Affinage

PTPRS

Receptor-type tyrosine-protein phosphatase S · UniProt Q13332

Length
1948 aa
Mass
217.0 kDa
Annotated
2026-06-10
74 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1995 Medium

    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

    PMID:8524829

    Open questions at the time
    • Physiological substrates not identified
    • Functional role of LIP.1 interaction not pursued
  2. 1997 High

    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)

    PMID:9245795

    Open questions at the time
    • Protease responsible for cleavage not identified
    • Consequence for downstream signaling not defined
  3. 1998 High

    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

    PMID:9566880

    Open questions at the time
    • In vivo relevance of D1-D2 trans-inhibition unclear
    • Endogenous regulators not established
  4. 2002 Medium

    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

    PMID:12077198

    Open questions at the time
    • Tectal ligand identity unknown
    • Downstream signaling not defined
  5. 2006 High

    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

    PMID:17060446

    Open questions at the time
    • Direct vs indirect dephosphorylation of β-catenin not fully resolved
    • Site-specific phosphotyrosines not mapped
  6. 2007 Medium

    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

    PMID:17967490

    Open questions at the time
    • TM-mediated interaction mechanism not structurally defined
    • In vivo substrate validation absent in this study
  7. 2009 High

    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

    PMID:19833921

    Open questions at the time
    • Intracellular signaling effectors not yet identified at this stage
    • Distinction from related RPTP receptors incomplete
  8. 2010 Medium

    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

    PMID:20139422

    Open questions at the time
    • In vivo requirement not tested
    • Intracellular coupling not addressed
  9. 2011 High

    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)

    PMID:21262467 PMID:21303930

    Open questions at the time
    • PtdIns3P substrate/effector of PTPσ in autophagy not defined
    • Link between synaptic and autophagy functions unclear
  10. 2013 Medium

    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

    PMID:23588220 PMID:23863482

    Open questions at the time
    • PTPσ-specific contribution not separable from LAR in double-KO
    • Direct substrates in Wnt/BMP pathways not identified
  11. 2014 High

    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

    PMID:25470046

    Open questions at the time
    • Precise molecular mechanism of ISP action on the wedge not fully defined
    • Downstream effectors not resolved in this study
  12. 2015 High

    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)

    PMID:25624497 PMID:26231120

    Open questions at the time
    • pDC ligand on activating cells not defined
    • Phosphatase substrates in pDC signaling not identified
  13. 2016 Medium

    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

    PMID:26896769 PMID:27122038

    Open questions at the time
    • NME2 enzymatic role downstream of PTPσ not defined
    • Single-lab characterization of NME2 axis
  14. 2018 High

    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

    PMID:29558941 PMID:29915291 PMID:29934346 PMID:30297691

    Open questions at the time
    • PTPσ-specific vs LAR contribution to microglia not separated
    • Direct phosphatase substrate in ERK regulation not defined
  15. 2019 High

    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)

    PMID:30688376 PMID:31191292 PMID:31413255 PMID:31417183 PMID:31875546

    Open questions at the time
    • Mechanism segregating phosphatase-dependent from adhesion functions incomplete
    • SRC-linked drug resistance mechanism (Low confidence) not rigorously demonstrated
  16. 2020 High

    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

    PMID:31995730 PMID:32142410 PMID:32516721 PMID:32665594 PMID:33293360

    Open questions at the time
    • Complete presynaptic substrate set not enumerated
    • How adhesion and phosphatase activities are coordinated in vivo unresolved
  17. 2024 High

    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

    PMID:39094827 PMID:39333774

    Open questions at the time
    • Direct phosphatase substrates mediating maturation not fully mapped
    • Whether EGFR is a direct PTPRS substrate not established
  18. 2025 High

    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

    PMID:40073860 PMID:40651610 PMID:41223222

    Open questions at the time
    • Direct PI3P-phosphatase substrate of PTPσ not biochemically defined
    • How oligomerization state controls catalytic activity not fully resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098631 cell adhesion mediator activity 4 GO:0016787 hydrolase activity 3 GO:0008289 lipid binding 2 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-1266738 Developmental Biology 5 R-HSA-162582 Signal Transduction 5 R-HSA-1474244 Extracellular matrix organization 4 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 2
Partners
CASKIN2GPC4LIPRIN-ALPHALRRTM4NEUREXIN-1NGL-3SDC4TRKC
Complex memberships
BMP10-PTPRS-STAT3 complexPTPσ-GPC4-LRRTM4 trimeric complexPTPσ-neurexin presynaptic complexTrkC-PTPσ trans-synaptic complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 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. Binding assays (fusion protein probe), PTPσ-/- neuron culture, in vivo spinal cord injury model with knockout mice Science High 19833921
2014 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. In vivo rat contusive SCI model with systemic peptide delivery (ISP), histology, behavioral assays Nature High 25470046
1998 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). Yeast two-hybrid screen, co-precipitation from mammalian cells, in vitro phosphatase assay against p-nitrophenylphosphate Molecular and cellular biology High 9566880
1997 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. Cell surface processing assays, confocal microscopy, identification of cleavage site by site mapping The Journal of cell biology High 9245795
1995 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. In vitro PTPase assay, co-association assay with LIP.1, Northern blot for isoform characterization Proceedings of the National Academy of Sciences of the United States of America Medium 8524829
2011 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. Hippocampal neuron-fibroblast coculture screen, co-IP, knockdown, neutralizing antibody, in vivo knockdown Neuron High 21262467
2010 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. Binding assays mapping domains, heterologous synapse formation assay, domain deletion constructs The Journal of biological chemistry Medium 20139422
2006 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. Substrate trapping in knockout brain lysates, mass spectrometry, immunoblotting, DRG neuron growth assays with inhibitory peptide/calcium chelation Molecular and cellular biology High 17060446
2011 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. RNAi screen of human phosphatases, PtdIns3P imaging, autophagy flux assays, subcellular fractionation/localization Journal of cell science Medium 21303930
2015 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. Affinity binding assays, co-immunoprecipitation from rat brains, single-KD in cultured neurons, heterologous synapse formation, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 25624497
2016 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. Binding affinity measurements, immunoblotting, optogenetics-based NT-3 release, point mutagenesis, synapse density quantification in cultured rat neurons The Journal of neuroscience Medium 27122038
2007 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. Co-IP in transfected HEK293T cells, in vitro dephosphorylation assays, domain deletion constructs, overexpression in primary sensory neurons Biochimica et biophysica acta Medium 17967490
2013 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. RNAi knockdown, PTPσ-/- oligodendrocyte cultures, Chondroitinase ABC treatment, ROCK inhibitor treatment, myelination assays Experimental neurology Medium 23588220
2020 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. Co-IP (PTPσ-TRKB interaction), PTPσ knockout mice (phosphorylation measurements), drug-binding assay (fluoxetine-TM domain), in vivo visual cortex plasticity assays The Journal of neuroscience High 33293360
2015 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. Flow cytometry, antibody crosslinking, shRNA knockdown in pDC cell line, conditional and haplodeficient knockout mice Immunity High 26231120
2018 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. Knockdown in cultured rat hippocampal neurons, rescue with deletion/point mutants and splice variants, heterologous synapse formation assays The Journal of neuroscience High 29934346
2018 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. ERK phosphorylation assays, nuclear fractionation, PTPRS mutant expression in cancer cells Scientific reports Medium 29915291
2019 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. Cell-based resistance assays, SRC activity measurement, combination drug treatment experiments Oncotarget Low 31827720
2019 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. In vitro phosphatase assays (competitive vs. allosteric), RAC1 and BCL-XL measurements, in vivo mouse irradiation model with HSC enumeration Nature communications High 31413255
2019 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. DHFR protein complementation assay, systematic point mutagenesis, molecular replacement (rescue experiments) in neurons Frontiers in synaptic neuroscience High 31191292
2020 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. PTPσ mutant mice, electrophysiology (NMDAR currents, LTP), phosphotyrosine proteomics, behavioral tests eLife High 32142410
2019 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. In vitro binding assays, cell-based interaction assays, motor explant assays, CCDD mutant constructs Cell reports Medium 31875546
2013 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. Double-knockout mouse model, signal transduction analysis (BMP-Smad, Wnt/β-catenin), MEF cultures, GSK3β inhibitor rescue Development Medium 23863482
2018 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. In vivo rat SCI model with ISP/ILP peptide delivery, flow cytometry, Western blotting, primary microglia culture experiments Journal of neuroinflammation Medium 29558941
2016 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. 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 Biochemical and biophysical research communications Medium 26896769
2019 BMP10 interacts with both PTPRS and STAT3 in the cytoplasm, facilitating dephosphorylation of STAT3 by PTPRS, thereby suppressing STAT3 signaling and HCC cell proliferation. Co-immunoprecipitation of BMP10-PTPRS-STAT3 complex, STAT3 phosphorylation assays, in vitro and in vivo tumor growth assays Oncogene Medium 31417183
2020 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. Binding assays (HS-dependent), co-immunoprecipitation, LRRTM4 knockin mutant mice, synapse structural/functional analysis Neuron High 31995730
2020 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. Small-angle X-ray scattering (SAXS), crystal structure of SALM3 LRR dimer domain, site-directed mutagenesis, cellular binding and synapse formation assays Scientific reports High 32665594
2025 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. CRISPRi screening in human-derived neurons, PI3P measurement, endolysosomal assays, patient-derived neuron cultures, in vivo mouse model with PTPσ inhibitor Neuron High 40073860
2018 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. In vitro OPC migration/differentiation assays, in vivo MS mouse models, MMP-2 activity assays, ISP peptide treatment Nature communications Medium 30297691
2019 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. Phase-contrast microscopy, transwell assays, immunofluorescence, RT-PCR, Western blot, siRNA knockdown Journal of cellular biochemistry Medium 30688376
2020 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. Single conditional knockout mice (PTPσ cKO), electrophysiology, electron microscopy, in vivo innervation analysis iScience High 32516721
2025 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. Conditional knockout mice for CASKIN1/2, electrophysiology, CASKIN2 phosphorylation and multimerization assays, F-actin imaging, behavioral memory tests Proceedings of the National Academy of Sciences of the United States of America High 41223222
2025 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. Antibody epitope mapping (Fn9 domain), PTPRS activity assays, co-localization imaging, PTPRS oligomerization assays, FLS migration assays, mouse arthritis model The Journal of biological chemistry Medium 40651610
2002 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. Retroviral ectopic expression of secretable PTPσ ectodomain in ovo, anterograde labeling of retinal axons The Journal of neuroscience Medium 12077198
2024 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. TrkC knockin mice with PTPσ-binding point mutations, electron microscopy, electrophysiology, phosphoproteomics, behavioral tests The EMBO journal High 39333774
2003 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. Ectodomain binding assays on myotubes, heparinase treatment, mutagenesis of heparin-binding residues Molecular and cellular neurosciences Medium 12595237
2024 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. RTK assay, Western blotting, PTPRS knockdown and overexpression in Nf1-deficient Schwann cell lines, EGFR knockdown and inhibitor rescue, cell migration assays Cancer letters Medium 39094827

Source papers

Stage 0 corpus · 74 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science (New York, N.Y.) 540 19833921
2014 Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury. Nature 375 25470046
2013 Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization. Trends in neurosciences 220 23835198
1995 The LAR/PTP delta/PTP sigma subfamily of transmembrane protein-tyrosine-phosphatases: multiple human LAR, PTP delta, and PTP sigma isoforms are expressed in a tissue-specific manner and associate with the LAR-interacting protein LIP.1. Proceedings of the National Academy of Sciences of the United States of America 188 8524829
2011 Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex. Neuron 170 21262467
1997 Cellular redistribution of protein tyrosine phosphatases LAR and PTPsigma by inducible proteolytic processing. The Journal of cell biology 143 9245795
2010 Trans-synaptic adhesions between netrin-G ligand-3 (NGL-3) and receptor tyrosine phosphatases LAR, protein-tyrosine phosphatase delta (PTPdelta), and PTPsigma via specific domains regulate excitatory synapse formation. The Journal of biological chemistry 126 20139422
2013 Chondroitin sulfate proteoglycans inhibit oligodendrocyte myelination through PTPσ. Experimental neurology 114 23588220
1999 Neuronal defects and posterior pituitary hypoplasia in mice lacking the receptor tyrosine phosphatase PTPsigma. Nature genetics 114 10080192
1998 The second catalytic domain of protein tyrosine phosphatase delta (PTP delta) binds to and inhibits the first catalytic domain of PTP sigma. Molecular and cellular biology 90 9566880
2011 Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers. Proceedings of the National Academy of Sciences of the United States of America 88 22065749
2015 PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission. Proceedings of the National Academy of Sciences of the United States of America 86 25624497
2018 Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPσ receptors promotes a beneficial inflammatory response following spinal cord injury. Journal of neuroinflammation 85 29558941
2016 Neurotrophin-3 Regulates Synapse Development by Modulating TrkC-PTPσ Synaptic Adhesion and Intracellular Signaling Pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 61 27122038
2018 Modulation of proteoglycan receptor PTPσ enhances MMP-2 activity to promote recovery from multiple sclerosis. Nature communications 60 30297691
2015 Protein Tyrosine Phosphatase PTPRS Is an Inhibitory Receptor on Human and Murine Plasmacytoid Dendritic Cells. Immunity 55 26231120
2006 N-cadherin is an in vivo substrate for protein tyrosine phosphatase sigma (PTPsigma) and participates in PTPsigma-mediated inhibition of axon growth. Molecular and cellular biology 52 17060446
2011 Identification of PTPsigma as an autophagic phosphatase. Journal of cell science 51 21303930
2020 LRRTMs Organize Synapses through Differential Engagement of Neurexin and PTPσ. Neuron 47 31995730
2018 PTPσ Drives Excitatory Presynaptic Assembly via Various Extracellular and Intracellular Mechanisms. The Journal of neuroscience : the official journal of the Society for Neuroscience 47 29934346
2018 LAR and PTPσ receptors are negative regulators of oligodendrogenesis and oligodendrocyte integrity in spinal cord injury. Glia 47 30394599
2020 Chondroitinase and Antidepressants Promote Plasticity by Releasing TRKB from Dephosphorylating Control of PTPσ in Parvalbumin Neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 33293360
2020 Regulation of autophagy by inhibitory CSPG interactions with receptor PTPσ and its impact on plasticity and regeneration after spinal cord injury. Experimental neurology 43 32145250
2002 Overexpression of protein-tyrosine phosphatase PTP sigma is linked to impaired glucose-induced insulin secretion in hereditary diabetic Goto-Kakizaki rats. Biochemical and biophysical research communications 39 11866457
2022 Inhibition of CSPG receptor PTPσ promotes migration of newly born neuroblasts, axonal sprouting, and recovery from stroke. Cell reports 37 35905716
2007 PTPsigma binds and dephosphorylates neurotrophin receptors and can suppress NGF-dependent neurite outgrowth from sensory neurons. Biochimica et biophysica acta 37 17967490
2015 Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPσ. Scientific reports 35 26464223
2017 PTPRS and PER3 methylation levels are associated with childhood obesity: results from a genome-wide methylation analysis. Pediatric obesity 32 28614626
2002 Chick PTPsigma regulates the targeting of retinal axons within the optic tectum. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 12077198
2019 PTPσ inhibitors promote hematopoietic stem cell regeneration. Nature communications 31 31413255
2019 Mechanisms of PTPσ-Mediated Presynaptic Differentiation. Frontiers in synaptic neuroscience 27 31191292
2020 Presynaptic PTPσ regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms. eLife 26 32142410
2019 Roles of Collagen XXV and Its Putative Receptors PTPσ/δ in Intramuscular Motor Innervation and Congenital Cranial Dysinnervation Disorder. Cell reports 26 31875546
2013 Inactivation of LAR family phosphatase genes Ptprs and Ptprf causes craniofacial malformations resembling Pierre-Robin sequence. Development (Cambridge, England) 26 23863482
2021 Intact synapse structure and function after combined knockout of PTPδ, PTPσ, and LAR. eLife 25 33656439
2022 Suppressing CSPG/LAR/PTPσ Axis Facilitates Neuronal Replacement and Synaptogenesis by Human Neural Precursor Grafts and Improves Recovery after Spinal Cord Injury. The Journal of neuroscience : the official journal of the Society for Neuroscience 24 35256527
2003 Isoform-specific binding of the tyrosine phosphatase PTPsigma to a ligand in developing muscle. Molecular and cellular neurosciences 24 12595237
2018 PTPRS Regulates Colorectal Cancer RAS Pathway Activity by Inactivating Erk and Preventing Its Nuclear Translocation. Scientific reports 21 29915291
2014 Selective expression of CSPG receptors PTPσ and LAR in poorly regenerating reticulospinal neurons of lamprey. The Journal of comparative neurology 21 24357129
2012 Identification of small molecule inhibitors of PTPσ through an integrative virtual and biochemical approach. PloS one 20 23185579
2020 PTPσ Controls Presynaptic Organization of Neurotransmitter Release Machinery at Excitatory Synapses. iScience 18 32516721
2019 Modulating proteoglycan receptor PTPσ using intracellular sigma peptide improves remyelination and functional recovery in mice with demyelinated optic chiasm. Molecular and cellular neurosciences 18 31276750
2022 Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice. Journal of neuroinflammation 17 35982473
2021 Perineuronal Net Receptor PTPσ Regulates Retention of Memories. Frontiers in synaptic neuroscience 15 34366821
2024 Schwann Cell-Derived Exosomes Induced Axon Growth after Spinal Cord Injury by Decreasing PTP-σ Activation on CSPGs via the Rho/ROCK Pathway. Neurochemical research 14 38819695
2018 Targeting proteoglycan receptor PTPσ restores sensory function after spinal cord dorsal root injury by activation of Erks/CREB signaling pathway. Neuropharmacology 14 30393073
2019 Chondroitin sulfate proteoglycan represses neural stem/progenitor cells migration via PTPσ/α-actinin4 signaling pathway. Journal of cellular biochemistry 13 30688376
2019 BMP10 suppresses hepatocellular carcinoma progression via PTPRS-STAT3 axis. Oncogene 13 31417183
2018 Recovery after spinal cord injury by modulation of the proteoglycan receptor PTPσ. Experimental neurology 13 30118740
1996 Physical mapping of receptor type protein tyrosine phosphatase sigma (PTPRS) to human chromosome 19p13.3. Genomics 12 8954782
2023 Recovery of Forearm and Fine Digit Function After Chronic Spinal Cord Injury by Simultaneous Blockade of Inhibitory Matrix Chondroitin Sulfate Proteoglycan Production and the Receptor PTPσ. Journal of neurotrauma 11 37606910
2022 Small Molecules Targeting PTPσ-Trk Interactions Promote Sympathetic Nerve Regeneration. ACS chemical neuroscience 11 35156811
2005 PTPsigma promotes retinal neurite outgrowth non-cell-autonomously. Journal of neurobiology 11 16003721
2019 PTPRS drives adaptive resistance to MEK/ERK inhibitors through SRC. Oncotarget 10 31827720
2024 PTPRS is a novel marker for early Tau pathology and synaptic integrity in Alzheimer's disease. Scientific reports 8 38926456
2020 PTPσ Knockdown in Lampreys Impairs Reticulospinal Axon Regeneration and Neuronal Survival After Spinal Cord Injury. Frontiers in cellular neuroscience 8 32265663
2025 PTPσ-mediated PI3P regulation modulates neurodegeneration in C9ORF72-ALS/FTD. Neuron 7 40073860
2024 Reduced PTPRS expression promotes epithelial-mesenchymal transition of Schwann cells in NF1-related plexiform neurofibromas. Cancer letters 7 39094827
2008 Apical junction complex proteins and ulcerative colitis: a focus on the PTPRS gene. Expert review of molecular diagnostics 7 18598228
2024 Inhibition of CSPG-PTPσ Activates Autophagy Flux and Lysosome Fusion, Aids Axon and Synaptic Reorganization in Spinal Cord Injury. Molecular neurobiology 6 38900368
2022 Distinct transcriptomic profile of small arteries of hypertensive patients with chronic kidney disease identified miR-338-3p targeting GPX3 and PTPRS. Journal of hypertension 6 35703228
2020 Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ. Scientific reports 6 32665594
2024 Loss of PTPRS elicits potent metastatic capability and resistance to temozolomide in glioblastoma. Molecular carcinogenesis 5 38517048
2023 Inhibition of the proteoglycan receptor PTPσ promotes functional recovery on a rodent model of preterm hypoxic-ischemic brain injury. Experimental neurology 5 37806512
2024 Calycosin promotes axon growth by inhibiting PTPRS and alleviates spinal cord injury. Journal of molecular neuroscience : MN 4 38904846
2016 NME2 associates with PTPσ to transduce signals from chondroitin sulfate proteoglycans. Biochemical and biophysical research communications 3 26896769
2024 Mass Spectrometry-Based Proteomics Analysis Unveils PTPRS Inhibits Proliferation and Inflammatory Response of Keratinocytes in Psoriasis. Inflammation 2 38739342
2024 The TrkC-PTPσ complex governs synapse maturation and anxiogenic avoidance via synaptic protein phosphorylation. The EMBO journal 2 39333774
2025 CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses. Proceedings of the National Academy of Sciences of the United States of America 1 41223222
2025 Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway. Neurobiology of disease 0 40623478
2025 Modulation of the PTPRS proteoglycan switch by antibodies binding to the membrane-proximal fibronectin-type III domain. The Journal of biological chemistry 0 40651610
2025 Structure-Based Engineering of a PTPsigma Ectodomain for Enhanced Solubility and Productivity. International journal of molecular sciences 0 40943264
2024 PTPRS is a novel marker for early tau pathology and synaptic integrity in Alzheimer's disease. bioRxiv : the preprint server for biology 0 38766183
2022 Crystallization and low-resolution structure solution of the SALM3-PTPσ synaptic adhesion complex. Acta crystallographica. Section F, Structural biology communications 0 34981774

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