phosphatase assay, phosphoproteomic comparison of KO vs. WT brain, allosteric modulation screening\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with substrate identification via KO comparison, single lab\",\n      \"pmids\": [\"35636503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"7-Butoxy illudalic acid analog (7-BIA) was identified as a small molecule that targets PTPRD and inhibits its phosphatase activity with some selectivity; reduced expression of PTPRD (heterozygous KO) robustly reduces cocaine self-administration in mice; 7-BIA reduced cocaine-conditioned place preference and cocaine self-administration in WT but not PTPRD heterozygous KO mice.\",\n      \"method\": \"Phosphatase inhibition assay (in vitro), heterozygous PTPRD KO mice, cocaine self-administration and conditioned place-preference behavioral paradigms\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphatase inhibition combined with genetic KO behavioral epistasis and pharmacological rescue, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"30348770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of PTPRD (Ptprd+/- or Ptprd-/- mice) increases excitatory cortical neuron number and impairs both excitatory and inhibitory synaptic transmission in the medial prefrontal cortex; this results from hyper-activation of pro-neurogenic receptors TrkB and PDGFRβ in neural precursor cells; adult mice display autistic-like behaviors.\",\n      \"method\": \"Constitutive PTPRD knockout mouse model, immunohistochemistry, electrophysiology (synaptic transmission), behavioral assays\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with cellular phenotype (neuron number) and electrophysiological readout plus pathway identification (TrkB, PDGFRβ), single lab\",\n      \"pmids\": [\"38890753\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Conditional knockout of PTPRD in telencephalon reduces glial precursors, astrocytes, and oligodendrocytes; this decrease in gliogenesis results from reduced radial glia at gliogenesis onset and lower gliogenic potential due to decreased JAK/STAT pathway activation and reduced expression of gliogenic genes.\",\n      \"method\": \"Conditional knockout mouse model (telencephalon-specific), immunohistochemistry, flow cytometry, gene expression analysis\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional in vivo KO with defined cellular phenotype and pathway placement (JAK/STAT), single lab\",\n      \"pmids\": [\"38487272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRD overexpression in 3T3-L1 pre-adipocytes inhibits adipogenesis; PTPRD is hypomethylated in first-degree relatives of T2D subjects and correspondingly upregulated in pre-adipocytes, linking PTPRD level to restricted adipogenesis.\",\n      \"method\": \"PTPRD overexpression in 3T3-L1 cells (adipogenesis assay), MeDIP-Seq, bisulfite sequencing\",\n      \"journal\": \"Epigenomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct overexpression with functional readout (adipogenesis) and epigenetic mechanistic link, single lab\",\n      \"pmids\": [\"32483983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRD overexpression in HepG2 hepatocellular carcinoma cells suppresses PD-L1 expression by downregulating STAT3 and phospho-STAT3; PTPRD knockdown promotes PD-L1 expression and increases STAT3/phospho-STAT3 levels.\",\n      \"method\": \"Transfection (overexpression and knockdown), western blotting for STAT3/p-STAT3/PD-L1, RT-PCR\",\n      \"journal\": \"Translational cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — bidirectional functional manipulation with molecular readout, but single lab and single publication\",\n      \"pmids\": [\"35117921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss-of-function mutations in PTPRD in melanoma are associated with enhanced cell migration (gain-of-function phenotype); mutant PTPRD cells are significantly more migratory than WT-PTPRD or vector-only cells.\",\n      \"method\": \"Overexpression of WT vs. somatic mutant PTPRD alleles, migration assays\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional comparison of WT vs. multiple cancer mutants with quantitative migration readout, single lab\",\n      \"pmids\": [\"25113440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NSUN2 methyltransferase stabilizes PTPRD mRNA via m5C methylation; in a traumatic brain injury model, NSUN2 promotes A1 (pro-inflammatory) astrocyte activation through PTPRD, and PTPRD overexpression reverses the inhibitory effects of NSUN2 knockdown on A1 phenotype activation.\",\n      \"method\": \"RNA immunoprecipitation, RNA stability assays, m5C methylation detection, NSUN2 knockdown and PTPRD overexpression mouse models, flow cytometry\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA immunoprecipitation and stability assays for m5C-mediated mechanism, in vivo validation with genetic rescue, single lab\",\n      \"pmids\": [\"40544933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRD is expressed in miR-516a-3p-targeted cells; luciferase reporter assay confirmed PTPRD 3'UTR as a direct target of miR-516a-3p; miR-516a-3p knockdown phenocopies PTPRD upregulation (reduced proliferation, invasion, migration; increased apoptosis) in lung adenocarcinoma.\",\n      \"method\": \"Dual luciferase reporter assay, RT-PCR, western blot, functional cell assays (migration, invasion, proliferation, apoptosis)\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase assay only for direct binding, no rescue experiment\",\n      \"pmids\": [\"31933822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MiR-324-5p targets PTPRD directly (luciferase reporter assay); PTPRD negatively regulates CEBPD; loss of PTPRD (via miR-324-5p) promotes VEGF and IL-4/IL-13 secretion, HUVEC invasion/migration, and macrophage M2 polarization.\",\n      \"method\": \"Luciferase reporter assay, lentiviral overexpression/knockdown, gene manipulation, cytokine ELISA, co-culture invasion assay\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase assay for miR-PTPRD interaction, downstream pathway mechanistically established but indirect\",\n      \"pmids\": [\"32151175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRD was identified as a novel substrate candidate for the protease BACE1; Western blot validation in human brain tissue samples confirmed differential expression of PTPRD protein in Alzheimer's disease consistent with BACE1 cleavage.\",\n      \"method\": \"Computational analysis of BACE1-dependent proteins, Western blot validation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3–4 / Weak — primarily computational with limited western blot validation, no direct cleavage assay performed\",\n      \"pmids\": [\"35562959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRD knockout mice display reduced behaviorally defined sleep at the end of their active periods; heterozygous knockouts display increased locomotion and shifted dose-response for cocaine reward (greater preference at 5 mg/kg, less at 10–20 mg/kg cocaine).\",\n      \"method\": \"Hetero- and homozygous PTPRD knockout mice, behavioral phenotyping (sleep, locomotion, cocaine conditioned place preference)\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined behavioral phenotypes across multiple paradigms, single lab\",\n      \"pmids\": [\"26181631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ptprd knockout mice display impaired nest-building (goal-directed behavior) and female-specific deficits in prepulse inhibition (sensorimotor gating); no effect on anxiety or open-field measures.\",\n      \"method\": \"Constitutive Ptprd KO mice, behavioral battery (nest building, prepulse inhibition, open field, dig test, splash test)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with specific behavioral readouts, sex-stratified analysis, single lab\",\n      \"pmids\": [\"37205689\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRD is a receptor-type protein tyrosine phosphatase whose cytoplasmic domain dephosphorylates STAT3 (and candidate substrates including GSK3α/β and desmoplakin), thereby suppressing oncogenic STAT3 signaling, inhibiting tumor cell growth and migration, and restraining SRC activity; dimerization of its phosphatase domain impairs catalytic activity; its juxta-membrane segment provides negative auto-regulation; in the brain, PTPRD acts as a neuronal cell-adhesion molecule/synaptic specifier that controls the balance of cortical neurogenesis and gliogenesis via TrkB, PDGFRβ, and JAK/STAT pathways, and influences synaptic function, sleep, and addiction-related reward circuits.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRD is a receptor-type protein tyrosine phosphatase that functions as a haploinsufficient tumor suppressor by dephosphorylating the oncoprotein STAT3, restraining STAT3-driven transcriptional programs that promote tumor growth, angiogenesis, and immune evasion [#0, #1, #19]. Its bacterially expressed cytoplasmic domain is an intrinsically active tyrosine phosphatase with a juxta-membrane segment that imposes negative autoregulation, and it shows substrate preference for Src Tyr-527, PDGF-R, and ERK1 phosphopeptides [#4, #5]. Beyond STAT3, substrate-trap and phosphoproteomic approaches have identified the desmosomal adhesion protein desmoplakin and the candidate brain substrates GSK3α/β as PTPRD targets [#3, #14]. Cancer-associated loss-of-function mutations reduce phosphatase activity toward these substrates, leading to phospho-STAT3 accumulation, while heterozygous Ptprd loss cooperates with Cdkn2a deletion to accelerate gliomagenesis in mice [#1, #2, #3]. PTPRD also restrains cell migration and invasion across multiple tumor types — engaging β-catenin/TCF–CD44, ERK/STAT3–CXCL8, and PDGFRB/PLCγ1 signaling — and its catalytic activity is impaired by induced dimerization of the phosphatase domain, which also suppresses SRC signaling [#8, #9, #12, #13, #20]. In the nervous system, PTPRD controls the balance of cortical neurogenesis and gliogenesis through TrkB, PDGFRβ, and JAK/STAT signaling and shapes synaptic transmission, with knockout mice showing autistic-like, sleep, sensorimotor, and cocaine-reward phenotypes that are pharmacologically tractable through phosphatase inhibitors and allosteric modulators [#14, #15, #16, #17, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that PTPRD's cytoplasmic domain is an autonomous, regulatable tyrosine phosphatase, defining its catalytic boundaries and an intramolecular negative-regulatory element.\",\n      \"evidence\": \"Bacterial expression with truncation/deletion mutagenesis and PTPase assays\",\n      \"pmids\": [\"1322915\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify physiological substrates\", \"Regulation in the context of the full-length receptor untested\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Quantified the enzyme's kinetics and substrate preference, ranking Src Tyr-527 above PDGF-R and ERK1, providing the first candidate substrate hierarchy.\",\n      \"evidence\": \"Purified recombinant intracellular domain, Malachite Green phosphatase assay on synthetic phosphopeptides\",\n      \"pmids\": [\"8135747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Synthetic peptides do not establish cellular substrates\", \"No structural basis for substrate selectivity\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Characterized PTPRD as a brain- and kidney-enriched multi-isoform adhesion-type receptor and mapped it to 9p24, laying the groundwork for its later tumor-suppressor and neural roles.\",\n      \"evidence\": \"cDNA cloning, Northern blot, in situ hybridization, FISH and somatic cell hybrid mapping\",\n      \"pmids\": [\"8355697\", \"8294211\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of isoform diversity unresolved\", \"Extracellular ligands not identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified STAT3 as a direct PTPRD substrate and demonstrated that cancer-specific mutations abolish growth suppression, defining PTPRD as a STAT3-restraining tumor suppressor.\",\n      \"evidence\": \"STAT3 dephosphorylation phosphatase assay and growth inhibition with WT vs. mutant reconstitution in GBM cells\",\n      \"pmids\": [\"19478061\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish in vivo tumor suppression\", \"Mechanism of STAT3 recognition unmapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Provided in vivo genetic proof of haploinsufficient tumor suppression and linked phospho-STAT3 accumulation causally to gliomagenesis upon Ptprd loss combined with Cdkn2a deletion.\",\n      \"evidence\": \"Heterozygous Ptprd/Cdkn2a mouse glioma models with phospho-STAT3 immunoblotting and tumor incidence analysis\",\n      \"pmids\": [\"24843164\", \"25138050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STAT3 is the sole effector of tumor suppression unclear\", \"Tissue specificity of cooperation not dissected\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Expanded the substrate repertoire by identifying desmoplakin via substrate-trapping, connecting PTPRD to desmosomal cell-cell adhesion, and showed cancer mutations impair this activity.\",\n      \"evidence\": \"Substrate-trap mutagenesis, mass spectrometry, co-IP, and phosphatase assays\",\n      \"pmids\": [\"25113440\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of desmoplakin dephosphorylation not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Generalized the STAT3-suppressor model to HNSCC and melanoma and showed loss-of-function mutations confer a pro-migratory gain-of-function phenotype, with mutant cells sensitized to STAT3 blockade.\",\n      \"evidence\": \"WT vs. somatic-mutant reconstitution, growth and migration assays, phospho-STAT3 immunoblotting\",\n      \"pmids\": [\"26267899\", \"25113440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking phosphatase loss to migration not fully resolved\", \"Therapeutic exploitation untested in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected PTPRD loss to migration and adhesion control through β-catenin/TCF–CD44 signaling in colon cancer.\",\n      \"evidence\": \"Knockdown/overexpression, migration and adhesion assays, β-catenin/TCF reporters\",\n      \"pmids\": [\"22977525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate in this axis not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined how PTPRD loss drives angiogenesis and metastasis via ERK/STAT3-dependent CXCL8 induction, with pathway inhibitors reversing the phenotype.\",\n      \"evidence\": \"Stable knockdown, transcriptomics, ELISA, HUVEC tube formation, pharmacological inhibitors\",\n      \"pmids\": [\"31805999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ERK vs. STAT3 not quantified\", \"In vivo metastasis mechanism partial\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended STAT3 control to immune evasion, showing PTPRD suppresses PD-L1 via STAT3 downregulation in hepatocellular carcinoma.\",\n      \"evidence\": \"Bidirectional overexpression/knockdown with STAT3/p-STAT3/PD-L1 readouts\",\n      \"pmids\": [\"35117921\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo immune-context validation\", \"Single publication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified PDGFRB/PLCγ1 as a PTPRD-restrained axis in vascular smooth muscle, with epigenetic silencing driving pathological remodeling.\",\n      \"evidence\": \"Knockdown, migration assays, DNMT1 inhibition, and heterozygous PTPRD KO rat hypoxia model\",\n      \"pmids\": [\"35848503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of PDGFRB not demonstrated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed that ectodomain-induced dimerization inactivates the phosphatase and suppresses SRC-driven invasion, establishing a therapeutic strategy and a dimerization-based regulatory mechanism.\",\n      \"evidence\": \"Monoclonal antibody RD-43, chemically-induced dimerization, phosphatase and invasion assays, degradation pathway dissection\",\n      \"pmids\": [\"37669874\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous physiological dimerization trigger unknown\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that PTPRD phosphatase activity is pharmacologically targetable and mediates cocaine reward, with a small-molecule inhibitor acting through PTPRD genetically.\",\n      \"evidence\": \"In vitro inhibition assay with 7-BIA, heterozygous KO behavioral epistasis, pharmacological rescue\",\n      \"pmids\": [\"30348770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Brain substrate(s) mediating reward not defined here\", \"Inhibitor selectivity partial\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified GSK3α/β as candidate brain substrates and discovered flavonols as substrate-selective positive allosteric modulators of PTPRD.\",\n      \"evidence\": \"Recombinant phosphatase assay, KO vs. WT brain phosphoproteomics, allosteric modulator screening\",\n      \"pmids\": [\"35636503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular validation of GSK3 dephosphorylation limited\", \"Modulator mechanism not structurally resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established PTPRD as a regulator of the neurogenesis–gliogenesis balance, restraining TrkB/PDGFRβ in precursors and promoting gliogenic JAK/STAT activation, with knockout causing autistic-like phenotypes.\",\n      \"evidence\": \"Constitutive and conditional KO mice, immunohistochemistry, flow cytometry, electrophysiology, gene expression, behavior\",\n      \"pmids\": [\"38890753\", \"38487272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor substrates in precursors not confirmed\", \"Link from cellular imbalance to behavior incomplete\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PTPRD is post-transcriptionally regulated by NSUN2-mediated m5C mRNA methylation, driving pro-inflammatory astrocyte activation after brain injury.\",\n      \"evidence\": \"RNA immunoprecipitation, RNA stability assays, m5C detection, NSUN2 knockdown with PTPRD-overexpression rescue in mice\",\n      \"pmids\": [\"40544933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream phosphatase substrates in astrocytes unidentified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked PTPRD dosage to behavioral phenotypes including sleep, locomotion, and cocaine reward, supporting a neuromodulatory role.\",\n      \"evidence\": \"Hetero- and homozygous KO mice with sleep, locomotion, and conditioned place-preference phenotyping\",\n      \"pmids\": [\"26181631\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Circuit and substrate basis of behaviors unresolved\", \"Dose-response complexity unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The extracellular ligand engagement and the structural/regulatory logic connecting adhesion, dimerization, and substrate selection to PTPRD's distinct tumor-suppressor versus neural-developmental functions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying structural model of receptor activation/inactivation\", \"Cell-type-specific substrate repertoire incompletely mapped\", \"Mechanism switching PTPRD between adhesion and phosphatase outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 4, 5, 14]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [6, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 9, 12, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 20]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STAT3\", \"DSP\", \"GSK3B\", \"PDGFRB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}