{"gene":"PTPRJ","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1994,"finding":"DEP-1 (PTPRJ) was cloned as a receptor-like protein tyrosine phosphatase with an extracellular segment containing eight fibronectin type III repeats, a single transmembrane segment, and a single intracellular PTP domain; PTP activity was demonstrated in immunocomplexes, and expression was dramatically increased in dense cell cultures relative to sparse cultures, suggesting a role in contact inhibition of cell growth.","method":"cDNA cloning, immunoprecipitation PTP activity assay, immunoblot analysis of endogenous DEP-1 in WI-38 fibroblasts at varying cell densities","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct enzymatic activity demonstrated in immunocomplexes plus structural domain mapping by cloning; foundational paper replicated in subsequent work","pmids":["7937872"],"is_preprint":false},{"year":2000,"finding":"DEP-1 dephosphorylates the PDGF beta-receptor in a site-selective manner: preferred site is pY1021 and poorly preferred sites include pY857 and pY562; selectivity is determined by the primary amino acid sequence surrounding each phosphorylation site, with basic residues at positions -4 and +3 reducing dephosphorylation efficiency. DEP-1–PDGF beta-receptor complexes were detected in DEP-1-inducible cells.","method":"Inducible DEP-1 expression cell line, in vitro dephosphorylation of PDGF beta-receptor, phosphopeptide mapping, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphopeptide dephosphorylation plus mutagenesis-derived sequence rules, reciprocal co-IP, independently confirmed in later FEBS Letters study (PMID 12062403)","pmids":["10821867","12062403"],"is_preprint":false},{"year":2001,"finding":"An extracellular ligand present in Matrigel upregulates the specific catalytic activity of DEP-1; the effect requires the DEP-1 extracellular domain (ECD), as a truncated DEP-1 lacking most of the ECD fails to respond, and soluble ECD blocks the activity increase, providing the first evidence for upregulation of a receptor-like PTP specific activity by extracellular ligands.","method":"Matrigel stimulation of cells, immunoprecipitation PTP activity assay, ECD-deletion mutant and soluble ECD competition experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (cell-based, in vitro, deletion mutant) in a single lab","pmids":["11526512"],"is_preprint":false},{"year":2002,"finding":"DEP-1 uses substrate-trapping to interact with and dephosphorylate the HGF receptor Met and the adaptor Gab1; DEP-1 preferentially dephosphorylates Gab1-binding pY1349 and morphogenesis-related pY1365 on Met, while activation-loop tyrosines Y1230/1234/1235 are not preferred targets, indicating substrate specificity that modulates Met signaling quality rather than simply turning it off.","method":"Substrate-trapping mutant (maltose-binding protein fusion), co-immunoprecipitation in 293 cells expressing CSF-Met chimera, in vitro dephosphorylation with site mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — substrate trapping + co-IP + in vitro dephosphorylation with site-specific mapping, multiple cell lines","pmids":["12475979"],"is_preprint":false},{"year":2002,"finding":"DEP-1 substrate-trapping mutants interact specifically with p120 catenin (p120ctn), beta-catenin, and gamma-catenin; DEP-1 is concentrated at cell-cell contacts in A549 cells where it colocalizes with p120ctn, suggesting a role in adherens junction regulation.","method":"GST-fusion substrate-trapping pulldown with D/A mutant catalytic domain, co-localization by immunofluorescence","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate trapping pulldown plus colocalization, single lab","pmids":["12370829"],"is_preprint":false},{"year":2003,"finding":"DEP-1/CD148 is required for contact inhibition of VEGF-induced endothelial cell proliferation: a dominant-negative DEP-1 mutant and RNAi-mediated DEP-1 knockdown both partially restored VEGFR-2 phosphorylation and MAP kinase activation that were suppressed by VE-cadherin–beta-catenin complex at junctions, placing DEP-1 as a junctional phosphatase that inactivates VEGFR-2 upon VEGF stimulation in confluent cells.","method":"Dominant-negative mutant overexpression, RNA interference, co-immunoprecipitation of VEGFR-2 with VE-cadherin complex, comparison of isogenic VE-cadherin-null vs. expressing cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic approaches (DN mutant + RNAi) with mechanistic readouts in isogenic cell systems, independently reproduced in subsequent work","pmids":["12771128"],"is_preprint":false},{"year":2003,"finding":"Homozygous knock-in mice expressing a catalytically inactive CD148 allele (CD148ΔCyGFP) die at mid-gestation (before E11.5) with vascularization failure: enlarged primitive vessels, increased endothelial mitosis, defective vascular remodeling/branching, impaired pericyte investment, and defective endocardial cushion formation, demonstrating that CD148 phosphatase activity is required for developmental vascular organization and regulation of endothelial proliferation.","method":"Gene targeting (knock-in of GFP replacing cytoplasmic domain), embryo phenotyping, immunostaining for endothelial markers","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean phosphatase-dead knock-in with defined vascular phenotype in vivo","pmids":["12588999"],"is_preprint":false},{"year":2003,"finding":"CD148 is excluded from the immunological synapse via its extracellular domain, limiting its access to TCR-proximal substrates; targeting the CD148 phosphatase domain to the synapse potently inhibited NFAT activation induced by all TCR triggers, whereas physiological CD148 only inhibited responses to soluble anti-TCR but not to APC-presented antigens, establishing that ectodomain-mediated spatial exclusion regulates CD148 function in T cells.","method":"Tetracycline-inducible CD148 expression in Jurkat, immunofluorescence microscopy, targeted chimeric constructs, NFAT-luciferase reporter","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — chimeric domain-swap experiments + live cell imaging + reporter assay; multiple orthogonal approaches","pmids":["12913111"],"is_preprint":false},{"year":2001,"finding":"Overexpression of CD148 in Jurkat T cells inhibited TCR-mediated NFAT activation, Ras pathway, and calcium pathway in a phosphatase-activity-dependent manner; downstream analysis revealed that PLCgamma1 and LAT were strikingly hypophosphorylated upon TCR stimulation in CD148-expressing cells, while Slp-76 and Itk were modestly reduced, placing CD148-mediated dephosphorylation upstream of the Ras and calcium branches of TCR signaling.","method":"Tetracycline-inducible expression of WT and phosphatase-dead CD148 in Jurkat, NFAT reporter assay, phosphotyrosine immunoblotting, calcium mobilization assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible expression plus phosphatase-dead controls plus multiple pathway readouts","pmids":["11259588"],"is_preprint":false},{"year":2008,"finding":"CD148 loss-of-function mice showed hyperphosphorylation of the C-terminal inhibitory tyrosine of Src family kinases (SFKs) in B cells and macrophages, and CD148/CD45 double-deficient cells exhibited more severe defects than either single knockout, establishing that CD148 positively regulates SFKs (by dephosphorylating their inhibitory C-terminal tyrosine) in B cells and macrophages and is partially redundant with CD45.","method":"CD148 conditional knockout mice, CD148/CD45 double knockout mice, phospho-specific immunoblotting for SFK C-terminal inhibitory tyrosine, B and myeloid lineage functional assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis via double KO plus direct phosphotyrosine readout; independently replicated in Zhu et al. 2011 and other labs","pmids":["18249142"],"is_preprint":false},{"year":2008,"finding":"DEP-1 dephosphorylates tyrosines in the VEGFR2 kinase activation loop (reducing all major autophosphorylation sites upon DEP-1 depletion); surprisingly, DEP-1 depletion increased phosphorylation of Src inhibitory Y529, impairing Src and Akt activation. Mechanistically, DEP-1 dephosphorylates Src inhibitory Y529 (activating Src), which promotes Gab1 phosphorylation and PI3K–Akt signaling needed for endothelial cell survival.","method":"siRNA knockdown, catalytically inactive DEP-1 expression, phospho-specific immunoblotting, Src-Y529F rescue experiment, Gab1 co-immunoprecipitation with PI3K","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal loss-of-function approaches (siRNA + dominant-negative) plus mutagenesis rescue, multiple pathway readouts","pmids":["18936167"],"is_preprint":false},{"year":2009,"finding":"DEP-1 physically associates with EGFR at the cell surface and dephosphorylates it, stabilizing EGFR by preventing CBL-GRB2 ubiquitin ligase complex association and subsequent endosomal sorting/degradation; DEP-1 remains confined to the cell surface while activated EGFR undergoes endocytosis, demonstrating bidirectional enzyme–substrate interaction with spatial segregation.","method":"siRNA screen of all human tyrosine phosphatases (unbiased), co-immunoprecipitation, phosphorylation and ubiquitination assays, confocal imaging of EGFR trafficking","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased siRNA screen + reciprocal co-IP + mechanistic trafficking assay with imaging; multiple orthogonal methods","pmids":["19836242"],"is_preprint":false},{"year":2009,"finding":"DEP-1 directly dephosphorylates ERK1/2 at phosphotyrosine Y204 (activation loop); DEP-1 contains a KIM-like motif that recruits ERK1/2 via the ERK common docking domain, and ERK mutants in the docking domain are insensitive to DEP-1 dephosphorylation. DEP-1 modulates ERK phosphorylation downstream of MEK without affecting MEK activity.","method":"High-density peptide array substrate screen, pulldown assays, in vitro dephosphorylation, site-directed mutagenesis of ERK docking domain, EGF stimulation with DEP-1 concentration variation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation + mutagenesis + peptide arrays + in-cell dose–response, multiple orthogonal methods","pmids":["19494114"],"is_preprint":false},{"year":2009,"finding":"CD148 is essential for platelet activation and arterial thrombosis: CD148-deficient mice exhibit a bleeding tendency, and their platelets show markedly reduced basal SFK activity, resulting in global hyporesponsiveness to agonists signaling through SFKs (collagen, fibrinogen) as well as modestly reduced responses to thrombin, identifying CD148 as the only receptor-like PTP in platelets and a global positive regulator of SFK activity.","method":"CD148 knockout mice, tail-bleeding assay, in vivo arterial thrombosis model, SFK phosphorylation immunoblotting, platelet aggregation and secretion assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mice with in vivo thrombosis phenotype plus mechanistic SFK phosphorylation readout; independently replicated in multiple subsequent platelet studies","pmids":["19246339"],"is_preprint":false},{"year":2008,"finding":"CD148 interacts with and dephosphorylates p85, the regulatory subunit of PI3K, when p85 is tyrosine-phosphorylated (e.g., by active Src); co-expression of CD148 reduced p85 phosphorylation and attenuated PI3K activity upon serum stimulation, while CD148 knockdown increased PI3K activity, demonstrating CD148 as a direct negative regulator of PI3K via p85 dephosphorylation.","method":"Yeast two-hybrid with substrate-trapping mutant bait, co-immunoprecipitation in cells, in vitro dephosphorylation of p85, PI3K activity assay, siRNA knockdown","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro dephosphorylation + yeast two-hybrid + co-IP + siRNA rescue, multiple orthogonal methods in one study","pmids":["18348712"],"is_preprint":false},{"year":2011,"finding":"DEP-1 is a direct negative regulator of FLT3 signaling: substrate-trapping mutants (D1205A, C1239S) co-immunoprecipitated with FLT3, recombinant DEP-1 dephosphorylated activated FLT3 in vitro, and DEP-1 depletion caused site-selective hyperphosphorylation of FLT3 pY589, pY591, pY842. DEP-1 loss enhanced FLT3-dependent ERK activation and cell proliferation.","method":"Substrate-trapping co-IP, in vitro dephosphorylation, shRNA knockdown in 32D myeloid cells and THP-1, overexpression in 32D and HEK293","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — substrate trapping + in vitro dephosphorylation + site-specific phospho mapping + multiple cell line validation","pmids":["21262971"],"is_preprint":false},{"year":2012,"finding":"FLT3 ITD causes oxidative inactivation of DEP-1 through reactive oxygen species (ROS)-mediated oxidation of the DEP-1 catalytic cysteine; FLT3 ITD kinase inhibition or NADPH-oxidase inhibition reactivated DEP-1. RNAi-mediated DEP-1 depletion partially abrogated the inhibitory effects of ROS quenching on FLT3 ITD cell transformation, establishing a DEP-1-dependent mechanism of ROS-mediated oncogenesis.","method":"DEP-1 activity assay with oxidation controls, FLT3 inhibitor treatment, NADPH-oxidase inhibition, catalase/Prx-1 overexpression, RNAi knockdown, mouse model with Prx-1 overexpression","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple intervention methods (pharmacological + genetic) with enzymatic activity assay and in vivo rescue model","pmids":["22438257"],"is_preprint":false},{"year":2011,"finding":"Syndecan-2 extracellular domain (S2ED) is a novel ligand for CD148; the region proximal to the transmembrane domain of syndecan-2 is the site of interaction with CD148; CD148 acts as a key intermediary between syndecan-2 and downstream beta1-integrin-mediated adhesion and cytoskeletal organization, requiring Src kinase and PI3K C2beta isoform.","method":"Co-immunoprecipitation, domain mapping using truncation mutants, cell adhesion assays with CD148 blocking, Src inhibitor and PI3K inhibitor experiments","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional domain mapping and inhibitor experiments; single lab","pmids":["21813734"],"is_preprint":false},{"year":2012,"finding":"Thrombospondin-1 (TSP1) is an extracellular ligand for CD148: soluble TSP1 binds CD148 ectodomain with high affinity, increases CD148 catalytic activity, and mediates TSP1-dependent inhibition of cell growth through CD148; soluble CD148 ectodomain or CD148 gene silencing antagonizes TSP1-mediated growth inhibition.","method":"Biotin surface labeling and affinity purification of CD148-interacting proteins, mass spectrometry identification, binding affinity assays, CD148 transfection in CD148-negative cells, CD148 siRNA knockdown, growth inhibition assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — unbiased mass spectrometry discovery + functional validation (gain-of-function + siRNA) with enzymatic activity assay","pmids":["22308318"],"is_preprint":false},{"year":2012,"finding":"DEP-1 is phosphorylated on Y1311 and Y1320 in a Src- and Fyn-dependent manner; these phosphotyrosines bind the Src SH2 domain, allowing DEP-1 to dephosphorylate Src inhibitory Y529 and promote activation of Src substrates VE-cadherin and Cortactin. RNAi knockdown or DEP-1 Y1311F/Y1320F expression impairs VEGF-induced Src-dependent permeability, invasion, and capillary formation. At high DEP-1 expression (confluent cells), DEP-1 also dephosphorylates Src Y418, attenuating downstream signaling.","method":"Phospho-site mutagenesis (Y1311F, Y1320F), co-immunoprecipitation, in vitro phosphorylation/dephosphorylation assays, siRNA knockdown, permeability and invasion assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with co-IP, in vitro enzymatic assays, and functional cellular readouts; multiple orthogonal methods","pmids":["22898603"],"is_preprint":false},{"year":2013,"finding":"The large ectodomains of CD148 and CD45 mediate their passive, size-based exclusion from ligated TCR at the immunological synapse; truncating the ectodomain of CD148 enhanced its co-localization with ligated TCR and increased its inhibitory effect on TCR signaling, supporting a kinetic-segregation model.","method":"Expression of WT vs. truncated ectodomain CD148 and CD45 in T cells, NFAT reporter assay, confocal imaging at immunological synapse","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-swap experiments with functional reporter and imaging; single lab","pmids":["23580664"],"is_preprint":false},{"year":2011,"finding":"In neutrophils, CD148 positively and negatively regulates GPCR-mediated chemoattractant signaling (Ca2+, PI3K, pERK) and preferentially targets the Src family kinase Lyn (versus CD45, which targets Hck and Fgr), revealing distinct SFK substrate preferences between CD45 and CD148 in GPCR pathways.","method":"CD148 and CD45 single and double knockout mice, neutrophil chemotaxis and Ca2+ flux assays, phospho-SFK immunoblotting, S. aureus infection model","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — double KO epistasis plus multiple functional readouts with specific SFK phosphorylation analysis","pmids":["22078799"],"is_preprint":false},{"year":2013,"finding":"CD148 promotes airway hyperresponsiveness (AHR) through positive regulation of Src family kinases in airway smooth muscle (ASM): CD148-deficient mice are protected from AHR in two asthma models; CD148 deficiency in smooth muscle reduces the frequency of calcium oscillations and causes hyperphosphorylation of SFK inhibitory C-terminal tyrosine in ASM, identifying CD148 as a critical SFK activator in ASM contractility.","method":"Ptprj whole-body and smooth-muscle-specific conditional knockout mice, two allergen-challenge asthma models, methacholine challenge for AHR, SFK phospho-immunoblotting, ASM calcium imaging","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO plus in vivo functional readout plus mechanistic SFK phosphorylation analysis","pmids":["23543053"],"is_preprint":false},{"year":2014,"finding":"CK2 phosphorylates DEP-1 on T1318, a residue proximal to Y1320; T1318 phosphorylation promotes Y1320 phosphorylation and Src SH2-domain recruitment to DEP-1, thereby enabling DEP-1-catalyzed Src Y529 dephosphorylation and VEGF-induced endothelial cell permeability. A T1318A mutant reduces Y1320 phosphorylation, Src association, and permeability, while the phosphomimetic T1318E enhances them.","method":"Site-directed mutagenesis (T1318A, T1318E), phospho-specific immunoblotting, co-immunoprecipitation, in vitro CK2 kinase assay, CK2 siRNA knockdown, permeability assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + co-IP + siRNA, multiple orthogonal methods in one study","pmids":["24583284"],"is_preprint":false},{"year":2016,"finding":"DEP-1-deficient mice show abrogated VEGF-induced vascular leakage and impaired Src activation and VE-cadherin phosphorylation in vivo; angiogenesis in Matrigel plug and aortic ring assays is defective in the absence of DEP-1; tumor growth-associated angiogenesis and experimental lung metastasis are markedly reduced in DEP-1 KO mice, establishing DEP-1 as an essential in vivo driver of VEGF-dependent permeability, angiogenesis, and metastasis via Src activation.","method":"DEP-1 knockout mice, systemic VEGF injection with vascular leakage measurement (Miles assay), Matrigel plug and aortic ring angiogenesis assays, tumor implantation and metastasis models, phospho-Src and phospho-VE-cadherin immunoblotting","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple in vivo assays in KO mice with mechanistic phosphorylation readouts; independently supports in vitro mechanistic work from same group","pmids":["27364551"],"is_preprint":false},{"year":2016,"finding":"DEP-1-deficient mouse retinas show increased tip cell number and vessel branching, increased ERK1/2 phosphorylation, and decreased Dll4 expression and Notch activation; mechanistically, DEP-1 promotes VEGF-induced Dll4 expression through a Src/Akt/beta-catenin signaling pathway, and DEP-1 mutants unable to activate Src do not rescue Dll4 expression, placing DEP-1 upstream of the Dll4-Notch pathway in sprouting angiogenesis.","method":"DEP-1 KO mice (retinal vascular analysis), DEP-1 siRNA in HUVECs, overexpression of WT and Src-activation-defective DEP-1 mutants, Src/Akt/beta-catenin inhibitor experiments, phospho-histone H3 staining","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO in vivo phenotype plus mechanistic pathway dissection with mutants and inhibitors in vitro","pmids":["31598898"],"is_preprint":false},{"year":2017,"finding":"PTPRJ dephosphorylates JAK2 at Y813 and Y868 autophosphorylation sites, thereby negatively regulating leptin receptor–JAK2 signaling in hypothalamic neurons; Ptprj-deficient mice show enhanced leptin signaling and reduced weight gain, and diet-induced obesity upregulates PTPRJ expression in the hypothalamus causing leptin resistance.","method":"Ptprj knockout mice, overexpression in hypothalamic neurons, in vitro dephosphorylation assay with site-specific mutants, JAK2 phosphorylation immunoblotting, food intake and body weight measurements","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro dephosphorylation with site-mapping + KO mouse phenotype + overexpression-induced leptin resistance; multiple methods","pmids":["28912580"],"is_preprint":false},{"year":2015,"finding":"DEP-1 is required for insulin signaling: Ptprj knockout mice on high-fat diet show enhanced insulin sensitivity and improved glucose tolerance; DEP-1 deficiency increases phosphorylation of insulin signaling cascade components (liver, muscle, adipose tissue) after insulin challenge, and DEP-1 downregulation in skeletal muscle cells increases glucose uptake, identifying DEP-1 as a negative regulator of insulin signaling.","method":"Ptprj conventional knockout mice, high-fat diet, metabolic phenotyping (glucose/insulin tolerance tests), phospho-insulin signaling immunoblotting in tissues, glucose uptake assay in skeletal muscle cells with DEP-1 siRNA","journal":"Molecular metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse metabolic phenotype plus in vitro cellular confirmation; single lab, two orthogonal approaches","pmids":["25830095"],"is_preprint":false},{"year":2018,"finding":"PTPRJ is required for megakaryocyte maturation and platelet biogenesis: biallelic loss-of-function PTPRJ variants in patients cause inherited thrombocytopenia with small platelets and impaired platelet responses to GPVI agonists; the mechanism involves reduced activation of Src family kinases. CRISPR/Cas9 ablation of ptprja in zebrafish reduced CD41+ thrombocytes in vivo. Silencing PTPRJ in human megakaryocytic cell line reproduced defects in SDF1-driven migration and proplatelet formation.","method":"Exome sequencing of patients, CRISPR/Cas9 zebrafish model, patient megakaryocyte functional assays (migration, proplatelet formation), PTPRJ siRNA in megakaryocytic cell line, phospho-SFK immunoblotting, platelet aggregation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics + zebrafish in vivo model + patient cell functional assays + cell-line mechanistic validation; multiple orthogonal methods","pmids":["30591527"],"is_preprint":false},{"year":2018,"finding":"PTPRJ negatively modulates CD98hc protein levels in A549 lung cancer cells; PTPRJ overexpression reduces CD98hc protein abundance, and co-treatment with the proteasome inhibitor MG132 prevents the decrease, indicating that PTPRJ promotes CD98hc proteasomal degradation; PTPRJ–CD98hc interaction was validated by co-immunoprecipitation.","method":"Proteomic pulldown to identify PTPRJ-interacting proteins, co-immunoprecipitation, overexpression with and without proteasome inhibitor MG132, cell proliferation and apoptosis assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP interaction plus proteasome inhibitor experiment; indirect mechanistic link, single lab","pmids":["29805737"],"is_preprint":false},{"year":2018,"finding":"PTPRJ regulates retinal axon projections by dephosphorylating EphA/EphB receptors and c-Abl kinase: Ptprj KO mice show enhanced Eph receptor phosphorylation in retinas, increased ipsilateral retinal axon projections, and anteriorly shifted ectopic terminal zones in the superior colliculus; c-Abl was identified as a novel PTPRJ substrate, with elevated c-Abl phosphorylation in Ptprj KO retinas.","method":"Ptprj knockout mice and Ptpro/Ptprj double knockout mice, retinal axon tracing, phospho-Eph and phospho-c-Abl immunoblotting, substrate identification in cultured mammalian cells","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse in vivo axon phenotype plus substrate phosphorylation evidence; single lab","pmids":["30082414"],"is_preprint":false},{"year":2017,"finding":"In C. elegans, DEP-1 dephosphorylates Y792 in the membrane-proximal NPXY motif of the beta-integrin subunit PAT-3, promoting integrin activation via talin recruitment; non-phosphorylatable pat-3(Y792F) partially suppresses the hyperactive EGFR signaling caused by dep-1 loss; FRAP analysis shows that the integrin/talin complex restricts EGFR mobility on the basolateral membrane, revealing a mechanism by which DEP-1 attenuates EGFR signaling partly through integrin activation in addition to direct EGFR dephosphorylation.","method":"Substrate-trapping DEP-1 mutant with proteomics, genetic epistasis (dep-1 loss-of-function + pat-3 phospho-mutant), in vivo FRAP analysis of EGFR mobility","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — proteomics-based substrate identification + mutagenesis epistasis + FRAP structural-functional analysis, multiple orthogonal methods in C. elegans (ortholog)","pmids":["28135265"],"is_preprint":false},{"year":1997,"finding":"DEP-1 is constitutively associated with a 64-kDa serine/threonine kinase in multiple tumor cell lines; this kinase forms a stable complex with DEP-1 and phosphorylates DEP-1 and DEP-1-interacting proteins in vitro, suggesting regulation of DEP-1 by serine/threonine phosphorylation.","method":"Co-immunoprecipitation, in vitro kinase assay with GST-DEP-1-C/S fusion, immunoblotting for serine/threonine phosphorylation","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP plus in vitro kinase assay; identity of kinase not established, single lab","pmids":["9115287"],"is_preprint":false},{"year":2010,"finding":"CD148 maintains a pool of active Src family kinases in platelets by directly dephosphorylating the inhibitory C-terminal tyrosines of Fyn, Lyn, and Src in vitro; this is essential for GPVI-FcR gamma-chain expression and collagen-mediated platelet activation. CD148 also paradoxically dephosphorylates the SFK activation loop in vitro.","method":"CD148 KO mouse platelets, DT40/NFAT-luciferase reporter system, biochemical in vitro dephosphorylation assay with recombinant CD148, phospho-specific immunoblotting","journal":"Journal of thrombosis and haemostasis","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant CD148 on specific SFK substrates + cell-based confirmation in KO platelets","pmids":["20345711"],"is_preprint":false},{"year":2011,"finding":"CD148 dephosphorylates the C-terminal inhibitory tyrosine of Src family kinases (SFKs) involved in TCR signaling; although CD148 has both activating and inhibitory effects on TCR SFKs, in the absence of CD45, CD148 activating effects prevail and functionally complement CD45 deficiency in human T cell lines. This complementation is independent of the tyrosines in the CD148 C-terminal tail, arguing against the phosphotyrosine displacement model as the sole activation mechanism.","method":"CD148-deficient and CD45/CD148-deficient primary murine B cells, T cell lines; phospho-SFK immunoblotting; T cell functional assays; CD148 C-terminal tail tyrosine mutants in human T cell lines","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic systems plus mutant analysis; single lab","pmids":["21543337"],"is_preprint":false},{"year":2016,"finding":"CD148 positively regulates Lyn kinase selectively in B1 but not B2 B cells: CD148 loss-of-function causes defective B1 B cell antigen receptor signaling downstream of Lyn, impaired TI antibody responses, and altered B1 BCR repertoire selection, while B2 cell signaling is intact.","method":"CD148 conditional knockout mice, B1 vs. B2 B cell functional assays, BCR signaling phospho-immunoblotting, NP-ficoll and Pneumovax 23 immunization","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-type-specific phenotype and mechanistic phosphorylation analysis showing selective Lyn regulation","pmids":["27889108"],"is_preprint":false},{"year":2021,"finding":"CD148 deficiency in fibroblasts promotes pulmonary fibrosis: fibroblast-specific CD148 KO mice exhibit increased bleomycin-induced fibrosis; mechanistically, CD148-deficient fibroblasts show hyperactivated PI3K/Akt/mTOR signaling, reduced autophagy, and p62 accumulation, which activates NF-κB and drives profibrotic gene expression. A syndecan-2-derived CD148-activating peptide (SDC2-pep) reduces fibrosis in vivo.","method":"Conditional fibroblast-specific CD148 KO mice (bleomycin model), CD148 siRNA and overexpression in IPF fibroblasts, PI3K/Akt/mTOR phospho-immunoblotting, autophagy and p62 assays, NF-κB reporter, precision-cut lung slices from IPF patients","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with in vivo phenotype + mechanistic pathway dissection in patient-derived cells + therapeutic peptide validation; multiple orthogonal methods","pmids":["33784491"],"is_preprint":false},{"year":2016,"finding":"DEP-1 promotes microglial migration and phagocytosis in part by inhibiting the Src family kinase Fyn: DEP-1 depletion in BV2 cells enhances pFyn Y420 and Fyn kinase activity, and DEP-1 loss or Fyn knockout in mice produces opposite effects on microglial function (DEP-1 KO reduces migration; Fyn KO increases migration), consistent with DEP-1 activating migration by suppressing Fyn.","method":"DEP-1 shRNA knockdown in BV2 cells, Ptprj−/− and Fyn−/− mice, in vitro migration/phagocytosis assays, in vivo wounding assay, Fyn immunoprecipitation kinase assay","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus in vitro mechanistic validation; single lab, mechanistic link to Fyn is indirect (activity assay, not direct dephosphorylation demonstrated)","pmids":["27859601"],"is_preprint":false},{"year":2011,"finding":"Syndecan-4 inhibits T cell activation by recruiting CD148 through syntenin as a bridging molecule; binding of DC-HIL to SD-4 assembles the SD-4/syntenin/CD148 complex and upregulates CD148 PTP activity, which mediates the inhibitory function of SD-4 in T cells.","method":"Co-immunoprecipitation of SD-4/syntenin/CD148 complex, PTP activity assay after DC-HIL ligation, T cell activation assays with CD148 inhibition","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP complex assembly plus enzymatic activity assay with functional readout; single lab","pmids":["21469128"],"is_preprint":false},{"year":2008,"finding":"In zebrafish, Dep1 (ortholog of mammalian PTPRJ) acts upstream of PI3K in arterial/venous cell fate specification: Dep1a/Dep1b morpholino knockdown causes defective circulation and reduced arterial markers with expanded venous markers; the arterial specification defect is rescued by PI3K inhibition and by active Notch/Grl expression, placing Dep1 upstream of PI3K in a pathway leading to Notch/Grl-dependent arterial identity.","method":"Morpholino knockdown of Dep1a and Dep1b in zebrafish, arterial/venous marker analysis, PI3K inhibitor rescue, active Notch/Grl rescue","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis via genetic knockdown plus pharmacological and genetic rescue in zebrafish (ortholog); single lab","pmids":["18835554"],"is_preprint":false},{"year":2020,"finding":"PTPRJ (CD148) and Csk are co-essential regulators of platelet SFK activity: Csk/CD148 double-deficient mice show dramatic increases in SFK activity but paradoxically reduced thrombosis due to negative feedback (upregulation of Chk, ITIM receptor G6b-B, Shp1/Shp2); deletion of PTPRJ in Chk/Csk double KO mice partially rescues thrombocytopenia and reduces inhibitory phosphorylation of Src and Fyn, revealing PTPRJ as the primary activating counterpart to Csk in maintaining platelet SFK balance.","method":"Triple KO mice (Chk, Csk, Ptprj in MK lineage), analog-sensitive Csk mouse, phospho-SFK immunoblotting, platelet count and aggregation assays, G6b-B/Shp1/Shp2 interaction assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with triple KO + analog-sensitive kinase model + mechanistic phosphorylation readouts; multiple orthogonal approaches","pmids":["32016283"],"is_preprint":false}],"current_model":"PTPRJ/DEP-1/CD148 is a receptor-type protein tyrosine phosphatase with eight extracellular fibronectin III repeats that is activated by extracellular ligands (thrombospondin-1, syndecan-2) and functions as a context-dependent signaling regulator: it dephosphorylates and attenuates multiple receptor tyrosine kinases (VEGFR2, PDGF-beta-R, Met, EGFR, FLT3, Eph receptors, JAK2) in a site-selective manner determined by the primary sequence surrounding each phosphosite, while simultaneously serving as a positive regulator of Src family kinases (SFKs) in endothelial, hematopoietic, platelet, smooth-muscle, and microglial cells by dephosphorylating the inhibitory C-terminal tyrosine of SFKs—a function promoted by CK2-mediated phosphorylation of DEP-1 T1318/Y1320 that recruits Src SH2; it also directly dephosphorylates ERK1/2 Y204 via a KIM docking motif, p85 PI3K subunit, c-Abl, and beta-integrin NPXY tyrosine; catalytic activity is subject to oxidative inactivation by ROS; spatial exclusion from the immunological synapse via the large ectodomain regulates its inhibitory access to TCR substrates; and DEP-1 is essential for developmental vascularization, arterial/venous fate specification, platelet biogenesis, airway smooth muscle contractility, and hypothalamic leptin signaling."},"narrative":{"mechanistic_narrative":"PTPRJ (DEP-1/CD148) is a receptor-type protein tyrosine phosphatase, cloned with an extracellular segment of eight fibronectin type III repeats, a single transmembrane span, and one intracellular PTP domain, whose expression rises sharply with cell density, implicating it in contact inhibition of growth [PMID:7937872]. Its catalytic activity is upregulated by extracellular ligands engaging the ectodomain, including a Matrigel-derived factor, thrombospondin-1, and syndecan-2 [PMID:11526512, PMID:22308318, PMID:21813734]. PTPRJ acts as a site-selective negative regulator of multiple receptor and cytoplasmic tyrosine kinases, dephosphorylating preferred phosphosites on the PDGF beta-receptor, Met/Gab1, EGFR, VEGFR2, FLT3, JAK2, and EphA/EphB receptors, with selectivity dictated by the primary sequence flanking each phosphotyrosine rather than wholesale kinase shutdown [PMID:10821867, PMID:12062403, PMID:12475979, PMID:19836242, PMID:18936167, PMID:21262971, PMID:28912580, PMID:30082414]. It additionally dephosphorylates ERK1/2 Y204 through a KIM-like docking motif, the PI3K regulatory subunit p85, c-Abl, and a beta-integrin NPXY tyrosine [PMID:19494114, PMID:18348712, PMID:30082414, PMID:28135265]. In apparent opposition, PTPRJ is a positive regulator of Src family kinases across endothelial, platelet, B-cell, neutrophil, smooth-muscle, and microglial contexts by dephosphorylating their inhibitory C-terminal tyrosine; in endothelium this SFK-activating function depends on CK2-mediated phosphorylation of T1318/Y1320 that recruits the Src SH2 domain to PTPRJ [PMID:18249142, PMID:19246339, PMID:22898603, PMID:24583284, PMID:20345711]. Through this dual logic, PTPRJ is essential in vivo for developmental and tumor-associated vascularization, arterial/venous fate specification, VEGF-induced permeability, platelet biogenesis, airway smooth-muscle contractility, and hypothalamic leptin signaling [PMID:12588999, PMID:27364551, PMID:18835554, PMID:30591527, PMID:23543053, PMID:28912580]. Biallelic loss-of-function PTPRJ variants cause inherited thrombocytopenia with small platelets and impaired GPVI responses [PMID:30591527]. Its catalytic cysteine is subject to oxidative inactivation, exploited by FLT3-ITD-driven ROS for oncogenic transformation [PMID:22438257].","teleology":[{"year":1994,"claim":"Established PTPRJ as a receptor-like tyrosine phosphatase and linked it to cell density, raising the question of whether it enforces contact inhibition.","evidence":"cDNA cloning, immunocomplex PTP activity assay, and density-dependent expression analysis in WI-38 fibroblasts","pmids":["7937872"],"confidence":"High","gaps":["Did not identify substrates","Did not test whether catalytic activity is regulated by extracellular ligands"]},{"year":2000,"claim":"Defined the biochemical logic of PTPRJ substrate selection, showing it targets specific RTK phosphosites rather than indiscriminately dephosphorylating.","evidence":"In vitro dephosphorylation and phosphopeptide mapping of the PDGF beta-receptor with sequence-context mutagenesis and co-IP","pmids":["10821867","12062403"],"confidence":"High","gaps":["Functional consequence for PDGF signaling output not established in vivo","Did not address ligand regulation of the phosphatase"]},{"year":2001,"claim":"Showed PTPRJ catalytic activity is upregulated by an extracellular ectodomain ligand, the first evidence that a receptor-type PTP is ligand-activated.","evidence":"Matrigel stimulation with immunocomplex PTP assay, ECD-deletion mutant, and soluble ECD competition","pmids":["11526512"],"confidence":"Medium","gaps":["Identity of the Matrigel ligand not determined","Single-lab finding"]},{"year":2001,"claim":"Placed PTPRJ as a negative regulator upstream of the Ras and calcium branches of TCR signaling, identifying immunoreceptor substrates.","evidence":"Tetracycline-inducible WT and phosphatase-dead CD148 in Jurkat with NFAT reporter, phosphotyrosine blotting, and calcium assays","pmids":["11259588"],"confidence":"High","gaps":["Direct vs indirect dephosphorylation of LAT/PLCgamma1 not resolved","Overexpression system"]},{"year":2002,"claim":"Demonstrated substrate-trapping-based interactions with Met/Gab1 and with adherens-junction catenins, expanding PTPRJ targets to RTK scaffolds and cell-cell contacts.","evidence":"Substrate-trapping mutants, co-IP, in vitro dephosphorylation with site mapping (Met), and colocalization at junctions (catenins)","pmids":["12475979","12370829"],"confidence":"High","gaps":["Catenin dephosphorylation shown by trapping/colocalization, not direct catalysis","Physiological impact on junction stability untested"]},{"year":2003,"claim":"Established PTPRJ as a junctional VEGFR2 phosphatase mediating contact inhibition of endothelial proliferation, and showed its phosphatase activity is required for vascular development in vivo.","evidence":"DN mutant + RNAi with VEGFR2/VE-cadherin co-IP in isogenic cells; catalytically dead knock-in mice with embryonic vascular phenotyping","pmids":["12771128","12588999"],"confidence":"High","gaps":["Did not yet reconcile VEGFR2 inhibition with later SFK-activating role","Cell-type-specific contributions in vivo unresolved"]},{"year":2003,"claim":"Defined ectodomain-mediated spatial exclusion from the immunological synapse as the regulator of PTPRJ access to TCR substrates, a kinetic-segregation mechanism.","evidence":"Inducible CD148 in Jurkat, domain-targeted chimeras, immunofluorescence at the synapse, NFAT reporter","pmids":["12913111","23580664"],"confidence":"High","gaps":["Quantitative basis of size-based exclusion in primary T cells incomplete","2013 truncation study is single-lab"]},{"year":2008,"claim":"Resolved the central paradox by showing PTPRJ positively regulates SFKs via dephosphorylation of their inhibitory C-terminal tyrosine, partially redundant with CD45.","evidence":"CD148 and CD148/CD45 double-KO B cells and macrophages with phospho-specific SFK immunoblotting and lineage functional assays","pmids":["18249142"],"confidence":"High","gaps":["Direct vs indirect SFK dephosphorylation not biochemically isolated here","Molecular determinant of activating vs inhibiting outcome unknown"]},{"year":2008,"claim":"Showed PTPRJ negatively regulates VEGFR2 yet sustains endothelial survival by activating Src, and directly dephosphorylates the PI3K p85 subunit.","evidence":"siRNA + DN PTPRJ with phospho-blotting and Src-Y529F rescue; yeast two-hybrid, co-IP, and in vitro dephosphorylation of p85 with PI3K assays","pmids":["18936167","18348712"],"confidence":"High","gaps":["Context determinants switching VEGFR2 vs Src targeting not defined","p85 dephosphorylation site not mapped"]},{"year":2009,"claim":"Extended PTPRJ targets to EGFR (with trafficking-coupled spatial segregation) and to direct ERK1/2 Y204 dephosphorylation via a KIM-like docking motif, and demonstrated platelet SFK regulation in vivo.","evidence":"Unbiased PTP siRNA screen with EGFR co-IP/ubiquitination/imaging; peptide-array screen, in vitro dephosphorylation and ERK docking mutagenesis; CD148-KO platelet thrombosis model","pmids":["19836242","19494114","19246339"],"confidence":"High","gaps":["How surface confinement is maintained mechanistically unclear","ERK Y204 role in vivo not tested"]},{"year":2010,"claim":"Reconstituted direct PTPRJ dephosphorylation of Fyn/Lyn/Src inhibitory tyrosines in platelets, while noting paradoxical activation-loop dephosphorylation in vitro.","evidence":"Recombinant CD148 in vitro dephosphorylation, DT40 reporter, and KO platelet phospho-blotting","pmids":["20345711"],"confidence":"High","gaps":["Balance between activation-loop and inhibitory-tyrosine targeting in vivo unresolved","Site selectivity determinants not defined"]},{"year":2011,"claim":"Identified syndecan-2 as an ectodomain ligand and defined lineage- and SFK-specific PTPRJ functions (FLT3 negative regulation, Lyn in neutrophils, syndecan-4/syntenin recruitment in T cells).","evidence":"Co-IP/domain mapping (SDC2); substrate trapping and in vitro dephosphorylation (FLT3); CD45/CD148 double-KO neutrophils; SD-4/syntenin/CD148 complex co-IP with PTP activity assay","pmids":["21813734","21262971","22078799","21469128","21543337"],"confidence":"High","gaps":["Basis of SFK substrate preference (Lyn vs Hck/Fgr) unknown","Ligand-to-activity coupling mechanism unresolved"]},{"year":2012,"claim":"Identified thrombospondin-1 as a high-affinity activating ligand and defined the CK2/Src-driven phospho-switch (T1318/Y1320, Y1311) that couples PTPRJ to SFK-dependent endothelial signaling, plus a ROS-driven oxidative inactivation route exploited by FLT3-ITD.","evidence":"MS identification and functional validation of TSP1; phospho-site mutagenesis with co-IP and in vitro assays (Y1311/Y1320); oxidation activity assays with pharmacologic/genetic ROS manipulation and in vivo rescue","pmids":["22308318","22898603","16","22438257"],"confidence":"High","gaps":["How ligand binding mechanically alters catalysis remains undefined","T1318/Y1320 switch demonstrated mainly in endothelium"]},{"year":2014,"claim":"Showed CK2 phosphorylation of T1318 licenses Y1320 phosphorylation and Src SH2 recruitment, mechanistically connecting a serine/threonine kinase input to PTPRJ-mediated Src activation.","evidence":"T1318A/T1318E mutagenesis, in vitro CK2 assay, co-IP, CK2 siRNA, and endothelial permeability assays","pmids":["24583284"],"confidence":"High","gaps":["Whether the 64-kDa kinase reported in 1997 corresponds to CK2 not established","Generality beyond endothelium untested"]},{"year":2016,"claim":"Established PTPRJ as an in vivo driver of VEGF-dependent permeability, angiogenesis, tumor angiogenesis/metastasis via Src, and as an upstream regulator of Dll4-Notch sprouting, plus a B1-selective Lyn activator and a microglial Fyn suppressor.","evidence":"PTPRJ-KO Miles/Matrigel/aortic ring/tumor models with phospho-Src/VE-cadherin; KO retina with Src/Akt/beta-catenin pathway dissection; conditional KO B1/B2 assays; BV2 and KO microglia migration assays","pmids":["27364551","31598898","27889108","27859601"],"confidence":"High","gaps":["Direct microglial Fyn dephosphorylation not demonstrated (activity assay only)","Coordination of opposing endothelial outputs across vascular beds incomplete"]},{"year":2017,"claim":"Defined PTPRJ as a JAK2-Y813/Y868 phosphatase controlling hypothalamic leptin signaling and energy balance, and (via the worm ortholog) as a beta-integrin NPXY-tyrosine phosphatase coupling integrin/talin activation to EGFR membrane confinement.","evidence":"Ptprj-KO mice with site-specific JAK2 dephosphorylation and metabolic phenotyping; C. elegans substrate-trapping proteomics, pat-3(Y792F) epistasis, and EGFR FRAP","pmids":["28912580","28135265"],"confidence":"High","gaps":["Conservation of the integrin/EGFR mechanism in mammals untested","How leptin engages PTPRJ regulation upstream unknown"]},{"year":2018,"claim":"Demonstrated PTPRJ is required for human platelet biogenesis via SFK regulation through patient genetics and modeling, and added CD98hc proteasomal turnover and retinal Eph/c-Abl dephosphorylation to its functions.","evidence":"Patient exome sequencing, zebrafish CRISPR thrombocyte assay, megakaryocyte functional and phospho assays; co-IP and MG132 (CD98hc); KO retinal axon tracing and phospho-Eph/c-Abl blotting","pmids":["30591527","29805737","30082414"],"confidence":"High","gaps":["Mechanism linking PTPRJ to CD98hc degradation indirect, single-lab","c-Abl dephosphorylation by PTPRJ shown in vivo but not fully reconstituted"]},{"year":2020,"claim":"Positioned PTPRJ as the principal activating counterpart to Csk in platelet SFK homeostasis, with feedback buffering, and (2015/2021) as a negative regulator of insulin signaling and a fibroblast suppressor of PI3K/Akt/mTOR-driven pulmonary fibrosis.","evidence":"Chk/Csk/Ptprj triple-KO and analog-sensitive Csk platelet models with phospho-SFK readouts; Ptprj-KO metabolic phenotyping with muscle glucose uptake; fibroblast-specific CD148-KO bleomycin model with pathway dissection and SDC2 peptide rescue","pmids":["32016283","25830095","33784491"],"confidence":"High","gaps":["Direct substrate mediating insulin-pathway suppression not mapped","How a single phosphatase integrates so many opposing context-specific outputs unresolved"]},{"year":null,"claim":"The unifying molecular rule determining when PTPRJ dephosphorylates an inhibitory SFK tyrosine (activating) versus an RTK/activation-loop tyrosine (inhibitory) in a given cell type remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model couples ectodomain ligand binding to catalytic regulation","The activating-vs-inhibiting substrate switch lacks a defined molecular determinant","Identity of the 64-kDa associated Ser/Thr kinase remains unconfirmed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,10,11,12,14,15,26,30,31,33]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,3,12,15]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,13,19,23,33,40]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,11,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,10,11,15,19,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9,21,35]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[13,28,33,40]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,25,30,39]}],"complexes":[],"partners":["SRC","FYN","LYN","VEGFR2","EGFR","FLT3","JAK2","SDC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12913","full_name":"Receptor-type tyrosine-protein phosphatase eta","aliases":["Density-enhanced phosphatase 1","DEP-1","HPTP eta","Protein-tyrosine phosphatase receptor type J","R-PTP-J"],"length_aa":1337,"mass_kda":145.9,"function":"Tyrosine phosphatase which dephosphorylates or contributes to the dephosphorylation of CTNND1, FLT3, PDGFRB, MET, KDR, LYN, SRC, MAPK1, MAPK3, EGFR, TJP1, OCLN, PIK3R1 and PIK3R2 (PubMed:10821867, PubMed:12062403, PubMed:12370829, PubMed:12475979, PubMed:18348712, PubMed:19494114, PubMed:19922411, PubMed:21262971). Plays a role in cell adhesion, migration, proliferation and differentiation (PubMed:12370829, PubMed:14709717, PubMed:16682945, PubMed:19836242). Has a role in megakaryocytes and platelet formation (PubMed:30591527). Involved in vascular development (By similarity). Regulator of macrophage adhesion and spreading (By similarity). Positively affects cell-matrix adhesion (By similarity). Positive regulator of platelet activation and thrombosis. Negative regulator of cell proliferation (PubMed:16682945). Negative regulator of PDGF-stimulated cell migration; through dephosphorylation of PDGFR (PubMed:21091576). Positive regulator of endothelial cell survival, as well as of VEGF-induced SRC and AKT activation; through KDR dephosphorylation (PubMed:18936167). Negative regulator of EGFR signaling pathway; through EGFR dephosphorylation (PubMed:19836242). Enhances the barrier function of epithelial junctions during reassembly (PubMed:19332538). Negatively regulates T-cell receptor (TCR) signaling (PubMed:11259588, PubMed:9531590, PubMed:9780142). Upon T-cell TCR activation, it is up-regulated and excluded from the immunological synapses, while upon T-cell-antigen presenting cells (APC) disengagement, it is no longer excluded and can dephosphorylate PLCG1 and LAT to down-regulate prolongation of signaling (PubMed:11259588, PubMed:12913111) Activates angiogenesis and cell migration (PubMed:28052032). Downregulates the expression of the endothelial adhesion molecules ICAM1 and VCAM1 (PubMed:28052032)","subcellular_location":"Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/Q12913/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRJ","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRJ","total_profiled":1310},"omim":[{"mim_id":"620484","title":"THROMBOCYTOPENIA 10; THC10","url":"https://www.omim.org/entry/620484"},{"mim_id":"606264","title":"C-TYPE LECTIN DOMAIN FAMILY 7, MEMBER A; CLEC7A","url":"https://www.omim.org/entry/606264"},{"mim_id":"600926","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, EPSILON; PTPRE","url":"https://www.omim.org/entry/600926"},{"mim_id":"600925","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, J; PTPRJ","url":"https://www.omim.org/entry/600925"},{"mim_id":"313900","title":"THROMBOCYTOPENIA 1; THC1","url":"https://www.omim.org/entry/313900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRJ"},"hgnc":{"alias_symbol":["DEP1","HPTPeta","CD148"],"prev_symbol":[]},"alphafold":{"accession":"Q12913","domains":[{"cath_id":"2.60.40.10","chopping":"124-206","consensus_level":"high","plddt":78.3898,"start":124,"end":206},{"cath_id":"2.60.40.10","chopping":"209-274_326-366","consensus_level":"medium","plddt":81.0231,"start":209,"end":366},{"cath_id":"2.60.40.10","chopping":"370-453","consensus_level":"medium","plddt":84.7075,"start":370,"end":453},{"cath_id":"2.60.40.10","chopping":"459-538","consensus_level":"medium","plddt":87.7584,"start":459,"end":538},{"cath_id":"2.60.40.10","chopping":"546-624","consensus_level":"high","plddt":88.0419,"start":546,"end":624},{"cath_id":"2.60.40.10","chopping":"638-717","consensus_level":"high","plddt":87.962,"start":638,"end":717},{"cath_id":"2.60.40.10","chopping":"727-803","consensus_level":"high","plddt":85.797,"start":727,"end":803},{"cath_id":"2.60.40.10","chopping":"825-891_903-967","consensus_level":"high","plddt":86.7173,"start":825,"end":967},{"cath_id":"3.90.190.10","chopping":"1022-1307","consensus_level":"high","plddt":93.7514,"start":1022,"end":1307}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12913","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12913-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12913-F1-predicted_aligned_error_v6.png","plddt_mean":77.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRJ","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRJ"},"sequence":{"accession":"Q12913","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12913.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12913/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12913"}},"corpus_meta":[{"pmid":"19305410","id":"PMC_19305410","title":"Natural 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in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/27066031","citation_count":268,"is_preprint":false},{"pmid":"7937872","id":"PMC_7937872","title":"Expression of DEP-1, a receptor-like protein-tyrosine-phosphatase, is enhanced with increasing cell density.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7937872","citation_count":206,"is_preprint":false},{"pmid":"12089527","id":"PMC_12089527","title":"Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers.","date":"2002","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12089527","citation_count":200,"is_preprint":false},{"pmid":"12475979","id":"PMC_12475979","title":"Hepatocyte growth factor receptor tyrosine kinase met is a substrate of the receptor protein-tyrosine phosphatase DEP-1.","date":"2002","source":"The Journal of biological 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 \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"DEP-1 (PTPRJ) was cloned as a receptor-like protein tyrosine phosphatase with an extracellular segment containing eight fibronectin type III repeats, a single transmembrane segment, and a single intracellular PTP domain; PTP activity was demonstrated in immunocomplexes, and expression was dramatically increased in dense cell cultures relative to sparse cultures, suggesting a role in contact inhibition of cell growth.\",\n      \"method\": \"cDNA cloning, immunoprecipitation PTP activity assay, immunoblot analysis of endogenous DEP-1 in WI-38 fibroblasts at varying cell densities\",\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 enzymatic activity demonstrated in immunocomplexes plus structural domain mapping by cloning; foundational paper replicated in subsequent work\",\n      \"pmids\": [\"7937872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"DEP-1 dephosphorylates the PDGF beta-receptor in a site-selective manner: preferred site is pY1021 and poorly preferred sites include pY857 and pY562; selectivity is determined by the primary amino acid sequence surrounding each phosphorylation site, with basic residues at positions -4 and +3 reducing dephosphorylation efficiency. DEP-1–PDGF beta-receptor complexes were detected in DEP-1-inducible cells.\",\n      \"method\": \"Inducible DEP-1 expression cell line, in vitro dephosphorylation of PDGF beta-receptor, phosphopeptide mapping, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphopeptide dephosphorylation plus mutagenesis-derived sequence rules, reciprocal co-IP, independently confirmed in later FEBS Letters study (PMID 12062403)\",\n      \"pmids\": [\"10821867\", \"12062403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"An extracellular ligand present in Matrigel upregulates the specific catalytic activity of DEP-1; the effect requires the DEP-1 extracellular domain (ECD), as a truncated DEP-1 lacking most of the ECD fails to respond, and soluble ECD blocks the activity increase, providing the first evidence for upregulation of a receptor-like PTP specific activity by extracellular ligands.\",\n      \"method\": \"Matrigel stimulation of cells, immunoprecipitation PTP activity assay, ECD-deletion mutant and soluble ECD competition experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (cell-based, in vitro, deletion mutant) in a single lab\",\n      \"pmids\": [\"11526512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DEP-1 uses substrate-trapping to interact with and dephosphorylate the HGF receptor Met and the adaptor Gab1; DEP-1 preferentially dephosphorylates Gab1-binding pY1349 and morphogenesis-related pY1365 on Met, while activation-loop tyrosines Y1230/1234/1235 are not preferred targets, indicating substrate specificity that modulates Met signaling quality rather than simply turning it off.\",\n      \"method\": \"Substrate-trapping mutant (maltose-binding protein fusion), co-immunoprecipitation in 293 cells expressing CSF-Met chimera, in vitro dephosphorylation with site mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — substrate trapping + co-IP + in vitro dephosphorylation with site-specific mapping, multiple cell lines\",\n      \"pmids\": [\"12475979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"DEP-1 substrate-trapping mutants interact specifically with p120 catenin (p120ctn), beta-catenin, and gamma-catenin; DEP-1 is concentrated at cell-cell contacts in A549 cells where it colocalizes with p120ctn, suggesting a role in adherens junction regulation.\",\n      \"method\": \"GST-fusion substrate-trapping pulldown with D/A mutant catalytic domain, co-localization by immunofluorescence\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate trapping pulldown plus colocalization, single lab\",\n      \"pmids\": [\"12370829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"DEP-1/CD148 is required for contact inhibition of VEGF-induced endothelial cell proliferation: a dominant-negative DEP-1 mutant and RNAi-mediated DEP-1 knockdown both partially restored VEGFR-2 phosphorylation and MAP kinase activation that were suppressed by VE-cadherin–beta-catenin complex at junctions, placing DEP-1 as a junctional phosphatase that inactivates VEGFR-2 upon VEGF stimulation in confluent cells.\",\n      \"method\": \"Dominant-negative mutant overexpression, RNA interference, co-immunoprecipitation of VEGFR-2 with VE-cadherin complex, comparison of isogenic VE-cadherin-null vs. expressing cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic approaches (DN mutant + RNAi) with mechanistic readouts in isogenic cell systems, independently reproduced in subsequent work\",\n      \"pmids\": [\"12771128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Homozygous knock-in mice expressing a catalytically inactive CD148 allele (CD148ΔCyGFP) die at mid-gestation (before E11.5) with vascularization failure: enlarged primitive vessels, increased endothelial mitosis, defective vascular remodeling/branching, impaired pericyte investment, and defective endocardial cushion formation, demonstrating that CD148 phosphatase activity is required for developmental vascular organization and regulation of endothelial proliferation.\",\n      \"method\": \"Gene targeting (knock-in of GFP replacing cytoplasmic domain), embryo phenotyping, immunostaining for endothelial markers\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean phosphatase-dead knock-in with defined vascular phenotype in vivo\",\n      \"pmids\": [\"12588999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD148 is excluded from the immunological synapse via its extracellular domain, limiting its access to TCR-proximal substrates; targeting the CD148 phosphatase domain to the synapse potently inhibited NFAT activation induced by all TCR triggers, whereas physiological CD148 only inhibited responses to soluble anti-TCR but not to APC-presented antigens, establishing that ectodomain-mediated spatial exclusion regulates CD148 function in T cells.\",\n      \"method\": \"Tetracycline-inducible CD148 expression in Jurkat, immunofluorescence microscopy, targeted chimeric constructs, NFAT-luciferase reporter\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — chimeric domain-swap experiments + live cell imaging + reporter assay; multiple orthogonal approaches\",\n      \"pmids\": [\"12913111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Overexpression of CD148 in Jurkat T cells inhibited TCR-mediated NFAT activation, Ras pathway, and calcium pathway in a phosphatase-activity-dependent manner; downstream analysis revealed that PLCgamma1 and LAT were strikingly hypophosphorylated upon TCR stimulation in CD148-expressing cells, while Slp-76 and Itk were modestly reduced, placing CD148-mediated dephosphorylation upstream of the Ras and calcium branches of TCR signaling.\",\n      \"method\": \"Tetracycline-inducible expression of WT and phosphatase-dead CD148 in Jurkat, NFAT reporter assay, phosphotyrosine immunoblotting, calcium mobilization assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible expression plus phosphatase-dead controls plus multiple pathway readouts\",\n      \"pmids\": [\"11259588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD148 loss-of-function mice showed hyperphosphorylation of the C-terminal inhibitory tyrosine of Src family kinases (SFKs) in B cells and macrophages, and CD148/CD45 double-deficient cells exhibited more severe defects than either single knockout, establishing that CD148 positively regulates SFKs (by dephosphorylating their inhibitory C-terminal tyrosine) in B cells and macrophages and is partially redundant with CD45.\",\n      \"method\": \"CD148 conditional knockout mice, CD148/CD45 double knockout mice, phospho-specific immunoblotting for SFK C-terminal inhibitory tyrosine, B and myeloid lineage functional assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis via double KO plus direct phosphotyrosine readout; independently replicated in Zhu et al. 2011 and other labs\",\n      \"pmids\": [\"18249142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DEP-1 dephosphorylates tyrosines in the VEGFR2 kinase activation loop (reducing all major autophosphorylation sites upon DEP-1 depletion); surprisingly, DEP-1 depletion increased phosphorylation of Src inhibitory Y529, impairing Src and Akt activation. Mechanistically, DEP-1 dephosphorylates Src inhibitory Y529 (activating Src), which promotes Gab1 phosphorylation and PI3K–Akt signaling needed for endothelial cell survival.\",\n      \"method\": \"siRNA knockdown, catalytically inactive DEP-1 expression, phospho-specific immunoblotting, Src-Y529F rescue experiment, Gab1 co-immunoprecipitation with PI3K\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal loss-of-function approaches (siRNA + dominant-negative) plus mutagenesis rescue, multiple pathway readouts\",\n      \"pmids\": [\"18936167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DEP-1 physically associates with EGFR at the cell surface and dephosphorylates it, stabilizing EGFR by preventing CBL-GRB2 ubiquitin ligase complex association and subsequent endosomal sorting/degradation; DEP-1 remains confined to the cell surface while activated EGFR undergoes endocytosis, demonstrating bidirectional enzyme–substrate interaction with spatial segregation.\",\n      \"method\": \"siRNA screen of all human tyrosine phosphatases (unbiased), co-immunoprecipitation, phosphorylation and ubiquitination assays, confocal imaging of EGFR trafficking\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased siRNA screen + reciprocal co-IP + mechanistic trafficking assay with imaging; multiple orthogonal methods\",\n      \"pmids\": [\"19836242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DEP-1 directly dephosphorylates ERK1/2 at phosphotyrosine Y204 (activation loop); DEP-1 contains a KIM-like motif that recruits ERK1/2 via the ERK common docking domain, and ERK mutants in the docking domain are insensitive to DEP-1 dephosphorylation. DEP-1 modulates ERK phosphorylation downstream of MEK without affecting MEK activity.\",\n      \"method\": \"High-density peptide array substrate screen, pulldown assays, in vitro dephosphorylation, site-directed mutagenesis of ERK docking domain, EGF stimulation with DEP-1 concentration variation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation + mutagenesis + peptide arrays + in-cell dose–response, multiple orthogonal methods\",\n      \"pmids\": [\"19494114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CD148 is essential for platelet activation and arterial thrombosis: CD148-deficient mice exhibit a bleeding tendency, and their platelets show markedly reduced basal SFK activity, resulting in global hyporesponsiveness to agonists signaling through SFKs (collagen, fibrinogen) as well as modestly reduced responses to thrombin, identifying CD148 as the only receptor-like PTP in platelets and a global positive regulator of SFK activity.\",\n      \"method\": \"CD148 knockout mice, tail-bleeding assay, in vivo arterial thrombosis model, SFK phosphorylation immunoblotting, platelet aggregation and secretion assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mice with in vivo thrombosis phenotype plus mechanistic SFK phosphorylation readout; independently replicated in multiple subsequent platelet studies\",\n      \"pmids\": [\"19246339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD148 interacts with and dephosphorylates p85, the regulatory subunit of PI3K, when p85 is tyrosine-phosphorylated (e.g., by active Src); co-expression of CD148 reduced p85 phosphorylation and attenuated PI3K activity upon serum stimulation, while CD148 knockdown increased PI3K activity, demonstrating CD148 as a direct negative regulator of PI3K via p85 dephosphorylation.\",\n      \"method\": \"Yeast two-hybrid with substrate-trapping mutant bait, co-immunoprecipitation in cells, in vitro dephosphorylation of p85, PI3K activity assay, siRNA knockdown\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro dephosphorylation + yeast two-hybrid + co-IP + siRNA rescue, multiple orthogonal methods in one study\",\n      \"pmids\": [\"18348712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"DEP-1 is a direct negative regulator of FLT3 signaling: substrate-trapping mutants (D1205A, C1239S) co-immunoprecipitated with FLT3, recombinant DEP-1 dephosphorylated activated FLT3 in vitro, and DEP-1 depletion caused site-selective hyperphosphorylation of FLT3 pY589, pY591, pY842. DEP-1 loss enhanced FLT3-dependent ERK activation and cell proliferation.\",\n      \"method\": \"Substrate-trapping co-IP, in vitro dephosphorylation, shRNA knockdown in 32D myeloid cells and THP-1, overexpression in 32D and HEK293\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — substrate trapping + in vitro dephosphorylation + site-specific phospho mapping + multiple cell line validation\",\n      \"pmids\": [\"21262971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FLT3 ITD causes oxidative inactivation of DEP-1 through reactive oxygen species (ROS)-mediated oxidation of the DEP-1 catalytic cysteine; FLT3 ITD kinase inhibition or NADPH-oxidase inhibition reactivated DEP-1. RNAi-mediated DEP-1 depletion partially abrogated the inhibitory effects of ROS quenching on FLT3 ITD cell transformation, establishing a DEP-1-dependent mechanism of ROS-mediated oncogenesis.\",\n      \"method\": \"DEP-1 activity assay with oxidation controls, FLT3 inhibitor treatment, NADPH-oxidase inhibition, catalase/Prx-1 overexpression, RNAi knockdown, mouse model with Prx-1 overexpression\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple intervention methods (pharmacological + genetic) with enzymatic activity assay and in vivo rescue model\",\n      \"pmids\": [\"22438257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Syndecan-2 extracellular domain (S2ED) is a novel ligand for CD148; the region proximal to the transmembrane domain of syndecan-2 is the site of interaction with CD148; CD148 acts as a key intermediary between syndecan-2 and downstream beta1-integrin-mediated adhesion and cytoskeletal organization, requiring Src kinase and PI3K C2beta isoform.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping using truncation mutants, cell adhesion assays with CD148 blocking, Src inhibitor and PI3K inhibitor experiments\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional domain mapping and inhibitor experiments; single lab\",\n      \"pmids\": [\"21813734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Thrombospondin-1 (TSP1) is an extracellular ligand for CD148: soluble TSP1 binds CD148 ectodomain with high affinity, increases CD148 catalytic activity, and mediates TSP1-dependent inhibition of cell growth through CD148; soluble CD148 ectodomain or CD148 gene silencing antagonizes TSP1-mediated growth inhibition.\",\n      \"method\": \"Biotin surface labeling and affinity purification of CD148-interacting proteins, mass spectrometry identification, binding affinity assays, CD148 transfection in CD148-negative cells, CD148 siRNA knockdown, growth inhibition assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — unbiased mass spectrometry discovery + functional validation (gain-of-function + siRNA) with enzymatic activity assay\",\n      \"pmids\": [\"22308318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DEP-1 is phosphorylated on Y1311 and Y1320 in a Src- and Fyn-dependent manner; these phosphotyrosines bind the Src SH2 domain, allowing DEP-1 to dephosphorylate Src inhibitory Y529 and promote activation of Src substrates VE-cadherin and Cortactin. RNAi knockdown or DEP-1 Y1311F/Y1320F expression impairs VEGF-induced Src-dependent permeability, invasion, and capillary formation. At high DEP-1 expression (confluent cells), DEP-1 also dephosphorylates Src Y418, attenuating downstream signaling.\",\n      \"method\": \"Phospho-site mutagenesis (Y1311F, Y1320F), co-immunoprecipitation, in vitro phosphorylation/dephosphorylation assays, siRNA knockdown, permeability and invasion assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with co-IP, in vitro enzymatic assays, and functional cellular readouts; multiple orthogonal methods\",\n      \"pmids\": [\"22898603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The large ectodomains of CD148 and CD45 mediate their passive, size-based exclusion from ligated TCR at the immunological synapse; truncating the ectodomain of CD148 enhanced its co-localization with ligated TCR and increased its inhibitory effect on TCR signaling, supporting a kinetic-segregation model.\",\n      \"method\": \"Expression of WT vs. truncated ectodomain CD148 and CD45 in T cells, NFAT reporter assay, confocal imaging at immunological synapse\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-swap experiments with functional reporter and imaging; single lab\",\n      \"pmids\": [\"23580664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In neutrophils, CD148 positively and negatively regulates GPCR-mediated chemoattractant signaling (Ca2+, PI3K, pERK) and preferentially targets the Src family kinase Lyn (versus CD45, which targets Hck and Fgr), revealing distinct SFK substrate preferences between CD45 and CD148 in GPCR pathways.\",\n      \"method\": \"CD148 and CD45 single and double knockout mice, neutrophil chemotaxis and Ca2+ flux assays, phospho-SFK immunoblotting, S. aureus infection model\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — double KO epistasis plus multiple functional readouts with specific SFK phosphorylation analysis\",\n      \"pmids\": [\"22078799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CD148 promotes airway hyperresponsiveness (AHR) through positive regulation of Src family kinases in airway smooth muscle (ASM): CD148-deficient mice are protected from AHR in two asthma models; CD148 deficiency in smooth muscle reduces the frequency of calcium oscillations and causes hyperphosphorylation of SFK inhibitory C-terminal tyrosine in ASM, identifying CD148 as a critical SFK activator in ASM contractility.\",\n      \"method\": \"Ptprj whole-body and smooth-muscle-specific conditional knockout mice, two allergen-challenge asthma models, methacholine challenge for AHR, SFK phospho-immunoblotting, ASM calcium imaging\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO plus in vivo functional readout plus mechanistic SFK phosphorylation analysis\",\n      \"pmids\": [\"23543053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CK2 phosphorylates DEP-1 on T1318, a residue proximal to Y1320; T1318 phosphorylation promotes Y1320 phosphorylation and Src SH2-domain recruitment to DEP-1, thereby enabling DEP-1-catalyzed Src Y529 dephosphorylation and VEGF-induced endothelial cell permeability. A T1318A mutant reduces Y1320 phosphorylation, Src association, and permeability, while the phosphomimetic T1318E enhances them.\",\n      \"method\": \"Site-directed mutagenesis (T1318A, T1318E), phospho-specific immunoblotting, co-immunoprecipitation, in vitro CK2 kinase assay, CK2 siRNA knockdown, permeability assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay + mutagenesis + co-IP + siRNA, multiple orthogonal methods in one study\",\n      \"pmids\": [\"24583284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DEP-1-deficient mice show abrogated VEGF-induced vascular leakage and impaired Src activation and VE-cadherin phosphorylation in vivo; angiogenesis in Matrigel plug and aortic ring assays is defective in the absence of DEP-1; tumor growth-associated angiogenesis and experimental lung metastasis are markedly reduced in DEP-1 KO mice, establishing DEP-1 as an essential in vivo driver of VEGF-dependent permeability, angiogenesis, and metastasis via Src activation.\",\n      \"method\": \"DEP-1 knockout mice, systemic VEGF injection with vascular leakage measurement (Miles assay), Matrigel plug and aortic ring angiogenesis assays, tumor implantation and metastasis models, phospho-Src and phospho-VE-cadherin immunoblotting\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple in vivo assays in KO mice with mechanistic phosphorylation readouts; independently supports in vitro mechanistic work from same group\",\n      \"pmids\": [\"27364551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DEP-1-deficient mouse retinas show increased tip cell number and vessel branching, increased ERK1/2 phosphorylation, and decreased Dll4 expression and Notch activation; mechanistically, DEP-1 promotes VEGF-induced Dll4 expression through a Src/Akt/beta-catenin signaling pathway, and DEP-1 mutants unable to activate Src do not rescue Dll4 expression, placing DEP-1 upstream of the Dll4-Notch pathway in sprouting angiogenesis.\",\n      \"method\": \"DEP-1 KO mice (retinal vascular analysis), DEP-1 siRNA in HUVECs, overexpression of WT and Src-activation-defective DEP-1 mutants, Src/Akt/beta-catenin inhibitor experiments, phospho-histone H3 staining\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO in vivo phenotype plus mechanistic pathway dissection with mutants and inhibitors in vitro\",\n      \"pmids\": [\"31598898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPRJ dephosphorylates JAK2 at Y813 and Y868 autophosphorylation sites, thereby negatively regulating leptin receptor–JAK2 signaling in hypothalamic neurons; Ptprj-deficient mice show enhanced leptin signaling and reduced weight gain, and diet-induced obesity upregulates PTPRJ expression in the hypothalamus causing leptin resistance.\",\n      \"method\": \"Ptprj knockout mice, overexpression in hypothalamic neurons, in vitro dephosphorylation assay with site-specific mutants, JAK2 phosphorylation immunoblotting, food intake and body weight measurements\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro dephosphorylation with site-mapping + KO mouse phenotype + overexpression-induced leptin resistance; multiple methods\",\n      \"pmids\": [\"28912580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DEP-1 is required for insulin signaling: Ptprj knockout mice on high-fat diet show enhanced insulin sensitivity and improved glucose tolerance; DEP-1 deficiency increases phosphorylation of insulin signaling cascade components (liver, muscle, adipose tissue) after insulin challenge, and DEP-1 downregulation in skeletal muscle cells increases glucose uptake, identifying DEP-1 as a negative regulator of insulin signaling.\",\n      \"method\": \"Ptprj conventional knockout mice, high-fat diet, metabolic phenotyping (glucose/insulin tolerance tests), phospho-insulin signaling immunoblotting in tissues, glucose uptake assay in skeletal muscle cells with DEP-1 siRNA\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse metabolic phenotype plus in vitro cellular confirmation; single lab, two orthogonal approaches\",\n      \"pmids\": [\"25830095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRJ is required for megakaryocyte maturation and platelet biogenesis: biallelic loss-of-function PTPRJ variants in patients cause inherited thrombocytopenia with small platelets and impaired platelet responses to GPVI agonists; the mechanism involves reduced activation of Src family kinases. CRISPR/Cas9 ablation of ptprja in zebrafish reduced CD41+ thrombocytes in vivo. Silencing PTPRJ in human megakaryocytic cell line reproduced defects in SDF1-driven migration and proplatelet formation.\",\n      \"method\": \"Exome sequencing of patients, CRISPR/Cas9 zebrafish model, patient megakaryocyte functional assays (migration, proplatelet formation), PTPRJ siRNA in megakaryocytic cell line, phospho-SFK immunoblotting, platelet aggregation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics + zebrafish in vivo model + patient cell functional assays + cell-line mechanistic validation; multiple orthogonal methods\",\n      \"pmids\": [\"30591527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRJ negatively modulates CD98hc protein levels in A549 lung cancer cells; PTPRJ overexpression reduces CD98hc protein abundance, and co-treatment with the proteasome inhibitor MG132 prevents the decrease, indicating that PTPRJ promotes CD98hc proteasomal degradation; PTPRJ–CD98hc interaction was validated by co-immunoprecipitation.\",\n      \"method\": \"Proteomic pulldown to identify PTPRJ-interacting proteins, co-immunoprecipitation, overexpression with and without proteasome inhibitor MG132, cell proliferation and apoptosis assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP interaction plus proteasome inhibitor experiment; indirect mechanistic link, single lab\",\n      \"pmids\": [\"29805737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRJ regulates retinal axon projections by dephosphorylating EphA/EphB receptors and c-Abl kinase: Ptprj KO mice show enhanced Eph receptor phosphorylation in retinas, increased ipsilateral retinal axon projections, and anteriorly shifted ectopic terminal zones in the superior colliculus; c-Abl was identified as a novel PTPRJ substrate, with elevated c-Abl phosphorylation in Ptprj KO retinas.\",\n      \"method\": \"Ptprj knockout mice and Ptpro/Ptprj double knockout mice, retinal axon tracing, phospho-Eph and phospho-c-Abl immunoblotting, substrate identification in cultured mammalian cells\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse in vivo axon phenotype plus substrate phosphorylation evidence; single lab\",\n      \"pmids\": [\"30082414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In C. elegans, DEP-1 dephosphorylates Y792 in the membrane-proximal NPXY motif of the beta-integrin subunit PAT-3, promoting integrin activation via talin recruitment; non-phosphorylatable pat-3(Y792F) partially suppresses the hyperactive EGFR signaling caused by dep-1 loss; FRAP analysis shows that the integrin/talin complex restricts EGFR mobility on the basolateral membrane, revealing a mechanism by which DEP-1 attenuates EGFR signaling partly through integrin activation in addition to direct EGFR dephosphorylation.\",\n      \"method\": \"Substrate-trapping DEP-1 mutant with proteomics, genetic epistasis (dep-1 loss-of-function + pat-3 phospho-mutant), in vivo FRAP analysis of EGFR mobility\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — proteomics-based substrate identification + mutagenesis epistasis + FRAP structural-functional analysis, multiple orthogonal methods in C. elegans (ortholog)\",\n      \"pmids\": [\"28135265\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"DEP-1 is constitutively associated with a 64-kDa serine/threonine kinase in multiple tumor cell lines; this kinase forms a stable complex with DEP-1 and phosphorylates DEP-1 and DEP-1-interacting proteins in vitro, suggesting regulation of DEP-1 by serine/threonine phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay with GST-DEP-1-C/S fusion, immunoblotting for serine/threonine phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP plus in vitro kinase assay; identity of kinase not established, single lab\",\n      \"pmids\": [\"9115287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD148 maintains a pool of active Src family kinases in platelets by directly dephosphorylating the inhibitory C-terminal tyrosines of Fyn, Lyn, and Src in vitro; this is essential for GPVI-FcR gamma-chain expression and collagen-mediated platelet activation. CD148 also paradoxically dephosphorylates the SFK activation loop in vitro.\",\n      \"method\": \"CD148 KO mouse platelets, DT40/NFAT-luciferase reporter system, biochemical in vitro dephosphorylation assay with recombinant CD148, phospho-specific immunoblotting\",\n      \"journal\": \"Journal of thrombosis and haemostasis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant CD148 on specific SFK substrates + cell-based confirmation in KO platelets\",\n      \"pmids\": [\"20345711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD148 dephosphorylates the C-terminal inhibitory tyrosine of Src family kinases (SFKs) involved in TCR signaling; although CD148 has both activating and inhibitory effects on TCR SFKs, in the absence of CD45, CD148 activating effects prevail and functionally complement CD45 deficiency in human T cell lines. This complementation is independent of the tyrosines in the CD148 C-terminal tail, arguing against the phosphotyrosine displacement model as the sole activation mechanism.\",\n      \"method\": \"CD148-deficient and CD45/CD148-deficient primary murine B cells, T cell lines; phospho-SFK immunoblotting; T cell functional assays; CD148 C-terminal tail tyrosine mutants in human T cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic systems plus mutant analysis; single lab\",\n      \"pmids\": [\"21543337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD148 positively regulates Lyn kinase selectively in B1 but not B2 B cells: CD148 loss-of-function causes defective B1 B cell antigen receptor signaling downstream of Lyn, impaired TI antibody responses, and altered B1 BCR repertoire selection, while B2 cell signaling is intact.\",\n      \"method\": \"CD148 conditional knockout mice, B1 vs. B2 B cell functional assays, BCR signaling phospho-immunoblotting, NP-ficoll and Pneumovax 23 immunization\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-type-specific phenotype and mechanistic phosphorylation analysis showing selective Lyn regulation\",\n      \"pmids\": [\"27889108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD148 deficiency in fibroblasts promotes pulmonary fibrosis: fibroblast-specific CD148 KO mice exhibit increased bleomycin-induced fibrosis; mechanistically, CD148-deficient fibroblasts show hyperactivated PI3K/Akt/mTOR signaling, reduced autophagy, and p62 accumulation, which activates NF-κB and drives profibrotic gene expression. A syndecan-2-derived CD148-activating peptide (SDC2-pep) reduces fibrosis in vivo.\",\n      \"method\": \"Conditional fibroblast-specific CD148 KO mice (bleomycin model), CD148 siRNA and overexpression in IPF fibroblasts, PI3K/Akt/mTOR phospho-immunoblotting, autophagy and p62 assays, NF-κB reporter, precision-cut lung slices from IPF patients\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with in vivo phenotype + mechanistic pathway dissection in patient-derived cells + therapeutic peptide validation; multiple orthogonal methods\",\n      \"pmids\": [\"33784491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DEP-1 promotes microglial migration and phagocytosis in part by inhibiting the Src family kinase Fyn: DEP-1 depletion in BV2 cells enhances pFyn Y420 and Fyn kinase activity, and DEP-1 loss or Fyn knockout in mice produces opposite effects on microglial function (DEP-1 KO reduces migration; Fyn KO increases migration), consistent with DEP-1 activating migration by suppressing Fyn.\",\n      \"method\": \"DEP-1 shRNA knockdown in BV2 cells, Ptprj−/− and Fyn−/− mice, in vitro migration/phagocytosis assays, in vivo wounding assay, Fyn immunoprecipitation kinase assay\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus in vitro mechanistic validation; single lab, mechanistic link to Fyn is indirect (activity assay, not direct dephosphorylation demonstrated)\",\n      \"pmids\": [\"27859601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Syndecan-4 inhibits T cell activation by recruiting CD148 through syntenin as a bridging molecule; binding of DC-HIL to SD-4 assembles the SD-4/syntenin/CD148 complex and upregulates CD148 PTP activity, which mediates the inhibitory function of SD-4 in T cells.\",\n      \"method\": \"Co-immunoprecipitation of SD-4/syntenin/CD148 complex, PTP activity assay after DC-HIL ligation, T cell activation assays with CD148 inhibition\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP complex assembly plus enzymatic activity assay with functional readout; single lab\",\n      \"pmids\": [\"21469128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In zebrafish, Dep1 (ortholog of mammalian PTPRJ) acts upstream of PI3K in arterial/venous cell fate specification: Dep1a/Dep1b morpholino knockdown causes defective circulation and reduced arterial markers with expanded venous markers; the arterial specification defect is rescued by PI3K inhibition and by active Notch/Grl expression, placing Dep1 upstream of PI3K in a pathway leading to Notch/Grl-dependent arterial identity.\",\n      \"method\": \"Morpholino knockdown of Dep1a and Dep1b in zebrafish, arterial/venous marker analysis, PI3K inhibitor rescue, active Notch/Grl rescue\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis via genetic knockdown plus pharmacological and genetic rescue in zebrafish (ortholog); single lab\",\n      \"pmids\": [\"18835554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRJ (CD148) and Csk are co-essential regulators of platelet SFK activity: Csk/CD148 double-deficient mice show dramatic increases in SFK activity but paradoxically reduced thrombosis due to negative feedback (upregulation of Chk, ITIM receptor G6b-B, Shp1/Shp2); deletion of PTPRJ in Chk/Csk double KO mice partially rescues thrombocytopenia and reduces inhibitory phosphorylation of Src and Fyn, revealing PTPRJ as the primary activating counterpart to Csk in maintaining platelet SFK balance.\",\n      \"method\": \"Triple KO mice (Chk, Csk, Ptprj in MK lineage), analog-sensitive Csk mouse, phospho-SFK immunoblotting, platelet count and aggregation assays, G6b-B/Shp1/Shp2 interaction assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with triple KO + analog-sensitive kinase model + mechanistic phosphorylation readouts; multiple orthogonal approaches\",\n      \"pmids\": [\"32016283\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRJ/DEP-1/CD148 is a receptor-type protein tyrosine phosphatase with eight extracellular fibronectin III repeats that is activated by extracellular ligands (thrombospondin-1, syndecan-2) and functions as a context-dependent signaling regulator: it dephosphorylates and attenuates multiple receptor tyrosine kinases (VEGFR2, PDGF-beta-R, Met, EGFR, FLT3, Eph receptors, JAK2) in a site-selective manner determined by the primary sequence surrounding each phosphosite, while simultaneously serving as a positive regulator of Src family kinases (SFKs) in endothelial, hematopoietic, platelet, smooth-muscle, and microglial cells by dephosphorylating the inhibitory C-terminal tyrosine of SFKs—a function promoted by CK2-mediated phosphorylation of DEP-1 T1318/Y1320 that recruits Src SH2; it also directly dephosphorylates ERK1/2 Y204 via a KIM docking motif, p85 PI3K subunit, c-Abl, and beta-integrin NPXY tyrosine; catalytic activity is subject to oxidative inactivation by ROS; spatial exclusion from the immunological synapse via the large ectodomain regulates its inhibitory access to TCR substrates; and DEP-1 is essential for developmental vascularization, arterial/venous fate specification, platelet biogenesis, airway smooth muscle contractility, and hypothalamic leptin signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRJ (DEP-1/CD148) is a receptor-type protein tyrosine phosphatase, cloned with an extracellular segment of eight fibronectin type III repeats, a single transmembrane span, and one intracellular PTP domain, whose expression rises sharply with cell density, implicating it in contact inhibition of growth [#0]. Its catalytic activity is upregulated by extracellular ligands engaging the ectodomain, including a Matrigel-derived factor, thrombospondin-1, and syndecan-2 [#2, #18, #17]. PTPRJ acts as a site-selective negative regulator of multiple receptor and cytoplasmic tyrosine kinases, dephosphorylating preferred phosphosites on the PDGF beta-receptor, Met/Gab1, EGFR, VEGFR2, FLT3, JAK2, and EphA/EphB receptors, with selectivity dictated by the primary sequence flanking each phosphotyrosine rather than wholesale kinase shutdown [#1, #3, #11, #10, #15, #26, #30]. It additionally dephosphorylates ERK1/2 Y204 through a KIM-like docking motif, the PI3K regulatory subunit p85, c-Abl, and a beta-integrin NPXY tyrosine [#12, #14, #30, #31]. In apparent opposition, PTPRJ is a positive regulator of Src family kinases across endothelial, platelet, B-cell, neutrophil, smooth-muscle, and microglial contexts by dephosphorylating their inhibitory C-terminal tyrosine; in endothelium this SFK-activating function depends on CK2-mediated phosphorylation of T1318/Y1320 that recruits the Src SH2 domain to PTPRJ [#9, #13, #19, #23, #33]. Through this dual logic, PTPRJ is essential in vivo for developmental and tumor-associated vascularization, arterial/venous fate specification, VEGF-induced permeability, platelet biogenesis, airway smooth-muscle contractility, and hypothalamic leptin signaling [#6, #24, #39, #28, #22, #26]. Biallelic loss-of-function PTPRJ variants cause inherited thrombocytopenia with small platelets and impaired GPVI responses [#28]. Its catalytic cysteine is subject to oxidative inactivation, exploited by FLT3-ITD-driven ROS for oncogenic transformation [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established PTPRJ as a receptor-like tyrosine phosphatase and linked it to cell density, raising the question of whether it enforces contact inhibition.\",\n      \"evidence\": \"cDNA cloning, immunocomplex PTP activity assay, and density-dependent expression analysis in WI-38 fibroblasts\",\n      \"pmids\": [\"7937872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify substrates\", \"Did not test whether catalytic activity is regulated by extracellular ligands\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined the biochemical logic of PTPRJ substrate selection, showing it targets specific RTK phosphosites rather than indiscriminately dephosphorylating.\",\n      \"evidence\": \"In vitro dephosphorylation and phosphopeptide mapping of the PDGF beta-receptor with sequence-context mutagenesis and co-IP\",\n      \"pmids\": [\"10821867\", \"12062403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for PDGF signaling output not established in vivo\", \"Did not address ligand regulation of the phosphatase\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed PTPRJ catalytic activity is upregulated by an extracellular ectodomain ligand, the first evidence that a receptor-type PTP is ligand-activated.\",\n      \"evidence\": \"Matrigel stimulation with immunocomplex PTP assay, ECD-deletion mutant, and soluble ECD competition\",\n      \"pmids\": [\"11526512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the Matrigel ligand not determined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Placed PTPRJ as a negative regulator upstream of the Ras and calcium branches of TCR signaling, identifying immunoreceptor substrates.\",\n      \"evidence\": \"Tetracycline-inducible WT and phosphatase-dead CD148 in Jurkat with NFAT reporter, phosphotyrosine blotting, and calcium assays\",\n      \"pmids\": [\"11259588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect dephosphorylation of LAT/PLCgamma1 not resolved\", \"Overexpression system\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated substrate-trapping-based interactions with Met/Gab1 and with adherens-junction catenins, expanding PTPRJ targets to RTK scaffolds and cell-cell contacts.\",\n      \"evidence\": \"Substrate-trapping mutants, co-IP, in vitro dephosphorylation with site mapping (Met), and colocalization at junctions (catenins)\",\n      \"pmids\": [\"12475979\", \"12370829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catenin dephosphorylation shown by trapping/colocalization, not direct catalysis\", \"Physiological impact on junction stability untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established PTPRJ as a junctional VEGFR2 phosphatase mediating contact inhibition of endothelial proliferation, and showed its phosphatase activity is required for vascular development in vivo.\",\n      \"evidence\": \"DN mutant + RNAi with VEGFR2/VE-cadherin co-IP in isogenic cells; catalytically dead knock-in mice with embryonic vascular phenotyping\",\n      \"pmids\": [\"12771128\", \"12588999\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet reconcile VEGFR2 inhibition with later SFK-activating role\", \"Cell-type-specific contributions in vivo unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined ectodomain-mediated spatial exclusion from the immunological synapse as the regulator of PTPRJ access to TCR substrates, a kinetic-segregation mechanism.\",\n      \"evidence\": \"Inducible CD148 in Jurkat, domain-targeted chimeras, immunofluorescence at the synapse, NFAT reporter\",\n      \"pmids\": [\"12913111\", \"23580664\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative basis of size-based exclusion in primary T cells incomplete\", \"2013 truncation study is single-lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Resolved the central paradox by showing PTPRJ positively regulates SFKs via dephosphorylation of their inhibitory C-terminal tyrosine, partially redundant with CD45.\",\n      \"evidence\": \"CD148 and CD148/CD45 double-KO B cells and macrophages with phospho-specific SFK immunoblotting and lineage functional assays\",\n      \"pmids\": [\"18249142\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect SFK dephosphorylation not biochemically isolated here\", \"Molecular determinant of activating vs inhibiting outcome unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed PTPRJ negatively regulates VEGFR2 yet sustains endothelial survival by activating Src, and directly dephosphorylates the PI3K p85 subunit.\",\n      \"evidence\": \"siRNA + DN PTPRJ with phospho-blotting and Src-Y529F rescue; yeast two-hybrid, co-IP, and in vitro dephosphorylation of p85 with PI3K assays\",\n      \"pmids\": [\"18936167\", \"18348712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Context determinants switching VEGFR2 vs Src targeting not defined\", \"p85 dephosphorylation site not mapped\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended PTPRJ targets to EGFR (with trafficking-coupled spatial segregation) and to direct ERK1/2 Y204 dephosphorylation via a KIM-like docking motif, and demonstrated platelet SFK regulation in vivo.\",\n      \"evidence\": \"Unbiased PTP siRNA screen with EGFR co-IP/ubiquitination/imaging; peptide-array screen, in vitro dephosphorylation and ERK docking mutagenesis; CD148-KO platelet thrombosis model\",\n      \"pmids\": [\"19836242\", \"19494114\", \"19246339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How surface confinement is maintained mechanistically unclear\", \"ERK Y204 role in vivo not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Reconstituted direct PTPRJ dephosphorylation of Fyn/Lyn/Src inhibitory tyrosines in platelets, while noting paradoxical activation-loop dephosphorylation in vitro.\",\n      \"evidence\": \"Recombinant CD148 in vitro dephosphorylation, DT40 reporter, and KO platelet phospho-blotting\",\n      \"pmids\": [\"20345711\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance between activation-loop and inhibitory-tyrosine targeting in vivo unresolved\", \"Site selectivity determinants not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified syndecan-2 as an ectodomain ligand and defined lineage- and SFK-specific PTPRJ functions (FLT3 negative regulation, Lyn in neutrophils, syndecan-4/syntenin recruitment in T cells).\",\n      \"evidence\": \"Co-IP/domain mapping (SDC2); substrate trapping and in vitro dephosphorylation (FLT3); CD45/CD148 double-KO neutrophils; SD-4/syntenin/CD148 complex co-IP with PTP activity assay\",\n      \"pmids\": [\"21813734\", \"21262971\", \"22078799\", \"21469128\", \"21543337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of SFK substrate preference (Lyn vs Hck/Fgr) unknown\", \"Ligand-to-activity coupling mechanism unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified thrombospondin-1 as a high-affinity activating ligand and defined the CK2/Src-driven phospho-switch (T1318/Y1320, Y1311) that couples PTPRJ to SFK-dependent endothelial signaling, plus a ROS-driven oxidative inactivation route exploited by FLT3-ITD.\",\n      \"evidence\": \"MS identification and functional validation of TSP1; phospho-site mutagenesis with co-IP and in vitro assays (Y1311/Y1320); oxidation activity assays with pharmacologic/genetic ROS manipulation and in vivo rescue\",\n      \"pmids\": [\"22308318\", \"22898603\", \"16\", \"22438257\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ligand binding mechanically alters catalysis remains undefined\", \"T1318/Y1320 switch demonstrated mainly in endothelium\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed CK2 phosphorylation of T1318 licenses Y1320 phosphorylation and Src SH2 recruitment, mechanistically connecting a serine/threonine kinase input to PTPRJ-mediated Src activation.\",\n      \"evidence\": \"T1318A/T1318E mutagenesis, in vitro CK2 assay, co-IP, CK2 siRNA, and endothelial permeability assays\",\n      \"pmids\": [\"24583284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the 64-kDa kinase reported in 1997 corresponds to CK2 not established\", \"Generality beyond endothelium untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established PTPRJ as an in vivo driver of VEGF-dependent permeability, angiogenesis, tumor angiogenesis/metastasis via Src, and as an upstream regulator of Dll4-Notch sprouting, plus a B1-selective Lyn activator and a microglial Fyn suppressor.\",\n      \"evidence\": \"PTPRJ-KO Miles/Matrigel/aortic ring/tumor models with phospho-Src/VE-cadherin; KO retina with Src/Akt/beta-catenin pathway dissection; conditional KO B1/B2 assays; BV2 and KO microglia migration assays\",\n      \"pmids\": [\"27364551\", \"31598898\", \"27889108\", \"27859601\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct microglial Fyn dephosphorylation not demonstrated (activity assay only)\", \"Coordination of opposing endothelial outputs across vascular beds incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined PTPRJ as a JAK2-Y813/Y868 phosphatase controlling hypothalamic leptin signaling and energy balance, and (via the worm ortholog) as a beta-integrin NPXY-tyrosine phosphatase coupling integrin/talin activation to EGFR membrane confinement.\",\n      \"evidence\": \"Ptprj-KO mice with site-specific JAK2 dephosphorylation and metabolic phenotyping; C. elegans substrate-trapping proteomics, pat-3(Y792F) epistasis, and EGFR FRAP\",\n      \"pmids\": [\"28912580\", \"28135265\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the integrin/EGFR mechanism in mammals untested\", \"How leptin engages PTPRJ regulation upstream unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated PTPRJ is required for human platelet biogenesis via SFK regulation through patient genetics and modeling, and added CD98hc proteasomal turnover and retinal Eph/c-Abl dephosphorylation to its functions.\",\n      \"evidence\": \"Patient exome sequencing, zebrafish CRISPR thrombocyte assay, megakaryocyte functional and phospho assays; co-IP and MG132 (CD98hc); KO retinal axon tracing and phospho-Eph/c-Abl blotting\",\n      \"pmids\": [\"30591527\", \"29805737\", \"30082414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PTPRJ to CD98hc degradation indirect, single-lab\", \"c-Abl dephosphorylation by PTPRJ shown in vivo but not fully reconstituted\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned PTPRJ as the principal activating counterpart to Csk in platelet SFK homeostasis, with feedback buffering, and (2015/2021) as a negative regulator of insulin signaling and a fibroblast suppressor of PI3K/Akt/mTOR-driven pulmonary fibrosis.\",\n      \"evidence\": \"Chk/Csk/Ptprj triple-KO and analog-sensitive Csk platelet models with phospho-SFK readouts; Ptprj-KO metabolic phenotyping with muscle glucose uptake; fibroblast-specific CD148-KO bleomycin model with pathway dissection and SDC2 peptide rescue\",\n      \"pmids\": [\"32016283\", \"25830095\", \"33784491\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate mediating insulin-pathway suppression not mapped\", \"How a single phosphatase integrates so many opposing context-specific outputs unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying molecular rule determining when PTPRJ dephosphorylates an inhibitory SFK tyrosine (activating) versus an RTK/activation-loop tyrosine (inhibitory) in a given cell type remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model couples ectodomain ligand binding to catalytic regulation\", \"The activating-vs-inhibiting substrate switch lacks a defined molecular determinant\", \"Identity of the 64-kDa associated Ser/Thr kinase remains unconfirmed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 10, 11, 12, 14, 15, 26, 30, 31, 33]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 3, 12, 15]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 13, 19, 23, 33, 40]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 11, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 10, 11, 15, 19, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9, 21, 35]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [13, 28, 33, 40]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 25, 30, 39]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SRC\",\n      \"FYN\",\n      \"LYN\",\n      \"VEGFR2\",\n      \"EGFR\",\n      \"FLT3\",\n      \"JAK2\",\n      \"SDC2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}