{"gene":"PTPRS","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2009,"finding":"PTPσ binds with high affinity to neural chondroitin sulfate proteoglycans (CSPGs); binding involves the chondroitin sulfate chains and a specific site on the first immunoglobulin-like domain of PTPσ. PTPσ-/- neurons show reduced inhibition by CSPG, and PTPσ gene disruption enhanced axon penetration into CSPG-rich regions after spinal cord injury.","method":"Binding assays (fusion protein probe), PTPσ-/- neuron culture, in vivo spinal cord injury model with knockout mice","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal loss-of-function (knockout neurons and mice), direct binding assay, replicated in multiple subsequent studies","pmids":["19833921"],"is_preprint":false},{"year":2014,"finding":"PTPσ converts growth cones into a dystrophic state by stabilizing them within CSPG-rich substrates. A membrane-permeable peptide mimetic of the PTPσ wedge domain binds to PTPσ and relieves CSPG-mediated inhibition, restoring serotonergic innervation and locomotor/urinary recovery after spinal cord injury in rats.","method":"In vivo rat contusive SCI model with systemic peptide delivery (ISP), histology, behavioral assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean mechanistic peptide intervention with defined binding target, functional recovery readouts replicated across multiple downstream studies","pmids":["25470046"],"is_preprint":false},{"year":1998,"finding":"The second catalytic domain of PTPδ (PTPδ-D2) binds to and inhibits the first catalytic domain of PTPσ (PTPσ-D1); this interaction requires the wedge sequence in PTPσ-D1. Addition of GST-PTPδ-D2 inhibited PTPσ-D1 catalytic activity by ~50% in vitro. The interaction was not reciprocal (PTPδ-D1 did not bind PTPσ-D2).","method":"Yeast two-hybrid screen, co-precipitation from mammalian cells, in vitro phosphatase assay against p-nitrophenylphosphate","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis (wedge domain requirement), yeast two-hybrid plus mammalian co-precipitation in single study","pmids":["9566880"],"is_preprint":false},{"year":1997,"finding":"PTPσ is expressed on the cell surface as a two-subunit complex and undergoes proteolytic processing upon treatment with calcium ionophore A23187 or phorbol ester TPA, resulting in shedding of its extracellular domain; a specific cleavage site was identified between amino acids Pro821 and Ile822. After shedding, the catalytically active intracellular portions are internalized and redistributed away from adherens junctions and desmosomes. Calcium withdrawal also causes internalization without prior proteolytic cleavage.","method":"Cell surface processing assays, confocal microscopy, identification of cleavage site by site mapping","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by confocal microscopy tied to functional consequence (redistribution from cell-cell contacts), cleavage site mapped, two independent triggers tested","pmids":["9245795"],"is_preprint":false},{"year":1995,"finding":"Human PTPσ exhibits in vitro PTPase activity and associates with the coiled-coil LAR-interacting protein LIP.1. Multiple isoforms are generated by tissue-specific alternative splicing of up to four mini-exon segments in both extracellular and intracellular regions.","method":"In vitro PTPase assay, co-association assay with LIP.1, Northern blot for isoform characterization","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro PTPase activity demonstrated and LIP.1 association shown, but single study and limited mechanistic follow-up on LIP.1 interaction","pmids":["8524829"],"is_preprint":false},{"year":2011,"finding":"Postsynaptic TrkC binds with high affinity in a neurotrophin-independent manner to presynaptic PTPσ, forming a trans-synaptic adhesion complex. PTPσ triggers presynaptic differentiation while TrkC mediates clustering of postsynaptic molecules. TrkC-neutralizing antibody blocking TrkC-PTPσ interaction and TrkC knockdown reduce glutamatergic synapse formation.","method":"Hippocampal neuron-fibroblast coculture screen, co-IP, knockdown, neutralizing antibody, in vivo knockdown","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased screen validated by co-IP, knockdown in culture and in vivo, neutralizing antibody, multiple orthogonal methods","pmids":["21262467"],"is_preprint":false},{"year":2010,"finding":"PTPσ interacts with postsynaptic NGL-3 via its first two fibronectin III (FNIII) domains. The PTPσ-NGL-3 interaction promotes bidirectional synapse formation, distinguishing PTPσ from PTPδ whose NGL-3 interaction drives only unidirectional presynaptic differentiation.","method":"Binding assays mapping domains, heterologous synapse formation assay, domain deletion constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapped binding assays plus functional synapse formation assay, single study","pmids":["20139422"],"is_preprint":false},{"year":2006,"finding":"N-cadherin is an in vivo substrate for PTPσ. Using substrate trapping in PTPσ knockout brain lysates, N-cadherin was found hyper-tyrosine-phosphorylated; β-catenin also co-precipitated and was a substrate. DRG neurons from PTPσ-/- mice grow faster on laminin or N-cadherin substrata, and this growth advantage was abolished when N-cadherin function was disrupted.","method":"Substrate trapping in knockout brain lysates, mass spectrometry, immunoblotting, DRG neuron growth assays with inhibitory peptide/calcium chelation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — substrate trapping with MS identification, confirmed with loss-of-function rescue experiment and functional phenotype in knockout neurons","pmids":["17060446"],"is_preprint":false},{"year":2011,"finding":"Loss of PTPσ increases cellular PtdIns3P levels, hyperactivates both constitutive and induced autophagy, and PTPσ localizes to PtdIns3P-positive membranes; this vesicular localization is enhanced during autophagy. PTPσ acts as a negative regulator of autophagy upstream of Vps34-generated PtdIns3P.","method":"RNAi screen of human phosphatases, PtdIns3P imaging, autophagy flux assays, subcellular fractionation/localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi loss-of-function with PtdIns3P measurement and autophagy readouts plus localization, single lab","pmids":["21303930"],"is_preprint":false},{"year":2015,"finding":"PTPσ acts as a presynaptic receptor for glypican-4 (GPC-4) in a heparan sulfate (HS)-dependent manner with nanomolar affinity. PTPσ, GPC-4, and LRRTM4 form a trimeric complex in rat brains. PTPσ knockdown (but not LAR knockdown) reduces LRRTM4 synaptogenic activity, and PTPσ KD decreases excitatory synaptic transmission frequency and amplitude; a HS-binding-defective PTPσ mutant cannot rescue this effect.","method":"Affinity binding assays, co-immunoprecipitation from rat brains, single-KD in cultured neurons, heterologous synapse formation, electrophysiology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from native brain tissue, domain-specific mutant rescue, electrophysiological readout, multiple orthogonal methods","pmids":["25624497"],"is_preprint":false},{"year":2016,"finding":"NT-3 enhances TrkC binding affinity for PTPσ. At low concentrations, NT-3 enhances TrkC-induced synapse density (dependent on ERK/Akt), while at high concentrations NT-3 abrogates TrkC-induced synapse density increase by additionally activating PLCγ1 and CREB independently of PTPσ. Point mutations disrupting TrkC intracellular signaling, extracellular binding, or kinase activity each compromise TrkC-induced synapse density.","method":"Binding affinity measurements, immunoblotting, optogenetics-based NT-3 release, point mutagenesis, synapse density quantification in cultured rat neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple point mutants, quantitative binding and signaling measurements, single lab","pmids":["27122038"],"is_preprint":false},{"year":2007,"finding":"PTPσ binds stably in complexes with TrkA and TrkC but not TrkB; this interaction is mediated at least in part by transmembrane domains. PTPσ dephosphorylates all three Trk receptors and suppresses their phosphorylation in the presence of neurotrophins. Overexpression of PTPσ in primary sensory neurons inhibits neurite outgrowth without affecting short-term survival.","method":"Co-IP in transfected HEK293T cells, in vitro dephosphorylation assays, domain deletion constructs, overexpression in primary sensory neurons","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, enzymatic dephosphorylation assay, domain mapping, neuronal overexpression with functional readout, single lab","pmids":["17967490"],"is_preprint":false},{"year":2013,"finding":"CSPGs inhibit oligodendrocyte process outgrowth and myelination through PTPσ; RNAi-mediated knockdown of PTPσ or use of PTPσ-/- oligodendrocytes reverses CSPG inhibition of OL process outgrowth and myelination. ROCK inhibition downstream of CSPG/PTPσ also increases OL process outgrowth and myelination.","method":"RNAi knockdown, PTPσ-/- oligodendrocyte cultures, Chondroitinase ABC treatment, ROCK inhibitor treatment, myelination assays","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (KO) and RNAi loss-of-function with functional myelination readout, downstream pathway placement via ROCK inhibitor, single lab","pmids":["23588220"],"is_preprint":false},{"year":2020,"finding":"PTPσ interacts with TRKB and restricts TRKB phosphorylation; PTPσ deletion increases TRKB phosphorylation in vitro and in vivo. The antidepressant fluoxetine disrupts the TRKB-PTPσ interaction by binding to the transmembrane domain of TRKB. Chondroitinase ABC treatment increases TRKB phosphorylation, and chondroitinase-induced visual cortical plasticity requires intact TRKB signaling in parvalbumin neurons.","method":"Co-IP (PTPσ-TRKB interaction), PTPσ knockout mice (phosphorylation measurements), drug-binding assay (fluoxetine-TM domain), in vivo visual cortex plasticity assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP interaction, KO phenotype measured in vivo, drug mechanism mapped to TM domain, multiple orthogonal methods across in vitro and in vivo","pmids":["33293360"],"is_preprint":false},{"year":2015,"finding":"PTPRS is specifically expressed on plasmacytoid dendritic cells (pDCs) within the human immune system, functions as an inhibitory receptor, and surface PTPRS is rapidly downregulated after pDC activation. Only PTPRS-negative pDCs produce IFN-α. Antibody-mediated PTPRS crosslinking inhibits pDC activation, whereas PTPRS knockdown enhances IFN response. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background leads to enhanced pDC IFN response and mild colitis.","method":"Flow cytometry, antibody crosslinking, shRNA knockdown in pDC cell line, conditional and haplodeficient knockout mice","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function approaches, antibody crosslinking, knockout mouse model with tissue phenotype, multiple orthogonal methods","pmids":["26231120"],"is_preprint":false},{"year":2018,"finding":"PTPσ knockdown reduces excitatory synapse number and transmission in hippocampal neurons, whereas PTPδ KD reduces inhibitory synapses. Extracellular interactions of PTPσ with Slitrks are required for excitatory synapse development. The intracellular D2 domain of PTPσ is required for heterologous synapse formation induced by Slitrk1 or TrkC. Double-KD of liprin-α2 and -α3, or KD of PTPσ substrates N-cadherin and p250RhoGAP, inhibits Slitrk6-induced, PTPσ-mediated synapse formation.","method":"Knockdown in cultured rat hippocampal neurons, rescue with deletion/point mutants and splice variants, heterologous synapse formation assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — extensive structure-function rescue experiments with multiple deletion variants, domain mutants, and double-KD epistasis, single lab but highly systematic","pmids":["29934346"],"is_preprint":false},{"year":2018,"finding":"PTPRS modulates ERK phosphorylation and prevents ERK nuclear translocation in colorectal cancer cells. Native mutations in PTPRS reduce its phosphatase activity while increasing ERK activation and downstream transcriptional signaling.","method":"ERK phosphorylation assays, nuclear fractionation, PTPRS mutant expression in cancer cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — phosphatase activity and ERK localization assays, single lab, limited mechanistic depth in abstract","pmids":["29915291"],"is_preprint":false},{"year":2019,"finding":"PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC activation; PTPRS loss or mutation leads to increased SRC activity, which can be targeted with dasatinib to prevent adaptive resistance.","method":"Cell-based resistance assays, SRC activity measurement, combination drug treatment experiments","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell-based assay but mechanism linking PTPRS phosphatase activity to SRC is not rigorously demonstrated in the abstract","pmids":["31827720"],"is_preprint":false},{"year":2019,"finding":"PTPσ small molecule inhibitor DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase RAC1 and induction of BCL-XL. DJ001 antagonizes PTPσ via non-competitive, allosteric binding and promotes HSC regeneration in vivo after irradiation and chemotherapy.","method":"In vitro phosphatase assays (competitive vs. allosteric), RAC1 and BCL-XL measurements, in vivo mouse irradiation model with HSC enumeration","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic characterization of binding mode, downstream pathway (RAC1/BCL-XL) identified, in vivo functional validation, single lab with multiple orthogonal methods","pmids":["31413255"],"is_preprint":false},{"year":2019,"finding":"PTPσ-mediated presynaptic differentiation requires interaction with liprin-α; disrupting the PTPσ-liprin-α interaction (but not PTPσ self-dimerization or caskin binding) abolishes presynaptic differentiation. Both the D1 and D2 phosphatase-like domains of PTPσ mediate binding to liprin-α. Phosphatase activity of PTPσ and heparan sulfate binding are dispensable for presynaptic induction.","method":"DHFR protein complementation assay, systematic point mutagenesis, molecular replacement (rescue experiments) in neurons","journal":"Frontiers in synaptic neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis with functional rescue assays, negative controls (phosphatase-dead mutants), two-domain requirement established, single lab","pmids":["31191292"],"is_preprint":false},{"year":2020,"finding":"Presynaptic PTPσ enhances postsynaptic NMDA receptor currents and NMDAR-dependent synaptic plasticity in the hippocampus through adhesion-independent, cytoplasmic domain-dependent mechanisms. Loss of PTPσ strongly increases phosphotyrosine levels of presynaptic proteins including neurexin-1. This PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition.","method":"PTPσ mutant mice, electrophysiology (NMDAR currents, LTP), phosphotyrosine proteomics, behavioral tests","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — electrophysiology with genetic KO, phosphoproteomics identifying substrates, behavioral validation, multiple orthogonal methods","pmids":["32142410"],"is_preprint":false},{"year":2019,"finding":"Collagen XXV directly interacts with PTPσ and PTPδ; this interaction attracts motor axons, but can be inhibited by exogenous PTPσ/δ. Congenital cranial dysinnervation disorder (CCDD) mutations attenuate motor axon attraction by reducing the collagen XXV-PTPσ/δ interaction.","method":"In vitro binding assays, cell-based interaction assays, motor explant assays, CCDD mutant constructs","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated in vitro, functional motor axon assay, disease mutant validation, single lab","pmids":["31875546"],"is_preprint":false},{"year":2013,"finding":"Loss of Ptprs together with Ptprf (LAR) causes craniofacial malformations associated with increased BMP-Smad signaling and abrogation of canonical Wnt/β-catenin signaling. Chemical inhibition of GSK3β rescues Wnt/β-catenin responsiveness in LAR-family phosphatase-deficient cells, indicating RPTPs are required for normal Wnt/β-catenin pathway activation.","method":"Double-knockout mouse model, signal transduction analysis (BMP-Smad, Wnt/β-catenin), MEF cultures, GSK3β inhibitor rescue","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with chemical rescue, pathway-level mechanistic placement, but PTPσ effects cannot be fully separated from LAR in the double-KO model","pmids":["23863482"],"is_preprint":false},{"year":2018,"finding":"CSPGs regulate microglia through activation of the Rho/ROCK pathway downstream of LAR and PTPσ. Inhibiting LAR and PTPσ reduces M1 microglia/macrophages and promotes M2 phenotype and T regulatory cells, enhancing IL-10 and Arginase-1. PTPσ blockade modulates phagocytosis and mobilization of microglia in vitro.","method":"In vivo rat SCI model with ISP/ILP peptide delivery, flow cytometry, Western blotting, primary microglia culture experiments","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — parallel in vivo and in vitro approaches with functional immunological readouts, but LAR and PTPσ targeted together limiting PTPσ-specific attribution","pmids":["29558941"],"is_preprint":false},{"year":2016,"finding":"NME2 (nucleoside diphosphate kinase 2) associates with the PTPσ intracellular domain and transduces CSPG inhibitory signals; NME2 knockdown in cortical neurons completely rescues neurite outgrowth inhibition induced by CSPGs.","method":"Mass spectrometry screen of PTPσ-associated proteins, co-immunoprecipitation of NME2 with PTPσ intracellular domain in HEK-293T cells, NME2 knockdown in cortical neurons with neurite outgrowth assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirmed NME2-PTPσ interaction, functional knockdown rescue experiment, but single lab with limited mechanistic depth","pmids":["26896769"],"is_preprint":false},{"year":2019,"finding":"BMP10 interacts with both PTPRS and STAT3 in the cytoplasm, facilitating dephosphorylation of STAT3 by PTPRS, thereby suppressing STAT3 signaling and HCC cell proliferation.","method":"Co-immunoprecipitation of BMP10-PTPRS-STAT3 complex, STAT3 phosphorylation assays, in vitro and in vivo tumor growth assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP identifying trimeric complex, phosphorylation assays demonstrating dephosphorylation, in vitro/in vivo tumor growth with functional consequence, single lab","pmids":["31417183"],"is_preprint":false},{"year":2020,"finding":"LRRTMs recruit PTPσ to induce presynaptic differentiation through the heparan sulfate (HS) modification of neurexin. PTPσ forms a robust complex with neurexin at presynaptic terminals. LRRTM4 mutant mice unable to bind HS show structural and functional deficits at dentate gyrus excitatory synapses.","method":"Binding assays (HS-dependent), co-immunoprecipitation, LRRTM4 knockin mutant mice, synapse structural/functional analysis","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-specific mutant mice, co-IP of PTPσ-neurexin complex, multiple synapse functional/structural readouts, HS-dependency mechanistically defined","pmids":["31995730"],"is_preprint":false},{"year":2020,"finding":"Structural determination: the SALM3-PTPσ complex forms a 2:2 trans-heterotetrameric complex as determined by small-angle X-ray scattering; mutational analysis of key interface residues confirmed their importance in cellular binding and synapse formation assays.","method":"Small-angle X-ray scattering (SAXS), crystal structure of SALM3 LRR dimer domain, site-directed mutagenesis, cellular binding and synapse formation assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SAXS-based complex structure plus mutagenesis validated in functional assays, single lab but multiple orthogonal structural/functional methods","pmids":["32665594"],"is_preprint":false},{"year":2025,"finding":"PTPσ-mediated PI3P regulation controls neurodegeneration in C9ORF72-ALS/FTD: reducing PTPσ elevates PI3P levels, restores early endosomes and lysosomes, and improves survival of poly-GR- and poly-PR-expressing neurons. PTPσ knockdown or inhibition rescues PI3P-endolysosomal defects in C9ORF72-ALS/FTD patient-derived neurons.","method":"CRISPRi screening in human-derived neurons, PI3P measurement, endolysosomal assays, patient-derived neuron cultures, in vivo mouse model with PTPσ inhibitor","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPRi screen validated by genetic knockdown and pharmacological inhibition, patient-derived neurons, in vivo mouse rescue, multiple orthogonal methods","pmids":["40073860"],"is_preprint":false},{"year":2018,"finding":"Inhibition of CSPG/PTPσ signaling by ISP peptide in oligodendrocyte progenitor cells (OPCs) promotes OPC migration, maturation, and remyelination; a downstream molecular target is upregulation of MMP-2, which allows OPCs to enzymatically digest CSPGs.","method":"In vitro OPC migration/differentiation assays, in vivo MS mouse models, MMP-2 activity assays, ISP peptide treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — downstream MMP-2 identified as effector, in vitro and in vivo functional readouts, single lab","pmids":["30297691"],"is_preprint":false},{"year":2019,"finding":"CSPG inhibition of neural stem/progenitor cell migration is mediated through PTPσ/α-actinin4 (ACTN4) signaling pathway: CSPG upregulates PTPσ expression and decreases ACTN4 expression, reducing filopodia formation. PTPσ-specific siRNA attenuates this inhibitory effect.","method":"Phase-contrast microscopy, transwell assays, immunofluorescence, RT-PCR, Western blot, siRNA knockdown","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA epistasis placing ACTN4 downstream of PTPσ, multiple readouts, single lab","pmids":["30688376"],"is_preprint":false},{"year":2020,"finding":"PTPσ conditional knockout reduces excitatory synapse number, impairs excitatory synaptic transmission, causes abnormal vesicle localization and synaptic ultrastructure, and reduces neurotransmitter release at excitatory synapses. Loss of presynaptic PTPσ in hippocampal CA1 neurons did not affect postsynaptic glutamate receptor responses in subicular neurons.","method":"Single conditional knockout mice (PTPσ cKO), electrophysiology, electron microscopy, in vivo innervation analysis","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional single KO mice with electrophysiology, electron microscopy, and in vivo innervation analysis; controls for postsynaptic effects; multiple orthogonal methods","pmids":["32516721"],"is_preprint":false},{"year":2025,"finding":"PTPσ-mediated tyrosine dephosphorylation and multimerization of CASKIN2 are critical for CASKIN2 to regulate excitatory synaptic transmission, NMDAR functions, and activity-dependent presynaptic F-actin rearrangement. CASKIN2 is a substrate/binding partner of PTPσ at hippocampal CA3 Schaffer collateral synapses.","method":"Conditional knockout mice for CASKIN1/2, electrophysiology, CASKIN2 phosphorylation and multimerization assays, F-actin imaging, behavioral memory tests","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice with electrophysiology and biochemistry, dephosphorylation mechanistically linked to multimerization and function, multiple orthogonal methods","pmids":["41223222"],"is_preprint":false},{"year":2025,"finding":"Antibodies targeting the membrane-proximal fibronectin type III-like 9 (Fn9) domain of PTPRS can activate PTPRS by disrupting its co-localization with syndecan-4 (SDC4) and reducing PTPRS oligomerization. Recombinant Fn9 protein acts as a decoy to disrupt PTPRS-SDC4 co-localization and inhibit FLS migration. This approach shows disease mitigation in a mouse arthritis model.","method":"Antibody epitope mapping (Fn9 domain), PTPRS activity assays, co-localization imaging, PTPRS oligomerization assays, FLS migration assays, mouse arthritis model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitope-mapped antibodies with functional activity assays, oligomerization mechanistically linked to regulation, in vivo disease model, single study","pmids":["40651610"],"is_preprint":false},{"year":2002,"finding":"Chick PTPσ regulates targeting of retinal axons within the optic tectum; secreted PTPσ ectodomains accumulate at tectal sites containing endogenous PTPσ ligands and cause premature stalling, excessive pretectal arbor formation, and diffuse termination zones of retinal axons, indicating PTPσ signaling is required for sustaining axonal growth and topographic mapping.","method":"Retroviral ectopic expression of secretable PTPσ ectodomain in ovo, anterograde labeling of retinal axons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo dominant-negative ectodomain approach with anterograde axon labeling, clean phenotypic readout, single study in chick model","pmids":["12077198"],"is_preprint":false},{"year":2024,"finding":"The TrkC-PTPσ trans-synaptic complex governs synapse maturation by regulating synaptic protein phosphorylation. TrkC point mutations that abolish PTPσ binding result in abnormal synaptic vesicle clustering, postsynaptic density elongation, more silent synapses, fewer active synapses with enhanced basal transmission but impaired release probability, and aberrant phosphorylation of synaptic proteins. These effects occur independently of neurotrophin-3 signaling.","method":"TrkC knockin mice with PTPσ-binding point mutations, electron microscopy, electrophysiology, phosphoproteomics, behavioral tests","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockin mouse dissecting TrkC-PTPσ from neurotrophin function, electrophysiology, EM ultrastructure, and phosphoproteomics, multiple orthogonal methods","pmids":["39333774"],"is_preprint":false},{"year":2003,"finding":"The shorter cPTPσ1 isoform, but not cPTPσ2, binds specifically to developing skeletal myotubes through a mechanism distinct from heparan sulfate binding; most mutations that abolish heparin binding do not affect myotube binding, indicating an isoform-specific, heparan sulfate-independent ligand on myotubes.","method":"Ectodomain binding assays on myotubes, heparinase treatment, mutagenesis of heparin-binding residues","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with mutagenesis distinguishing two mechanisms, isoform-specific result, single lab","pmids":["12595237"],"is_preprint":false},{"year":2024,"finding":"PTPRS knockdown promotes EGFR expression and phosphorylation in Nf1-deficient Schwann cells, driving epithelial-mesenchymal transition and increased migration; these effects are reversed by EGFR knockdown or EGFR inhibitor, placing PTPRS upstream of EGFR-mediated EMT.","method":"RTK assay, Western blotting, PTPRS knockdown and overexpression in Nf1-deficient Schwann cell lines, EGFR knockdown and inhibitor rescue, cell migration assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (PTPRS KD + EGFR KD rescue), RTK phosphorylation assays, functional migration readout, single lab","pmids":["39094827"],"is_preprint":false}],"current_model":"PTPRS (PTPσ) is a transmembrane receptor protein tyrosine phosphatase that acts as a high-affinity receptor for chondroitin sulfate proteoglycans (CSPGs) via its Ig1 domain and for heparan sulfate proteoglycans via a basic amino acid domain, transducing inhibitory signals through downstream effectors including Rho/ROCK, NME2, and ACTN4 to suppress axon regeneration, oligodendrocyte myelination, and neural stem cell migration; at synapses, presynaptic PTPσ organizes excitatory presynaptic assembly by binding extracellular ligands (TrkC, NGL-3, Slitrks, GPC-4/LRRTM4, SALM3, collagen XXV, neurexin) and intracellularly coupling to liprin-α and CASKIN2 to regulate neurotransmitter release and NMDAR function, while also dephosphorylating substrates including N-cadherin, β-catenin, Trk neurotrophin receptors, TRKB (regulating critical period plasticity), and STAT3 (suppressing tumor growth); additionally, PTPσ negatively regulates PI3P levels and autophagy, functions as an inhibitory receptor on plasmacytoid dendritic cells to restrain IFN-α production, and undergoes regulated proteolytic shedding of its ectodomain that redistributes the catalytically active intracellular fragment away from cell-cell contacts."},"narrative":{"mechanistic_narrative":"PTPRS (PTPσ) is a transmembrane receptor protein tyrosine phosphatase that serves dual roles as an inhibitory cell-surface receptor for extracellular matrix proteoglycans and as an organizer of synaptic connectivity [PMID:19833921, PMID:21262467]. In the injured CNS, PTPσ acts as a high-affinity receptor for chondroitin sulfate proteoglycans (CSPGs) through a defined site on its first Ig-like domain, converting growth cones into a dystrophic state and transducing inhibitory signals that suppress axon regeneration, oligodendrocyte myelination, and neural stem cell migration [PMID:19833921, PMID:25470046, PMID:23588220]; these effects are relayed through Rho/ROCK signaling and intracellular effectors including NME2 and α-actinin-4 (ACTN4), and a wedge-domain peptide mimetic (ISP) relieves this inhibition to restore innervation and functional recovery after spinal cord injury [PMID:25470046, PMID:23588220, PMID:26896769, PMID:30688376]. As a presynaptic adhesion receptor, PTPσ binds an array of postsynaptic and matrix ligands—TrkC, NGL-3, Slitrks, glypican-4/LRRTM4, SALM3, and collagen XXV—often in a heparan-sulfate-dependent manner, to drive excitatory presynaptic differentiation, neurotransmitter release, and NMDAR-dependent plasticity [PMID:21262467, PMID:20139422, PMID:25624497, PMID:29934346, PMID:31875546, PMID:31995730, PMID:32665594]. Presynaptic induction requires intracellular coupling to liprin-α and is independent of phosphatase activity, whereas regulation of synaptic transmission and CASKIN2 multimerization depends on its cytoplasmic phosphatase domains [PMID:31191292, PMID:32142410, PMID:41223222]. PTPσ dephosphorylates substrates including N-cadherin and β-catenin, the Trk neurotrophin receptors TrkA/TrkC and TRKB (the latter regulating critical-period plasticity and being disrupted by fluoxetine), and STAT3 to suppress tumor growth [PMID:17060446, PMID:17967490, PMID:33293360, PMID:31417183]. Beyond the nervous system, PTPσ negatively regulates PtdIns3P levels and autophagy upstream of Vps34, with implications for endolysosomal homeostasis in C9ORF72-ALS/FTD, and functions as an inhibitory receptor on plasmacytoid dendritic cells to restrain IFN-α production [PMID:21303930, PMID:26231120, PMID:40073860]. Its activity is further controlled by regulated ectodomain shedding that redistributes the active intracellular fragment away from cell-cell contacts, and by oligomerization with syndecan-4 [PMID:9245795, PMID:40651610].","teleology":[{"year":1995,"claim":"Establishing that human PTPσ is a catalytically active tyrosine phosphatase with multiple splice isoforms and an intracellular binding partner defined its basic biochemical identity.","evidence":"In vitro PTPase assay, LIP.1 co-association, Northern blot isoform analysis","pmids":["8524829"],"confidence":"Medium","gaps":["Physiological substrates not identified","Functional role of LIP.1 interaction not pursued"]},{"year":1997,"claim":"Discovery of regulated ectodomain shedding and internalization addressed how PTPσ activity and localization are post-translationally controlled.","evidence":"Cell-surface processing assays, confocal microscopy, cleavage-site mapping (Pro821/Ile822)","pmids":["9245795"],"confidence":"High","gaps":["Protease responsible for cleavage not identified","Consequence for downstream signaling not defined"]},{"year":1998,"claim":"Demonstrating that a paralog's D2 domain inhibits the PTPσ catalytic D1 domain via the wedge sequence revealed an intermolecular regulatory mechanism for RPTP activity.","evidence":"Yeast two-hybrid, mammalian co-precipitation, in vitro phosphatase assay with wedge mutants","pmids":["9566880"],"confidence":"High","gaps":["In vivo relevance of D1-D2 trans-inhibition unclear","Endogenous regulators not established"]},{"year":2002,"claim":"In vivo ectodomain perturbation in chick established that PTPσ signaling sustains axonal growth and topographic mapping, linking it to developmental axon guidance.","evidence":"Retroviral secretable ectodomain expression in ovo, anterograde retinal axon labeling","pmids":["12077198"],"confidence":"Medium","gaps":["Tectal ligand identity unknown","Downstream signaling not defined"]},{"year":2006,"claim":"Substrate trapping in knockout brain identified N-cadherin and β-catenin as in vivo substrates, providing a molecular basis for PTPσ control of neurite growth on adhesive substrata.","evidence":"Substrate trapping in PTPσ-/- brain lysates, mass spectrometry, DRG growth assays","pmids":["17060446"],"confidence":"High","gaps":["Direct vs indirect dephosphorylation of β-catenin not fully resolved","Site-specific phosphotyrosines not mapped"]},{"year":2007,"claim":"Showing PTPσ binds and dephosphorylates TrkA and TrkC (but not TrkB) connected the phosphatase to neurotrophin receptor signaling and neurite outgrowth.","evidence":"Co-IP in HEK293T, in vitro dephosphorylation, domain deletion, neuronal overexpression","pmids":["17967490"],"confidence":"Medium","gaps":["TM-mediated interaction mechanism not structurally defined","In vivo substrate validation absent in this study"]},{"year":2009,"claim":"Identifying PTPσ as a high-affinity CSPG receptor via its Ig1 domain established the receptor that transduces ECM-encoded inhibition of axon regeneration.","evidence":"Binding assays, PTPσ-/- neurons, in vivo spinal cord injury in knockout mice","pmids":["19833921"],"confidence":"High","gaps":["Intracellular signaling effectors not yet identified at this stage","Distinction from related RPTP receptors incomplete"]},{"year":2010,"claim":"Mapping the PTPσ-NGL-3 interaction to FNIII domains and showing bidirectional synaptogenesis positioned PTPσ as a synaptic organizer distinct from its paralog.","evidence":"Domain-mapped binding assays, heterologous synapse formation assay","pmids":["20139422"],"confidence":"Medium","gaps":["In vivo requirement not tested","Intracellular coupling not addressed"]},{"year":2011,"claim":"Identification of TrkC as a neurotrophin-independent trans-synaptic ligand, together with the discovery that PTPσ negatively regulates Vps34-dependent PtdIns3P and autophagy, expanded its roles into synapse formation and membrane trafficking.","evidence":"Coculture screen, co-IP, knockdown, neutralizing antibody (TrkC); RNAi phosphatase screen, PtdIns3P imaging, autophagy flux (autophagy)","pmids":["21262467","21303930"],"confidence":"High","gaps":["PtdIns3P substrate/effector of PTPσ in autophagy not defined","Link between synaptic and autophagy functions unclear"]},{"year":2013,"claim":"Loss-of-function in oligodendrocytes and LAR-family double knockouts extended PTPσ inhibitory signaling to myelination and to Wnt/β-catenin and BMP-Smad developmental pathways.","evidence":"RNAi/KO oligodendrocyte cultures with ROCK inhibitor; double-KO mice with GSK3β-inhibitor rescue and signaling analysis","pmids":["23588220","23863482"],"confidence":"Medium","gaps":["PTPσ-specific contribution not separable from LAR in double-KO","Direct substrates in Wnt/BMP pathways not identified"]},{"year":2014,"claim":"A wedge-domain peptide mimetic (ISP) that relieves CSPG-mediated growth-cone entrapment and restores function provided proof-of-concept that targeting PTPσ promotes recovery after spinal cord injury.","evidence":"In vivo rat contusive SCI with systemic ISP delivery, histology, behavioral assays","pmids":["25470046"],"confidence":"High","gaps":["Precise molecular mechanism of ISP action on the wedge not fully defined","Downstream effectors not resolved in this study"]},{"year":2015,"claim":"Discovery of glypican-4/LRRTM4 as HS-dependent presynaptic ligands and of PTPRS as an inhibitory pDC receptor restraining IFN-α revealed both synaptic and immune signaling roles distinct from CSPG inhibition.","evidence":"Affinity binding, native-brain co-IP, KD, electrophysiology (synapse); flow cytometry, antibody crosslinking, shRNA, KO mice (immune)","pmids":["25624497","26231120"],"confidence":"High","gaps":["pDC ligand on activating cells not defined","Phosphatase substrates in pDC signaling not identified"]},{"year":2016,"claim":"Mechanistic dissection of NT-3 modulation of TrkC-PTPσ and identification of NME2 as an intracellular effector clarified ligand-tuning and downstream signal transduction of CSPG inhibition.","evidence":"Binding/signaling measurements with optogenetic NT-3 (synapse); MS screen, co-IP, NME2 KD rescue of neurite outgrowth","pmids":["27122038","26896769"],"confidence":"Medium","gaps":["NME2 enzymatic role downstream of PTPσ not defined","Single-lab characterization of NME2 axis"]},{"year":2018,"claim":"Systematic structure-function work tied PTPσ-Slitrk binding and the D2 domain to excitatory synapse development, while CSPG/PTPσ signaling was extended to microglial polarization, OPC remyelination via MMP-2, and ERK regulation in colorectal cancer.","evidence":"KD/rescue with mutants and electrophysiology (Slitrk); ISP/ILP peptide in SCI and microglia culture; OPC migration with MMP-2 assays; ERK phosphorylation and nuclear fractionation in cancer cells","pmids":["29934346","29558941","30297691","29915291"],"confidence":"High","gaps":["PTPσ-specific vs LAR contribution to microglia not separated","Direct phosphatase substrate in ERK regulation not defined"]},{"year":2019,"claim":"A series of studies defined intracellular coupling to liprin-α as the phosphatase-independent driver of presynaptic differentiation and uncovered additional roles in tumor STAT3 suppression, HSC regeneration via allosteric inhibition, ACTN4-mediated NSPC migration, and collagen XXV-dependent motor axon attraction.","evidence":"DHFR complementation and mutagenesis (liprin-α); BMP10-PTPRS-STAT3 co-IP and tumor assays; DJ001 enzymatic and in vivo HSC assays; siRNA epistasis (ACTN4); binding and motor explant assays with CCDD mutants (collagen XXV)","pmids":["31191292","31417183","31413255","30688376","31875546"],"confidence":"High","gaps":["Mechanism segregating phosphatase-dependent from adhesion functions incomplete","SRC-linked drug resistance mechanism (Low confidence) not rigorously demonstrated"]},{"year":2020,"claim":"In vivo genetic and structural studies established that presynaptic PTPσ controls NMDAR currents, neurotransmitter release, vesicle organization, and synaptic ultrastructure through cytoplasmic-domain mechanisms, dephosphorylating presynaptic substrates including neurexin-1, while also restricting TRKB phosphorylation to gate critical-period plasticity.","evidence":"PTPσ mutant/conditional KO mice, electrophysiology, EM, phosphotyrosine proteomics, behavioral tests; SALM3-PTPσ SAXS structure; LRRTM4-neurexin HS knockin mice; TRKB co-IP and fluoxetine TM-binding assay","pmids":["32142410","32516721","32665594","31995730","33293360"],"confidence":"High","gaps":["Complete presynaptic substrate set not enumerated","How adhesion and phosphatase activities are coordinated in vivo unresolved"]},{"year":2024,"claim":"Knockin mice separating TrkC-PTPσ adhesion from neurotrophin signaling demonstrated the complex governs synapse maturation via phosphorylation control, and PTPRS was placed upstream of EGFR-driven EMT in Nf1-deficient Schwann cells.","evidence":"TrkC binding-mutant knockin mice, EM, electrophysiology, phosphoproteomics; PTPRS KD/OE with EGFR KD/inhibitor rescue and migration assays","pmids":["39333774","39094827"],"confidence":"High","gaps":["Direct phosphatase substrates mediating maturation not fully mapped","Whether EGFR is a direct PTPRS substrate not established"]},{"year":2025,"claim":"Recent work linked PTPσ-mediated PI3P regulation to endolysosomal rescue in C9ORF72-ALS/FTD, defined CASKIN2 as a phosphatase-regulated substrate organizing presynaptic transmission, and developed Fn9-domain antibodies that activate PTPRS by disrupting syndecan-4 co-localization and oligomerization in arthritis.","evidence":"CRISPRi screen, PI3P/endolysosomal assays, patient neurons, in vivo inhibitor (C9-ALS); CASKIN1/2 conditional KO, electrophysiology, phospho/multimerization assays; antibody epitope mapping, oligomerization and FLS migration assays, arthritis model","pmids":["40073860","41223222","40651610"],"confidence":"High","gaps":["Direct PI3P-phosphatase substrate of PTPσ not biochemically defined","How oligomerization state controls catalytic activity not fully resolved"]},{"year":null,"claim":"How PTPσ integrates its dual roles as an extracellular ligand receptor and an intracellular tyrosine phosphatase—and how ectodomain shedding, oligomerization, and ligand binding are coordinated to switch between adhesion and catalytic signaling—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model of full-length receptor signaling states","Complete in vivo substrate map across tissues lacking","Regulation of catalytic activity by ligand engagement not mechanistically resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,11,13,25,32]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,4,18]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[5,9,26,27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[8,28]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,5,14,33]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[5,15,20,31,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,12,22,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,11,13,16,25]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,28]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[14,23]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[0,9,21,26]}],"complexes":["TrkC-PTPσ trans-synaptic complex","PTPσ-GPC4-LRRTM4 trimeric complex","PTPσ-neurexin presynaptic complex","BMP10-PTPRS-STAT3 complex"],"partners":["TRKC","NGL-3","GPC4","LRRTM4","NEUREXIN-1","LIPRIN-ALPHA","CASKIN2","SDC4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13332","full_name":"Receptor-type tyrosine-protein phosphatase S","aliases":["Receptor-type tyrosine-protein phosphatase sigma","R-PTP-sigma"],"length_aa":1948,"mass_kda":217.0,"function":"Cell surface receptor that binds to glycosaminoglycans, including chondroitin sulfate proteoglycans and heparan sulfate proteoglycan (PubMed:21454754). Binding to chondroitin sulfate and heparan sulfate proteoglycans has opposite effects on PTPRS oligomerization and regulation of neurite outgrowth. Contributes to the inhibition of neurite and axonal outgrowth by chondroitin sulfate proteoglycans, also after nerve transection. Plays a role in stimulating neurite outgrowth in response to the heparan sulfate proteoglycan GPC2. Required for normal brain development, especially for normal development of the pituitary gland and the olfactory bulb. Functions as a tyrosine phosphatase (PubMed:8524829). Mediates dephosphorylation of NTRK1, NTRK2 and NTRK3 (By similarity). Plays a role in down-regulation of signaling cascades that lead to the activation of Akt and MAP kinases (By similarity). Down-regulates TLR9-mediated activation of NF-kappa-B, as well as production of TNF, interferon alpha and interferon beta (PubMed:26231120)","subcellular_location":"Cell membrane; Cell projection, axon; Perikaryon; Cytoplasmic vesicle, secretory vesicle, synaptic vesicle membrane; Synapse, synaptosome; Postsynaptic density; Cell projection, neuron projection; Cell projection, growth cone","url":"https://www.uniprot.org/uniprotkb/Q13332/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRS","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/PTPRS","total_profiled":1310},"omim":[{"mim_id":"611054","title":"PTPRF-INTERACTING PROTEIN ALPHA-1; PPFIA1","url":"https://www.omim.org/entry/611054"},{"mim_id":"601576","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, SIGMA; PTPRS","url":"https://www.omim.org/entry/601576"},{"mim_id":"179590","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, F; PTPRF","url":"https://www.omim.org/entry/179590"},{"mim_id":"155760","title":"AGGRECAN; ACAN","url":"https://www.omim.org/entry/155760"},{"mim_id":"142460","title":"SYNDECAN 2; SDC2","url":"https://www.omim.org/entry/142460"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRS"},"hgnc":{"alias_symbol":["PTPsigma","PTP-sigma"],"prev_symbol":[]},"alphafold":{"accession":"Q13332","domains":[{"cath_id":"2.60.40.10","chopping":"32-236","consensus_level":"medium","plddt":85.9732,"start":32,"end":236},{"cath_id":"2.60.40.10","chopping":"244-329","consensus_level":"high","plddt":85.2624,"start":244,"end":329},{"cath_id":"2.60.40.10","chopping":"340-421","consensus_level":"high","plddt":86.0883,"start":340,"end":421},{"cath_id":"2.60.40.10","chopping":"439-523","consensus_level":"medium","plddt":86.846,"start":439,"end":523},{"cath_id":"2.60.40.10","chopping":"555-615","consensus_level":"medium","plddt":88.0487,"start":555,"end":615},{"cath_id":"2.60.40.10","chopping":"726-832","consensus_level":"medium","plddt":78.4775,"start":726,"end":832},{"cath_id":"2.60.40.10","chopping":"838-856_863-924","consensus_level":"medium","plddt":82.3215,"start":838,"end":924},{"cath_id":"2.60.40.10","chopping":"934-1030","consensus_level":"medium","plddt":76.9326,"start":934,"end":1030},{"cath_id":"2.60.40.10","chopping":"1039-1117","consensus_level":"high","plddt":77.2132,"start":1039,"end":1117},{"cath_id":"3.90.190.10","chopping":"1374-1653","consensus_level":"high","plddt":91.2808,"start":1374,"end":1653},{"cath_id":"3.90.190.10","chopping":"1737-1942","consensus_level":"high","plddt":93.0643,"start":1737,"end":1942}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13332","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13332-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13332-F1-predicted_aligned_error_v6.png","plddt_mean":81.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRS","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRS"},"sequence":{"accession":"Q13332","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13332.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13332/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13332"}},"corpus_meta":[{"pmid":"19833921","id":"PMC_19833921","title":"PTPsigma 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PTPσ-/- neurons show reduced inhibition by CSPG, and PTPσ gene disruption enhanced axon penetration into CSPG-rich regions after spinal cord injury.\",\n      \"method\": \"Binding assays (fusion protein probe), PTPσ-/- neuron culture, in vivo spinal cord injury model with knockout mice\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal loss-of-function (knockout neurons and mice), direct binding assay, replicated in multiple subsequent studies\",\n      \"pmids\": [\"19833921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPσ converts growth cones into a dystrophic state by stabilizing them within CSPG-rich substrates. A membrane-permeable peptide mimetic of the PTPσ wedge domain binds to PTPσ and relieves CSPG-mediated inhibition, restoring serotonergic innervation and locomotor/urinary recovery after spinal cord injury in rats.\",\n      \"method\": \"In vivo rat contusive SCI model with systemic peptide delivery (ISP), histology, behavioral assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean mechanistic peptide intervention with defined binding target, functional recovery readouts replicated across multiple downstream studies\",\n      \"pmids\": [\"25470046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The second catalytic domain of PTPδ (PTPδ-D2) binds to and inhibits the first catalytic domain of PTPσ (PTPσ-D1); this interaction requires the wedge sequence in PTPσ-D1. Addition of GST-PTPδ-D2 inhibited PTPσ-D1 catalytic activity by ~50% in vitro. The interaction was not reciprocal (PTPδ-D1 did not bind PTPσ-D2).\",\n      \"method\": \"Yeast two-hybrid screen, co-precipitation from mammalian cells, in vitro phosphatase assay against p-nitrophenylphosphate\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis (wedge domain requirement), yeast two-hybrid plus mammalian co-precipitation in single study\",\n      \"pmids\": [\"9566880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PTPσ is expressed on the cell surface as a two-subunit complex and undergoes proteolytic processing upon treatment with calcium ionophore A23187 or phorbol ester TPA, resulting in shedding of its extracellular domain; a specific cleavage site was identified between amino acids Pro821 and Ile822. After shedding, the catalytically active intracellular portions are internalized and redistributed away from adherens junctions and desmosomes. Calcium withdrawal also causes internalization without prior proteolytic cleavage.\",\n      \"method\": \"Cell surface processing assays, confocal microscopy, identification of cleavage site by site mapping\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by confocal microscopy tied to functional consequence (redistribution from cell-cell contacts), cleavage site mapped, two independent triggers tested\",\n      \"pmids\": [\"9245795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Human PTPσ exhibits in vitro PTPase activity and associates with the coiled-coil LAR-interacting protein LIP.1. Multiple isoforms are generated by tissue-specific alternative splicing of up to four mini-exon segments in both extracellular and intracellular regions.\",\n      \"method\": \"In vitro PTPase assay, co-association assay with LIP.1, Northern blot for isoform characterization\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro PTPase activity demonstrated and LIP.1 association shown, but single study and limited mechanistic follow-up on LIP.1 interaction\",\n      \"pmids\": [\"8524829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Postsynaptic TrkC binds with high affinity in a neurotrophin-independent manner to presynaptic PTPσ, forming a trans-synaptic adhesion complex. PTPσ triggers presynaptic differentiation while TrkC mediates clustering of postsynaptic molecules. TrkC-neutralizing antibody blocking TrkC-PTPσ interaction and TrkC knockdown reduce glutamatergic synapse formation.\",\n      \"method\": \"Hippocampal neuron-fibroblast coculture screen, co-IP, knockdown, neutralizing antibody, in vivo knockdown\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased screen validated by co-IP, knockdown in culture and in vivo, neutralizing antibody, multiple orthogonal methods\",\n      \"pmids\": [\"21262467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTPσ interacts with postsynaptic NGL-3 via its first two fibronectin III (FNIII) domains. The PTPσ-NGL-3 interaction promotes bidirectional synapse formation, distinguishing PTPσ from PTPδ whose NGL-3 interaction drives only unidirectional presynaptic differentiation.\",\n      \"method\": \"Binding assays mapping domains, heterologous synapse formation assay, domain deletion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapped binding assays plus functional synapse formation assay, single study\",\n      \"pmids\": [\"20139422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"N-cadherin is an in vivo substrate for PTPσ. Using substrate trapping in PTPσ knockout brain lysates, N-cadherin was found hyper-tyrosine-phosphorylated; β-catenin also co-precipitated and was a substrate. DRG neurons from PTPσ-/- mice grow faster on laminin or N-cadherin substrata, and this growth advantage was abolished when N-cadherin function was disrupted.\",\n      \"method\": \"Substrate trapping in knockout brain lysates, mass spectrometry, immunoblotting, DRG neuron growth assays with inhibitory peptide/calcium chelation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — substrate trapping with MS identification, confirmed with loss-of-function rescue experiment and functional phenotype in knockout neurons\",\n      \"pmids\": [\"17060446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of PTPσ increases cellular PtdIns3P levels, hyperactivates both constitutive and induced autophagy, and PTPσ localizes to PtdIns3P-positive membranes; this vesicular localization is enhanced during autophagy. PTPσ acts as a negative regulator of autophagy upstream of Vps34-generated PtdIns3P.\",\n      \"method\": \"RNAi screen of human phosphatases, PtdIns3P imaging, autophagy flux assays, subcellular fractionation/localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi loss-of-function with PtdIns3P measurement and autophagy readouts plus localization, single lab\",\n      \"pmids\": [\"21303930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPσ acts as a presynaptic receptor for glypican-4 (GPC-4) in a heparan sulfate (HS)-dependent manner with nanomolar affinity. PTPσ, GPC-4, and LRRTM4 form a trimeric complex in rat brains. PTPσ knockdown (but not LAR knockdown) reduces LRRTM4 synaptogenic activity, and PTPσ KD decreases excitatory synaptic transmission frequency and amplitude; a HS-binding-defective PTPσ mutant cannot rescue this effect.\",\n      \"method\": \"Affinity binding assays, co-immunoprecipitation from rat brains, single-KD in cultured neurons, heterologous synapse formation, electrophysiology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from native brain tissue, domain-specific mutant rescue, electrophysiological readout, multiple orthogonal methods\",\n      \"pmids\": [\"25624497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NT-3 enhances TrkC binding affinity for PTPσ. At low concentrations, NT-3 enhances TrkC-induced synapse density (dependent on ERK/Akt), while at high concentrations NT-3 abrogates TrkC-induced synapse density increase by additionally activating PLCγ1 and CREB independently of PTPσ. Point mutations disrupting TrkC intracellular signaling, extracellular binding, or kinase activity each compromise TrkC-induced synapse density.\",\n      \"method\": \"Binding affinity measurements, immunoblotting, optogenetics-based NT-3 release, point mutagenesis, synapse density quantification in cultured rat neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple point mutants, quantitative binding and signaling measurements, single lab\",\n      \"pmids\": [\"27122038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPσ binds stably in complexes with TrkA and TrkC but not TrkB; this interaction is mediated at least in part by transmembrane domains. PTPσ dephosphorylates all three Trk receptors and suppresses their phosphorylation in the presence of neurotrophins. Overexpression of PTPσ in primary sensory neurons inhibits neurite outgrowth without affecting short-term survival.\",\n      \"method\": \"Co-IP in transfected HEK293T cells, in vitro dephosphorylation assays, domain deletion constructs, overexpression in primary sensory neurons\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, enzymatic dephosphorylation assay, domain mapping, neuronal overexpression with functional readout, single lab\",\n      \"pmids\": [\"17967490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CSPGs inhibit oligodendrocyte process outgrowth and myelination through PTPσ; RNAi-mediated knockdown of PTPσ or use of PTPσ-/- oligodendrocytes reverses CSPG inhibition of OL process outgrowth and myelination. ROCK inhibition downstream of CSPG/PTPσ also increases OL process outgrowth and myelination.\",\n      \"method\": \"RNAi knockdown, PTPσ-/- oligodendrocyte cultures, Chondroitinase ABC treatment, ROCK inhibitor treatment, myelination assays\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (KO) and RNAi loss-of-function with functional myelination readout, downstream pathway placement via ROCK inhibitor, single lab\",\n      \"pmids\": [\"23588220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPσ interacts with TRKB and restricts TRKB phosphorylation; PTPσ deletion increases TRKB phosphorylation in vitro and in vivo. The antidepressant fluoxetine disrupts the TRKB-PTPσ interaction by binding to the transmembrane domain of TRKB. Chondroitinase ABC treatment increases TRKB phosphorylation, and chondroitinase-induced visual cortical plasticity requires intact TRKB signaling in parvalbumin neurons.\",\n      \"method\": \"Co-IP (PTPσ-TRKB interaction), PTPσ knockout mice (phosphorylation measurements), drug-binding assay (fluoxetine-TM domain), in vivo visual cortex plasticity assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP interaction, KO phenotype measured in vivo, drug mechanism mapped to TM domain, multiple orthogonal methods across in vitro and in vivo\",\n      \"pmids\": [\"33293360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTPRS is specifically expressed on plasmacytoid dendritic cells (pDCs) within the human immune system, functions as an inhibitory receptor, and surface PTPRS is rapidly downregulated after pDC activation. Only PTPRS-negative pDCs produce IFN-α. Antibody-mediated PTPRS crosslinking inhibits pDC activation, whereas PTPRS knockdown enhances IFN response. Haplodeficiency or DC-specific deletion of Ptprs on Ptprf-deficient background leads to enhanced pDC IFN response and mild colitis.\",\n      \"method\": \"Flow cytometry, antibody crosslinking, shRNA knockdown in pDC cell line, conditional and haplodeficient knockout mice\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function approaches, antibody crosslinking, knockout mouse model with tissue phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26231120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPσ knockdown reduces excitatory synapse number and transmission in hippocampal neurons, whereas PTPδ KD reduces inhibitory synapses. Extracellular interactions of PTPσ with Slitrks are required for excitatory synapse development. The intracellular D2 domain of PTPσ is required for heterologous synapse formation induced by Slitrk1 or TrkC. Double-KD of liprin-α2 and -α3, or KD of PTPσ substrates N-cadherin and p250RhoGAP, inhibits Slitrk6-induced, PTPσ-mediated synapse formation.\",\n      \"method\": \"Knockdown in cultured rat hippocampal neurons, rescue with deletion/point mutants and splice variants, heterologous synapse formation assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — extensive structure-function rescue experiments with multiple deletion variants, domain mutants, and double-KD epistasis, single lab but highly systematic\",\n      \"pmids\": [\"29934346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPRS modulates ERK phosphorylation and prevents ERK nuclear translocation in colorectal cancer cells. Native mutations in PTPRS reduce its phosphatase activity while increasing ERK activation and downstream transcriptional signaling.\",\n      \"method\": \"ERK phosphorylation assays, nuclear fractionation, PTPRS mutant expression in cancer cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — phosphatase activity and ERK localization assays, single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"29915291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC activation; PTPRS loss or mutation leads to increased SRC activity, which can be targeted with dasatinib to prevent adaptive resistance.\",\n      \"method\": \"Cell-based resistance assays, SRC activity measurement, combination drug treatment experiments\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell-based assay but mechanism linking PTPRS phosphatase activity to SRC is not rigorously demonstrated in the abstract\",\n      \"pmids\": [\"31827720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPσ small molecule inhibitor DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase RAC1 and induction of BCL-XL. DJ001 antagonizes PTPσ via non-competitive, allosteric binding and promotes HSC regeneration in vivo after irradiation and chemotherapy.\",\n      \"method\": \"In vitro phosphatase assays (competitive vs. allosteric), RAC1 and BCL-XL measurements, in vivo mouse irradiation model with HSC enumeration\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic characterization of binding mode, downstream pathway (RAC1/BCL-XL) identified, in vivo functional validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31413255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPσ-mediated presynaptic differentiation requires interaction with liprin-α; disrupting the PTPσ-liprin-α interaction (but not PTPσ self-dimerization or caskin binding) abolishes presynaptic differentiation. Both the D1 and D2 phosphatase-like domains of PTPσ mediate binding to liprin-α. Phosphatase activity of PTPσ and heparan sulfate binding are dispensable for presynaptic induction.\",\n      \"method\": \"DHFR protein complementation assay, systematic point mutagenesis, molecular replacement (rescue experiments) in neurons\",\n      \"journal\": \"Frontiers in synaptic neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis with functional rescue assays, negative controls (phosphatase-dead mutants), two-domain requirement established, single lab\",\n      \"pmids\": [\"31191292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Presynaptic PTPσ enhances postsynaptic NMDA receptor currents and NMDAR-dependent synaptic plasticity in the hippocampus through adhesion-independent, cytoplasmic domain-dependent mechanisms. Loss of PTPσ strongly increases phosphotyrosine levels of presynaptic proteins including neurexin-1. This PTPσ-dependent NMDAR regulation is important for social and reward-related novelty recognition.\",\n      \"method\": \"PTPσ mutant mice, electrophysiology (NMDAR currents, LTP), phosphotyrosine proteomics, behavioral tests\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — electrophysiology with genetic KO, phosphoproteomics identifying substrates, behavioral validation, multiple orthogonal methods\",\n      \"pmids\": [\"32142410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Collagen XXV directly interacts with PTPσ and PTPδ; this interaction attracts motor axons, but can be inhibited by exogenous PTPσ/δ. Congenital cranial dysinnervation disorder (CCDD) mutations attenuate motor axon attraction by reducing the collagen XXV-PTPσ/δ interaction.\",\n      \"method\": \"In vitro binding assays, cell-based interaction assays, motor explant assays, CCDD mutant constructs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated in vitro, functional motor axon assay, disease mutant validation, single lab\",\n      \"pmids\": [\"31875546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of Ptprs together with Ptprf (LAR) causes craniofacial malformations associated with increased BMP-Smad signaling and abrogation of canonical Wnt/β-catenin signaling. Chemical inhibition of GSK3β rescues Wnt/β-catenin responsiveness in LAR-family phosphatase-deficient cells, indicating RPTPs are required for normal Wnt/β-catenin pathway activation.\",\n      \"method\": \"Double-knockout mouse model, signal transduction analysis (BMP-Smad, Wnt/β-catenin), MEF cultures, GSK3β inhibitor rescue\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with chemical rescue, pathway-level mechanistic placement, but PTPσ effects cannot be fully separated from LAR in the double-KO model\",\n      \"pmids\": [\"23863482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CSPGs regulate microglia through activation of the Rho/ROCK pathway downstream of LAR and PTPσ. Inhibiting LAR and PTPσ reduces M1 microglia/macrophages and promotes M2 phenotype and T regulatory cells, enhancing IL-10 and Arginase-1. PTPσ blockade modulates phagocytosis and mobilization of microglia in vitro.\",\n      \"method\": \"In vivo rat SCI model with ISP/ILP peptide delivery, flow cytometry, Western blotting, primary microglia culture experiments\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — parallel in vivo and in vitro approaches with functional immunological readouts, but LAR and PTPσ targeted together limiting PTPσ-specific attribution\",\n      \"pmids\": [\"29558941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NME2 (nucleoside diphosphate kinase 2) associates with the PTPσ intracellular domain and transduces CSPG inhibitory signals; NME2 knockdown in cortical neurons completely rescues neurite outgrowth inhibition induced by CSPGs.\",\n      \"method\": \"Mass spectrometry screen of PTPσ-associated proteins, co-immunoprecipitation of NME2 with PTPσ intracellular domain in HEK-293T cells, NME2 knockdown in cortical neurons with neurite outgrowth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirmed NME2-PTPσ interaction, functional knockdown rescue experiment, but single lab with limited mechanistic depth\",\n      \"pmids\": [\"26896769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"BMP10 interacts with both PTPRS and STAT3 in the cytoplasm, facilitating dephosphorylation of STAT3 by PTPRS, thereby suppressing STAT3 signaling and HCC cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation of BMP10-PTPRS-STAT3 complex, STAT3 phosphorylation assays, in vitro and in vivo tumor growth assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP identifying trimeric complex, phosphorylation assays demonstrating dephosphorylation, in vitro/in vivo tumor growth with functional consequence, single lab\",\n      \"pmids\": [\"31417183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRRTMs recruit PTPσ to induce presynaptic differentiation through the heparan sulfate (HS) modification of neurexin. PTPσ forms a robust complex with neurexin at presynaptic terminals. LRRTM4 mutant mice unable to bind HS show structural and functional deficits at dentate gyrus excitatory synapses.\",\n      \"method\": \"Binding assays (HS-dependent), co-immunoprecipitation, LRRTM4 knockin mutant mice, synapse structural/functional analysis\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-specific mutant mice, co-IP of PTPσ-neurexin complex, multiple synapse functional/structural readouts, HS-dependency mechanistically defined\",\n      \"pmids\": [\"31995730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Structural determination: the SALM3-PTPσ complex forms a 2:2 trans-heterotetrameric complex as determined by small-angle X-ray scattering; mutational analysis of key interface residues confirmed their importance in cellular binding and synapse formation assays.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS), crystal structure of SALM3 LRR dimer domain, site-directed mutagenesis, cellular binding and synapse formation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SAXS-based complex structure plus mutagenesis validated in functional assays, single lab but multiple orthogonal structural/functional methods\",\n      \"pmids\": [\"32665594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPσ-mediated PI3P regulation controls neurodegeneration in C9ORF72-ALS/FTD: reducing PTPσ elevates PI3P levels, restores early endosomes and lysosomes, and improves survival of poly-GR- and poly-PR-expressing neurons. PTPσ knockdown or inhibition rescues PI3P-endolysosomal defects in C9ORF72-ALS/FTD patient-derived neurons.\",\n      \"method\": \"CRISPRi screening in human-derived neurons, PI3P measurement, endolysosomal assays, patient-derived neuron cultures, in vivo mouse model with PTPσ inhibitor\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPRi screen validated by genetic knockdown and pharmacological inhibition, patient-derived neurons, in vivo mouse rescue, multiple orthogonal methods\",\n      \"pmids\": [\"40073860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Inhibition of CSPG/PTPσ signaling by ISP peptide in oligodendrocyte progenitor cells (OPCs) promotes OPC migration, maturation, and remyelination; a downstream molecular target is upregulation of MMP-2, which allows OPCs to enzymatically digest CSPGs.\",\n      \"method\": \"In vitro OPC migration/differentiation assays, in vivo MS mouse models, MMP-2 activity assays, ISP peptide treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — downstream MMP-2 identified as effector, in vitro and in vivo functional readouts, single lab\",\n      \"pmids\": [\"30297691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CSPG inhibition of neural stem/progenitor cell migration is mediated through PTPσ/α-actinin4 (ACTN4) signaling pathway: CSPG upregulates PTPσ expression and decreases ACTN4 expression, reducing filopodia formation. PTPσ-specific siRNA attenuates this inhibitory effect.\",\n      \"method\": \"Phase-contrast microscopy, transwell assays, immunofluorescence, RT-PCR, Western blot, siRNA knockdown\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA epistasis placing ACTN4 downstream of PTPσ, multiple readouts, single lab\",\n      \"pmids\": [\"30688376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPσ conditional knockout reduces excitatory synapse number, impairs excitatory synaptic transmission, causes abnormal vesicle localization and synaptic ultrastructure, and reduces neurotransmitter release at excitatory synapses. Loss of presynaptic PTPσ in hippocampal CA1 neurons did not affect postsynaptic glutamate receptor responses in subicular neurons.\",\n      \"method\": \"Single conditional knockout mice (PTPσ cKO), electrophysiology, electron microscopy, in vivo innervation analysis\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional single KO mice with electrophysiology, electron microscopy, and in vivo innervation analysis; controls for postsynaptic effects; multiple orthogonal methods\",\n      \"pmids\": [\"32516721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPσ-mediated tyrosine dephosphorylation and multimerization of CASKIN2 are critical for CASKIN2 to regulate excitatory synaptic transmission, NMDAR functions, and activity-dependent presynaptic F-actin rearrangement. CASKIN2 is a substrate/binding partner of PTPσ at hippocampal CA3 Schaffer collateral synapses.\",\n      \"method\": \"Conditional knockout mice for CASKIN1/2, electrophysiology, CASKIN2 phosphorylation and multimerization assays, F-actin imaging, behavioral memory tests\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice with electrophysiology and biochemistry, dephosphorylation mechanistically linked to multimerization and function, multiple orthogonal methods\",\n      \"pmids\": [\"41223222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Antibodies targeting the membrane-proximal fibronectin type III-like 9 (Fn9) domain of PTPRS can activate PTPRS by disrupting its co-localization with syndecan-4 (SDC4) and reducing PTPRS oligomerization. Recombinant Fn9 protein acts as a decoy to disrupt PTPRS-SDC4 co-localization and inhibit FLS migration. This approach shows disease mitigation in a mouse arthritis model.\",\n      \"method\": \"Antibody epitope mapping (Fn9 domain), PTPRS activity assays, co-localization imaging, PTPRS oligomerization assays, FLS migration assays, mouse arthritis model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitope-mapped antibodies with functional activity assays, oligomerization mechanistically linked to regulation, in vivo disease model, single study\",\n      \"pmids\": [\"40651610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Chick PTPσ regulates targeting of retinal axons within the optic tectum; secreted PTPσ ectodomains accumulate at tectal sites containing endogenous PTPσ ligands and cause premature stalling, excessive pretectal arbor formation, and diffuse termination zones of retinal axons, indicating PTPσ signaling is required for sustaining axonal growth and topographic mapping.\",\n      \"method\": \"Retroviral ectopic expression of secretable PTPσ ectodomain in ovo, anterograde labeling of retinal axons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo dominant-negative ectodomain approach with anterograde axon labeling, clean phenotypic readout, single study in chick model\",\n      \"pmids\": [\"12077198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The TrkC-PTPσ trans-synaptic complex governs synapse maturation by regulating synaptic protein phosphorylation. TrkC point mutations that abolish PTPσ binding result in abnormal synaptic vesicle clustering, postsynaptic density elongation, more silent synapses, fewer active synapses with enhanced basal transmission but impaired release probability, and aberrant phosphorylation of synaptic proteins. These effects occur independently of neurotrophin-3 signaling.\",\n      \"method\": \"TrkC knockin mice with PTPσ-binding point mutations, electron microscopy, electrophysiology, phosphoproteomics, behavioral tests\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockin mouse dissecting TrkC-PTPσ from neurotrophin function, electrophysiology, EM ultrastructure, and phosphoproteomics, multiple orthogonal methods\",\n      \"pmids\": [\"39333774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The shorter cPTPσ1 isoform, but not cPTPσ2, binds specifically to developing skeletal myotubes through a mechanism distinct from heparan sulfate binding; most mutations that abolish heparin binding do not affect myotube binding, indicating an isoform-specific, heparan sulfate-independent ligand on myotubes.\",\n      \"method\": \"Ectodomain binding assays on myotubes, heparinase treatment, mutagenesis of heparin-binding residues\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with mutagenesis distinguishing two mechanisms, isoform-specific result, single lab\",\n      \"pmids\": [\"12595237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRS knockdown promotes EGFR expression and phosphorylation in Nf1-deficient Schwann cells, driving epithelial-mesenchymal transition and increased migration; these effects are reversed by EGFR knockdown or EGFR inhibitor, placing PTPRS upstream of EGFR-mediated EMT.\",\n      \"method\": \"RTK assay, Western blotting, PTPRS knockdown and overexpression in Nf1-deficient Schwann cell lines, EGFR knockdown and inhibitor rescue, cell migration assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (PTPRS KD + EGFR KD rescue), RTK phosphorylation assays, functional migration readout, single lab\",\n      \"pmids\": [\"39094827\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRS (PTPσ) is a transmembrane receptor protein tyrosine phosphatase that acts as a high-affinity receptor for chondroitin sulfate proteoglycans (CSPGs) via its Ig1 domain and for heparan sulfate proteoglycans via a basic amino acid domain, transducing inhibitory signals through downstream effectors including Rho/ROCK, NME2, and ACTN4 to suppress axon regeneration, oligodendrocyte myelination, and neural stem cell migration; at synapses, presynaptic PTPσ organizes excitatory presynaptic assembly by binding extracellular ligands (TrkC, NGL-3, Slitrks, GPC-4/LRRTM4, SALM3, collagen XXV, neurexin) and intracellularly coupling to liprin-α and CASKIN2 to regulate neurotransmitter release and NMDAR function, while also dephosphorylating substrates including N-cadherin, β-catenin, Trk neurotrophin receptors, TRKB (regulating critical period plasticity), and STAT3 (suppressing tumor growth); additionally, PTPσ negatively regulates PI3P levels and autophagy, functions as an inhibitory receptor on plasmacytoid dendritic cells to restrain IFN-α production, and undergoes regulated proteolytic shedding of its ectodomain that redistributes the catalytically active intracellular fragment away from cell-cell contacts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPRS (PTPσ) is a transmembrane receptor protein tyrosine phosphatase that serves dual roles as an inhibitory cell-surface receptor for extracellular matrix proteoglycans and as an organizer of synaptic connectivity [#0, #5]. In the injured CNS, PTPσ acts as a high-affinity receptor for chondroitin sulfate proteoglycans (CSPGs) through a defined site on its first Ig-like domain, converting growth cones into a dystrophic state and transducing inhibitory signals that suppress axon regeneration, oligodendrocyte myelination, and neural stem cell migration [#0, #1, #12]; these effects are relayed through Rho/ROCK signaling and intracellular effectors including NME2 and α-actinin-4 (ACTN4), and a wedge-domain peptide mimetic (ISP) relieves this inhibition to restore innervation and functional recovery after spinal cord injury [#1, #12, #24, #30]. As a presynaptic adhesion receptor, PTPσ binds an array of postsynaptic and matrix ligands—TrkC, NGL-3, Slitrks, glypican-4/LRRTM4, SALM3, and collagen XXV—often in a heparan-sulfate-dependent manner, to drive excitatory presynaptic differentiation, neurotransmitter release, and NMDAR-dependent plasticity [#5, #6, #9, #15, #21, #26, #27]. Presynaptic induction requires intracellular coupling to liprin-α and is independent of phosphatase activity, whereas regulation of synaptic transmission and CASKIN2 multimerization depends on its cytoplasmic phosphatase domains [#19, #20, #32]. PTPσ dephosphorylates substrates including N-cadherin and β-catenin, the Trk neurotrophin receptors TrkA/TrkC and TRKB (the latter regulating critical-period plasticity and being disrupted by fluoxetine), and STAT3 to suppress tumor growth [#7, #11, #13, #25]. Beyond the nervous system, PTPσ negatively regulates PtdIns3P levels and autophagy upstream of Vps34, with implications for endolysosomal homeostasis in C9ORF72-ALS/FTD, and functions as an inhibitory receptor on plasmacytoid dendritic cells to restrain IFN-α production [#8, #14, #28]. Its activity is further controlled by regulated ectodomain shedding that redistributes the active intracellular fragment away from cell-cell contacts, and by oligomerization with syndecan-4 [#3, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Establishing that human PTPσ is a catalytically active tyrosine phosphatase with multiple splice isoforms and an intracellular binding partner defined its basic biochemical identity.\",\n      \"evidence\": \"In vitro PTPase assay, LIP.1 co-association, Northern blot isoform analysis\",\n      \"pmids\": [\"8524829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological substrates not identified\", \"Functional role of LIP.1 interaction not pursued\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery of regulated ectodomain shedding and internalization addressed how PTPσ activity and localization are post-translationally controlled.\",\n      \"evidence\": \"Cell-surface processing assays, confocal microscopy, cleavage-site mapping (Pro821/Ile822)\",\n      \"pmids\": [\"9245795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for cleavage not identified\", \"Consequence for downstream signaling not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that a paralog's D2 domain inhibits the PTPσ catalytic D1 domain via the wedge sequence revealed an intermolecular regulatory mechanism for RPTP activity.\",\n      \"evidence\": \"Yeast two-hybrid, mammalian co-precipitation, in vitro phosphatase assay with wedge mutants\",\n      \"pmids\": [\"9566880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of D1-D2 trans-inhibition unclear\", \"Endogenous regulators not established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"In vivo ectodomain perturbation in chick established that PTPσ signaling sustains axonal growth and topographic mapping, linking it to developmental axon guidance.\",\n      \"evidence\": \"Retroviral secretable ectodomain expression in ovo, anterograde retinal axon labeling\",\n      \"pmids\": [\"12077198\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Tectal ligand identity unknown\", \"Downstream signaling not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Substrate trapping in knockout brain identified N-cadherin and β-catenin as in vivo substrates, providing a molecular basis for PTPσ control of neurite growth on adhesive substrata.\",\n      \"evidence\": \"Substrate trapping in PTPσ-/- brain lysates, mass spectrometry, DRG growth assays\",\n      \"pmids\": [\"17060446\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect dephosphorylation of β-catenin not fully resolved\", \"Site-specific phosphotyrosines not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showing PTPσ binds and dephosphorylates TrkA and TrkC (but not TrkB) connected the phosphatase to neurotrophin receptor signaling and neurite outgrowth.\",\n      \"evidence\": \"Co-IP in HEK293T, in vitro dephosphorylation, domain deletion, neuronal overexpression\",\n      \"pmids\": [\"17967490\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TM-mediated interaction mechanism not structurally defined\", \"In vivo substrate validation absent in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identifying PTPσ as a high-affinity CSPG receptor via its Ig1 domain established the receptor that transduces ECM-encoded inhibition of axon regeneration.\",\n      \"evidence\": \"Binding assays, PTPσ-/- neurons, in vivo spinal cord injury in knockout mice\",\n      \"pmids\": [\"19833921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intracellular signaling effectors not yet identified at this stage\", \"Distinction from related RPTP receptors incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping the PTPσ-NGL-3 interaction to FNIII domains and showing bidirectional synaptogenesis positioned PTPσ as a synaptic organizer distinct from its paralog.\",\n      \"evidence\": \"Domain-mapped binding assays, heterologous synapse formation assay\",\n      \"pmids\": [\"20139422\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo requirement not tested\", \"Intracellular coupling not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of TrkC as a neurotrophin-independent trans-synaptic ligand, together with the discovery that PTPσ negatively regulates Vps34-dependent PtdIns3P and autophagy, expanded its roles into synapse formation and membrane trafficking.\",\n      \"evidence\": \"Coculture screen, co-IP, knockdown, neutralizing antibody (TrkC); RNAi phosphatase screen, PtdIns3P imaging, autophagy flux (autophagy)\",\n      \"pmids\": [\"21262467\", \"21303930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PtdIns3P substrate/effector of PTPσ in autophagy not defined\", \"Link between synaptic and autophagy functions unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss-of-function in oligodendrocytes and LAR-family double knockouts extended PTPσ inhibitory signaling to myelination and to Wnt/β-catenin and BMP-Smad developmental pathways.\",\n      \"evidence\": \"RNAi/KO oligodendrocyte cultures with ROCK inhibitor; double-KO mice with GSK3β-inhibitor rescue and signaling analysis\",\n      \"pmids\": [\"23588220\", \"23863482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PTPσ-specific contribution not separable from LAR in double-KO\", \"Direct substrates in Wnt/BMP pathways not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A wedge-domain peptide mimetic (ISP) that relieves CSPG-mediated growth-cone entrapment and restores function provided proof-of-concept that targeting PTPσ promotes recovery after spinal cord injury.\",\n      \"evidence\": \"In vivo rat contusive SCI with systemic ISP delivery, histology, behavioral assays\",\n      \"pmids\": [\"25470046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise molecular mechanism of ISP action on the wedge not fully defined\", \"Downstream effectors not resolved in this study\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Discovery of glypican-4/LRRTM4 as HS-dependent presynaptic ligands and of PTPRS as an inhibitory pDC receptor restraining IFN-α revealed both synaptic and immune signaling roles distinct from CSPG inhibition.\",\n      \"evidence\": \"Affinity binding, native-brain co-IP, KD, electrophysiology (synapse); flow cytometry, antibody crosslinking, shRNA, KO mice (immune)\",\n      \"pmids\": [\"25624497\", \"26231120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"pDC ligand on activating cells not defined\", \"Phosphatase substrates in pDC signaling not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mechanistic dissection of NT-3 modulation of TrkC-PTPσ and identification of NME2 as an intracellular effector clarified ligand-tuning and downstream signal transduction of CSPG inhibition.\",\n      \"evidence\": \"Binding/signaling measurements with optogenetic NT-3 (synapse); MS screen, co-IP, NME2 KD rescue of neurite outgrowth\",\n      \"pmids\": [\"27122038\", \"26896769\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NME2 enzymatic role downstream of PTPσ not defined\", \"Single-lab characterization of NME2 axis\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Systematic structure-function work tied PTPσ-Slitrk binding and the D2 domain to excitatory synapse development, while CSPG/PTPσ signaling was extended to microglial polarization, OPC remyelination via MMP-2, and ERK regulation in colorectal cancer.\",\n      \"evidence\": \"KD/rescue with mutants and electrophysiology (Slitrk); ISP/ILP peptide in SCI and microglia culture; OPC migration with MMP-2 assays; ERK phosphorylation and nuclear fractionation in cancer cells\",\n      \"pmids\": [\"29934346\", \"29558941\", \"30297691\", \"29915291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PTPσ-specific vs LAR contribution to microglia not separated\", \"Direct phosphatase substrate in ERK regulation not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A series of studies defined intracellular coupling to liprin-α as the phosphatase-independent driver of presynaptic differentiation and uncovered additional roles in tumor STAT3 suppression, HSC regeneration via allosteric inhibition, ACTN4-mediated NSPC migration, and collagen XXV-dependent motor axon attraction.\",\n      \"evidence\": \"DHFR complementation and mutagenesis (liprin-α); BMP10-PTPRS-STAT3 co-IP and tumor assays; DJ001 enzymatic and in vivo HSC assays; siRNA epistasis (ACTN4); binding and motor explant assays with CCDD mutants (collagen XXV)\",\n      \"pmids\": [\"31191292\", \"31417183\", \"31413255\", \"30688376\", \"31875546\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism segregating phosphatase-dependent from adhesion functions incomplete\", \"SRC-linked drug resistance mechanism (Low confidence) not rigorously demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo genetic and structural studies established that presynaptic PTPσ controls NMDAR currents, neurotransmitter release, vesicle organization, and synaptic ultrastructure through cytoplasmic-domain mechanisms, dephosphorylating presynaptic substrates including neurexin-1, while also restricting TRKB phosphorylation to gate critical-period plasticity.\",\n      \"evidence\": \"PTPσ mutant/conditional KO mice, electrophysiology, EM, phosphotyrosine proteomics, behavioral tests; SALM3-PTPσ SAXS structure; LRRTM4-neurexin HS knockin mice; TRKB co-IP and fluoxetine TM-binding assay\",\n      \"pmids\": [\"32142410\", \"32516721\", \"32665594\", \"31995730\", \"33293360\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Complete presynaptic substrate set not enumerated\", \"How adhesion and phosphatase activities are coordinated in vivo unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Knockin mice separating TrkC-PTPσ adhesion from neurotrophin signaling demonstrated the complex governs synapse maturation via phosphorylation control, and PTPRS was placed upstream of EGFR-driven EMT in Nf1-deficient Schwann cells.\",\n      \"evidence\": \"TrkC binding-mutant knockin mice, EM, electrophysiology, phosphoproteomics; PTPRS KD/OE with EGFR KD/inhibitor rescue and migration assays\",\n      \"pmids\": [\"39333774\", \"39094827\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phosphatase substrates mediating maturation not fully mapped\", \"Whether EGFR is a direct PTPRS substrate not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Recent work linked PTPσ-mediated PI3P regulation to endolysosomal rescue in C9ORF72-ALS/FTD, defined CASKIN2 as a phosphatase-regulated substrate organizing presynaptic transmission, and developed Fn9-domain antibodies that activate PTPRS by disrupting syndecan-4 co-localization and oligomerization in arthritis.\",\n      \"evidence\": \"CRISPRi screen, PI3P/endolysosomal assays, patient neurons, in vivo inhibitor (C9-ALS); CASKIN1/2 conditional KO, electrophysiology, phospho/multimerization assays; antibody epitope mapping, oligomerization and FLS migration assays, arthritis model\",\n      \"pmids\": [\"40073860\", \"41223222\", \"40651610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PI3P-phosphatase substrate of PTPσ not biochemically defined\", \"How oligomerization state controls catalytic activity not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPσ integrates its dual roles as an extracellular ligand receptor and an intracellular tyrosine phosphatase—and how ectodomain shedding, oligomerization, and ligand binding are coordinated to switch between adhesion and catalytic signaling—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model of full-length receptor signaling states\", \"Complete in vivo substrate map across tissues lacking\", \"Regulation of catalytic activity by ligand engagement not mechanistically resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 11, 13, 25, 32]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 4, 18]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 9, 26, 27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 5, 14, 33]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [5, 15, 20, 31, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 12, 22, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 11, 13, 16, 25]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 28]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [14, 23]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [0, 9, 21, 26]}\n    ],\n    \"complexes\": [\n      \"TrkC-PTPσ trans-synaptic complex\",\n      \"PTPσ-GPC4-LRRTM4 trimeric complex\",\n      \"PTPσ-neurexin presynaptic complex\",\n      \"BMP10-PTPRS-STAT3 complex\"\n    ],\n    \"partners\": [\n      \"TrkC\",\n      \"NGL-3\",\n      \"GPC4\",\n      \"LRRTM4\",\n      \"neurexin-1\",\n      \"liprin-alpha\",\n      \"CASKIN2\",\n      \"SDC4\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}