{"gene":"PTPN23","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2008,"finding":"HD-PTP/PTPN23 is required for endosomal cargo sorting and multivesicular body morphogenesis; its Bro1 domain is essential for function, and ESCRT-III binding correlates with full biological activity. Depletion causes accumulation of ubiquitinated proteins on endosomal compartments and disrupts MVB morphogenesis.","method":"RNAi depletion in mammalian cells, RNAi-resistant rescue with HD-PTP mutants, fluorescence microscopy, electron microscopy","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal rescue experiments with domain mutants, multiple orthogonal readouts, replicated by subsequent studies","pmids":["18434552"],"is_preprint":false},{"year":2013,"finding":"HD-PTP acts as a central coordinator of the ESCRT pathway for EGFR sorting: (1) the HD-PTP Bro1 domain binds the core domain of STAM2 (ESCRT-0), competed by CHMP4B (ESCRT-III) at an overlapping site; (2) a proline-rich peptide in HD-PTP binds the SH3 domain of STAM2; (3) HD-PTP recruits UBPY/USP8 to deubiquitinate EGFR, with UBPY interacting with HD-PTP-bound CHMP4B and with HD-PTP directly; concerted CHMP4B/UBPY recruitment displaces ESCRT-0 from cargo in favor of ESCRT-III.","method":"Co-immunoprecipitation, pulldown assays, RNAi depletion, fluorescence microscopy, EGFR trafficking assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal binding and functional assays, mechanistic model validated with domain-specific interactions and competition experiments","pmids":["23477725"],"is_preprint":false},{"year":2011,"finding":"PTPN23 suppression in mammary epithelial cells increases E-cadherin internalization, impairs early endosome trafficking of E-cadherin, elevates SRC and β-catenin activity, and promotes cell invasion. SRC, E-cadherin, and β-catenin were identified as direct substrates of PTPN23. Inhibition of SRC blocked the invasive effects of PTPN23 depletion.","method":"RNAi loss-of-function screen, shRNA knockdown, phosphorylation assays, migration/invasion assays, SRC inhibitor epistasis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic loss-of-function with substrate identification, epistasis with SRC inhibitor, multiple orthogonal readouts","pmids":["21724833"],"is_preprint":false},{"year":2006,"finding":"HD-PTP interacts with CHMP4b/Shax1 (ESCRT-III), TSG101 (ESCRT-I), endophilin A1, and ALG-2 via its Bro1 domain and proline-rich region. Interaction with ALG-2 is Ca2+-dependent; interaction with TSG101 is Ca2+-independent (unlike Alix). HD-PTP does not interact with CIN85.","method":"Yeast two-hybrid, Strep-tag pulldown from HEK293T cell lysates, Western blotting","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown and Y2H, two orthogonal methods, single lab","pmids":["17174262"],"is_preprint":false},{"year":2009,"finding":"HD-PTP is catalytically inactive as a tyrosine phosphatase due to evolutionary divergence of a key catalytic residue in its phosphatase domain; back-mutation of this residue restores tyrosine phosphatase activity. HD-PTP also lacks lipid phosphatase activity. Its colony growth reduction activity is independent of catalytic PTP activity.","method":"In vitro enzymatic assay using DiFMUP substrate and phosphoinositide phosphates, site-directed mutagenesis, colony formation assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro enzymatic analysis with mutagenesis rescue, single lab with multiple substrates tested","pmids":["19340315"],"is_preprint":false},{"year":2011,"finding":"Myopic (Drosophila HD-PTP ortholog) regulates the Salvador/Warts/Hippo pathway by binding Yorkie via PPxY motifs interacting with Yorkie WW domains; Myopic colocalizes with Yorkie at endosomes and controls Yorkie endosomal association and protein levels, influencing expression of some Yorkie target genes.","method":"Genetic screen, co-immunoprecipitation, colocalization by fluorescence microscopy, in vivo Drosophila genetics","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Drosophila combined with co-IP and colocalization, single lab","pmids":["21571226"],"is_preprint":false},{"year":2016,"finding":"Haploinsufficiency of HD-PTP/PTPN23 in mice promotes tumor formation (lung adenoma, B cell lymphoma) and enhances integrin β1-dependent lymphoma survival and dissemination, consistent with a role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion.","method":"Mouse Ptpn23+/- heterozygous knockout model, tumor monitoring, integrin trafficking assays, cell migration assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function with defined tumor phenotype, integrin trafficking readout, single lab with multiple models","pmids":["27210750"],"is_preprint":false},{"year":2015,"finding":"HD-PTP acts as an alternative to ESCRT-II and VPS20/CHMP6 as a link between ESCRT-I and ESCRT-III in the non-canonical ESCRT pathway used for sorting virally ubiquitinated (K63-linked) MHC class I into MVBs for lysosomal degradation.","method":"RNAi-mediated depletion of individual ESCRT proteins, rescue experiments with WT and mutant HD-PTP, flow cytometry for cell-surface MHC class I","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — systematic RNAi depletion of multiple ESCRT components with defined epistatic relationship, rescue with mutants, single lab","pmids":["26221024"],"is_preprint":false},{"year":2016,"finding":"Crystal structure of the HD-PTP Bro1 domain in complex with the STAM2 core region revealed that STAM2 binds the hydrophobic concave pocket of the Bro1 domain in the opposite orientation compared to CHMP4B binding to Alix/Brox. Thr145 of HD-PTP (vs. Lys151 of Alix) is a determinant residue enabling STAM2 binding; Alix- or Brox-mimicking mutations at this position abolish STAM2 interaction.","method":"X-ray crystallography, site-directed mutagenesis, binding assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with mutagenesis validation, single lab but rigorous structural and biochemical analysis","pmids":["26866605"],"is_preprint":false},{"year":2017,"finding":"HD-PTP adopts an open and extended conformation (determined by SAXS and hydrodynamic analysis), optimal for simultaneous interactions with multiple ESCRTs, contrasting with the compact conformation of Alix. This open conformation is functionally competent for binding cellular ESCRT partners.","method":"Small angle X-ray scattering (SAXS), hydrodynamic analyses, binding assays with cellular partners","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural analysis by SAXS with functional binding validation, single lab","pmids":["28831121"],"is_preprint":false},{"year":2017,"finding":"SARA and endofin bind with high affinity to the conserved hydrophobic region of the HD-PTP Bro1 domain (the same site as CHMP4/ESCRT-III) and compete with CHMP4 for this site. The interaction is specific to HD-PTP among Bro1 proteins due to a neighboring pocket unique to HD-PTP. Crystal structures of HD-PTPBro1 with SARA, endofin, and three CHMP4 isoforms were determined.","method":"X-ray crystallography, mutagenesis, binding/competition assays, co-immunoprecipitation","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures plus mutagenesis and competition binding, single lab, multiple orthogonal methods","pmids":["28602823"],"is_preprint":false},{"year":2014,"finding":"PTPN23/HD-PTP interacts with SMN and regulates SMN complex localization: PTPN23 knockdown reduces SMN accumulation in Cajal bodies and alters the phosphorylation pattern of SMN without affecting SMN complex assembly. PTPN23 shuttles between nucleus and cytoplasm.","method":"Systematic phosphatase RNAi screen, SMN-Cajal body accumulation assay, co-immunoprecipitation, phosphorylation analysis, subcellular fractionation/imaging","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic screen plus co-IP and phosphorylation readout, single lab, two orthogonal methods","pmids":["25392300"],"is_preprint":false},{"year":2007,"finding":"HD-PTP binds Focal Adhesion Kinase (FAK) in endothelial cells; this interaction is inhibited by bFGF treatment. In cells depleted of HD-PTP, FAK is hyperphosphorylated on tyrosine residues and localizes in focal adhesions at the leading edge, promoting cell migration.","method":"siRNA knockdown, co-immunoprecipitation, immunofluorescence, migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus functional migration readout and localization, single lab, two orthogonal methods","pmids":["17959146"],"is_preprint":false},{"year":2008,"finding":"Src binds HD-PTP in endothelial cells; this interaction is enhanced by bFGF. Src phosphorylates HD-PTP on tyrosine residues, which inhibits HD-PTP's enzymatic (phosphatase) activity. HD-PTP does not modulate Src phosphorylation levels.","method":"Co-immunoprecipitation, in vitro phosphorylation assay, tyrosine phosphatase activity assay, RNAi, pharmacological Src inhibition","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase and phosphatase assays plus co-IP and functional readout, single lab","pmids":["18762272"],"is_preprint":false},{"year":2008,"finding":"In T24 bladder carcinoma cells, Src binds and phosphorylates HD-PTP on tyrosine residues upon EGF stimulation; FAK also binds and phosphorylates HD-PTP, reducing the HD-PTP–FAK interaction. HD-PTP depletion enhances FAK phosphorylation and its localization in focal complexes, promoting migration in a Src-dependent manner.","method":"RNAi, co-immunoprecipitation, phosphorylation assays, pharmacological Src inhibition, immunofluorescence, migration assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and phosphorylation assays with functional epistasis using Src inhibitor, single lab","pmids":["18835089"],"is_preprint":false},{"year":2019,"finding":"HD-PTP is required for ephrin-B2:EphB2 signaling: HD-PTP associates with EphB2 (identified by BioID and confirmed by co-IP). HD-PTP loss attenuates ephrin-B2-induced EphB2 clustering and EphB2/Src family kinase activation, accelerates ligand-induced EphB2 degradation, and impairs axonal growth cone collapse and spinal motor neuron axon guidance in vivo.","method":"BioID proximity labeling, co-immunoprecipitation, RNAi knockdown, cell collapse assay, in vivo chick spinal motor neuron axon guidance","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — BioID plus co-IP plus in vivo axon guidance phenotype, multiple orthogonal methods, single lab","pmids":["31420572"],"is_preprint":false},{"year":2020,"finding":"PTPN23 binds the N-terminus of the dynein adaptor BICD1 (not as canonical cargo); loss of PTPN23 leads to accumulation of BDNF-activated p75NTR and TrkB in swollen vacuole-like compartments, identifying PTPN23 as a regulator of endocytic sorting of neurotrophin receptors in motor neurons.","method":"Proteomics/mass spectrometry of BICD1 interactome, molecular mapping, RNAi knockdown, fluorescence microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS interactome identification with domain mapping and loss-of-function cellular phenotype, single lab","pmids":["32079660"],"is_preprint":false},{"year":2021,"finding":"Endofin forms a complex with ESCRT constituents including HD-PTP and is required for HD-PTP/ESCRT-0-interdependent sorting of ubiquitinated transmembrane cargoes (integrin α5, EGFR). Mutants with impaired Endofin/HD-PTP association or cytosolic Endofin fail to restore EGFR lysosomal delivery. Endofin also promotes indirect interaction between Hrs (ESCRT-0) and HD-PTP.","method":"Proximity biotinylation (BioID), co-immunoprecipitation, RNAi depletion, complementation with mutants, receptor trafficking assays, cell migration assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — BioID plus co-IP plus rescue with mutants plus trafficking readout, multiple orthogonal methods, single lab","pmids":["34761192"],"is_preprint":false},{"year":2022,"finding":"HD-PTP Bro1 domain directly interacts with the HAV capsid pX export signal (confirmed by co-IP with recombinant proteins and biotin-tagged peptides). RNAi-mediated depletion of HD-PTP impedes quasi-enveloped HAV (eHAV) release. HD-PTP and ALIX activities are non-redundant and both required for eHAV release.","method":"Co-immunoprecipitation with recombinant proteins, biotin-tagged peptide pulldown, RNAi depletion, super-resolution fluorescence microscopy, quantitative virus release assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct binding with recombinant proteins, multiple binding assays, functional RNAi readout, single lab with orthogonal methods","pmids":["35969644"],"is_preprint":false},{"year":2023,"finding":"WDR4-based Cullin 4 ubiquitin ligase ubiquitinates PTPN23, leading to its proteasomal degradation, thereby suppressing lysosomal trafficking and degradation of EGFR (WT, mutant) and c-MET. A competing peptide blocking PTPN23–WDR4 interaction restores EGFR/c-MET degradation.","method":"Unbiased ubiquitylome mass spectrometry, co-immunoprecipitation, proteasome inhibitor assays, receptor trafficking/degradation assays, competitive peptide intervention","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ubiquitylome MS identification with mechanistic follow-up, co-IP, and functional rescue, single lab with multiple orthogonal methods","pmids":["37821451"],"is_preprint":false},{"year":2024,"finding":"PTPN23 is essential for cardiac T-tubule formation and maintenance along Z-discs. PTPN23 interacts with sarcomeric α-actinin and dystrophin and promotes assembly of the dystrophin-glycoprotein complex (DGC) at costameres. Deletion of α-actinin alters PTPN23 subcellular localization; genetic inactivation of dystrophin causes similar T-tubule defects without affecting PTPN23 localization at Z-discs.","method":"Cardiomyocyte-specific Cre/LoxP and CRISPR/Cas9 knockout mice, AAV9-mediated mosaic mutagenesis, glycerol-gradient fractionation, co-immunoprecipitation, electron microscopy, T-tubule fluorescence staining","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple genetic mouse models, biochemical fractionation, and structural imaging with multiple orthogonal approaches, single lab","pmids":["38214189"],"is_preprint":false},{"year":2024,"finding":"PTPN23-dependent ESCRT machinery functions as a cell death checkpoint: loss of PTPN23 causes accumulation of death receptors (TNFR1) and TLRs in endosomes, activating NF-κB, apoptotic, necroptotic, and pyroptotic pathways. NAK-associated protein 1 (NAP1) interacts with PTPN23 to facilitate endosomal sorting of TNFR1, sensitizing cells to TNF-α-induced cytotoxicity.","method":"CRISPR screen in AML cells, proximity-dependent biotin labeling (BioID), co-immunoprecipitation, receptor localization imaging, cell death assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — CRISPR screen plus BioID interactomics plus co-IP plus functional cell death assays, single lab, multiple orthogonal methods","pmids":["39609437"],"is_preprint":false},{"year":2025,"finding":"PTPN23 bridges ESCRT-I and ESCRT-III (instead of ESCRT-II) to mediate endosomal microautophagy of ubiquitylated tau (tauRD) aggregates. ESCRT-I subunit TSG101 recognizes polyubiquitinated tauRD via its UEV domain; PTPN23 acts as the adaptor linking ESCRT-I to ESCRT-III for microautophagic engulfment. A disease-associated UBAP1 mutation disrupts UBAP1–PTPN23 interaction and impairs tau clearance.","method":"Genome-wide CRISPR knockout screen, co-immunoprecipitation, domain mapping, fluorescence microscopy, tau aggregate degradation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — unbiased genome-wide CRISPR screen with mechanistic co-IP and domain-mapping follow-up, single lab, multiple orthogonal methods","pmids":["40197510"],"is_preprint":false},{"year":2025,"finding":"PTPN23 activates PI3KC2α by inducing WNK3-mediated phosphorylation of PI3KC2α at Ser329, enhancing PI3KC2α catalytic activity at endosomes, increasing PI(3,4)P2 production and subsequent AKT2 activation to support BRAF-mutant cancer cell survival. PTPN23 catalytic activity is not required for this function.","method":"RNAi/CRISPR knockdown, in vitro kinase assay, PI lipid mass spectrometry, co-immunoprecipitation, mouse melanoma models","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus lipidomics plus co-IP plus in vivo validation, single lab, multiple orthogonal methods","pmids":["39841180"],"is_preprint":false},{"year":2026,"finding":"PTPN23 is required for constitutive secretion from the trans-Golgi network: loss of PTPN23 (and ESCRT subunits CHMP1 and VPS4) disrupts tubule fission from the trans-Golgi and impairs delivery of cargo to the plasma membrane, as well as constitutive secretion of soluble cargoes and endogenous hormones/antibodies in specialized cells.","method":"Affinity isolation of post-Golgi carriers with mass spectrometry, pooled CRISPR-KO screen, live-cell imaging of trans-Golgi tubules, cargo secretion assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pooled CRISPR screen with mechanistic live-imaging and secretion assay validation, multiple orthogonal methods, single lab","pmids":["41848521"],"is_preprint":false},{"year":2012,"finding":"HD-PTP undergoes calcium-dependent proteolytic degradation by calpains in T24 bladder carcinoma cells; calpain inhibition prevents this degradation and causes redistribution of HD-PTP to the cell periphery.","method":"Calpain inhibitor treatment, calcium manipulation, Western blotting, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological inhibitor evidence plus redistribution readout, single lab, two orthogonal readouts","pmids":["22510412"],"is_preprint":false},{"year":2006,"finding":"HD-PTP protein is degraded via the proteasome system in response to FGF-2 in endothelial cells; VEGF does not affect HD-PTP protein levels.","method":"Proteasome inhibitor treatment, Western blotting, growth factor stimulation","journal":"Frontiers in bioscience : a journal and virtual library","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (pharmacological inhibitor + Western blot), no mechanistic detail of ubiquitin ligase","pmids":["16720300"],"is_preprint":false},{"year":2024,"finding":"A PTPN23 variant (rs6780013, p.Thr) binds EGFR and modulates its phosphorylation at Thr699, substantially inhibiting ESCC cell proliferation in vitro and in vivo.","method":"Co-immunoprecipitation, in vitro and in vivo proliferation assays, phosphorylation analysis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP plus functional assay showing variant-specific EGFR phosphorylation, single lab, limited mechanistic detail","pmids":["38704135"],"is_preprint":false},{"year":2018,"finding":"Myopic (HD-PTP/PTPN23 Drosophila ortholog) selectively inhibits activity-induced Ca2+-dependent neuropeptide (DCV) release at the NMJ without affecting small synaptic vesicle (SSV) release. This function does not require interaction with ESCRT-III protein CHMP4/Shrub. Presynaptic Myopic is abundant at early endosomes.","method":"Transgenic overexpression/knockdown in Drosophila NMJ, optical imaging of synaptic neuropeptide release, DCV counting, genetic rescue with CHMP4-interaction mutants","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Drosophila gain/loss-of-function with functional secretion readout and domain-specific rescue, single lab","pmids":["29378961"],"is_preprint":false},{"year":2021,"finding":"PTPN23 acts as a cofactor for HIV-1 Vpu-directed degradation of BST-2 and decrease of CD4 at the cell surface by supporting ESCRT-dependent sorting at multivesicular bodies; identified as part of the Vpu proximal proteome by APEX2 proximity labeling.","method":"APEX2 proximity proteomics, hierarchical clustering, RNAi depletion, flow cytometry for cell-surface protein levels","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics with functional RNAi validation, single lab","pmids":["34843601"],"is_preprint":false},{"year":2024,"finding":"HD-PTP hypomorphic mice with reduced protein expression develop lipodystrophy, decreased receptor-mediated EGFR signaling in white adipose tissue (decreased trans-autophosphorylation and downstream effector activation despite normal EGF binding), decreased plasma membrane cholesterol, and increased lysosomal cholesterol, attributable to defective endosomal maturation and cholesterol trafficking.","method":"Hypomorphic mouse model, adipose tissue signaling assays, cholesterol fractionation, in vitro EGFR assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model with biochemical dissection of signaling and cholesterol trafficking, single lab","pmids":["39155850"],"is_preprint":false}],"current_model":"PTPN23/HD-PTP is a catalytically inactive pseudophosphatase that functions as a master coordinator of the ESCRT pathway: its open, extended Bro1 domain simultaneously engages ESCRT-0 (via STAM2), ESCRT-I (via TSG101), and ESCRT-III (via CHMP4B) to drive ubiquitinated cargo (EGFR, integrins, death receptors, neurotrophin receptors, tau aggregates) from early endosomes into multivesicular body intraluminal vesicles for lysosomal degradation; it recruits the deubiquitinase UBPY/USP8 to transfer cargo from ESCRT-0 to ESCRT-III, acts as a non-canonical ESCRT-II substitute bridging ESCRT-I to ESCRT-III, mediates endosomal microautophagy of ubiquitylated aggregates, and also functions at the trans-Golgi to enable constitutive secretion; beyond endosomes, PTPN23 promotes DGC assembly at cardiac costameres, controls SMN phosphorylation and Cajal body localization, activates a WNK3–PI3KC2α–AKT2 survival axis at endosomes, and is itself regulated by WDR4-mediated ubiquitination/proteasomal degradation and by calpain-dependent calcium-regulated proteolysis."},"narrative":{"mechanistic_narrative":"PTPN23/HD-PTP is a catalytically inactive pseudophosphatase that serves as a central coordinator of the ESCRT pathway, driving the endosomal sorting of ubiquitinated transmembrane cargo into multivesicular bodies for lysosomal degradation [PMID:18434552, PMID:19340315]. Its Bro1 domain is the functional hub: it adopts an open, extended conformation optimal for simultaneous engagement of multiple ESCRT components [PMID:28831121], binding ESCRT-0 (STAM2 core, via a hydrophobic pocket that orients STAM2 oppositely to CHMP4B on Alix/Brox), ESCRT-I (TSG101), and ESCRT-III (CHMP4B), with overlapping binding sites enabling competitive handoff [PMID:23477725, PMID:17174262, PMID:26866605]. PTPN23 recruits the deubiquitinase UBPY/USP8 and coordinately displaces ESCRT-0 in favor of ESCRT-III to transfer cargo such as EGFR [PMID:23477725], and it can act as a non-canonical substitute for ESCRT-II, bridging ESCRT-I directly to ESCRT-III for sorting of cargoes including MHC class I and ubiquitylated tau aggregates [PMID:26221024, PMID:40197510]. Through this machinery PTPN23 governs the fate of diverse receptors — EGFR, integrins, death receptors (TNFR1) and TLRs, and neurotrophin receptors — thereby attenuating downstream signaling, suppressing invasion and tumorigenesis, and acting as a cell-death checkpoint [PMID:21724833, PMID:27210750, PMID:39609437, PMID:32079660]. PTPN23 also functions beyond endosomes: it is essential for cardiac T-tubule formation, interacting with sarcomeric α-actinin and dystrophin to promote dystrophin-glycoprotein complex assembly at costameres [PMID:38214189], is required for constitutive secretion via tubule fission at the trans-Golgi network [PMID:41848521], and activates a WNK3–PI3KC2α–AKT2 endosomal survival axis independently of its catalytic activity [PMID:39841180]. PTPN23 levels are controlled by WDR4–Cullin 4-mediated ubiquitination and proteasomal degradation, which restrains EGFR and c-MET turnover [PMID:37821451].","teleology":[{"year":2008,"claim":"Established PTPN23 as a required factor for endosomal cargo sorting and MVB morphogenesis, defining its core cellular role and the indispensability of its Bro1 domain.","evidence":"RNAi depletion with domain-mutant rescue and EM/fluorescence imaging in mammalian cells","pmids":["18434552"],"confidence":"High","gaps":["Did not resolve which ESCRT contacts are direct versus indirect","Catalytic status of the phosphatase domain not yet defined"]},{"year":2009,"claim":"Resolved the paradox of a phosphatase-named protein lacking enzymatic activity by showing PTPN23 is a catalytically dead pseudophosphatase whose biological activity is catalysis-independent.","evidence":"In vitro DiFMUP and phosphoinositide assays with catalytic back-mutation and colony formation assay","pmids":["19340315"],"confidence":"High","gaps":["Did not establish what the divergent phosphatase domain does instead","No structural basis for the scaffolding function"]},{"year":2006,"claim":"Mapped the first Bro1-domain interaction network, distinguishing PTPN23 from Alix by Ca2+-independent TSG101 binding and lack of CIN85 interaction.","evidence":"Yeast two-hybrid and Strep-tag pulldowns from HEK293T lysates","pmids":["17174262"],"confidence":"Medium","gaps":["Binding affinities and stoichiometry not quantified","Functional consequence of ALG-2 Ca2+-dependence untested"]},{"year":2013,"claim":"Built the mechanistic model of PTPN23 as a coordinator that hands EGFR cargo from ESCRT-0 to ESCRT-III, including recruitment of the deubiquitinase UBPY/USP8.","evidence":"Co-IP, pulldowns, competition assays, RNAi, and EGFR trafficking readouts","pmids":["23477725"],"confidence":"High","gaps":["Temporal order of competition events on endosomes not directly visualized","Did not address cargoes other than EGFR"]},{"year":2011,"claim":"Connected PTPN23 endosomal function to tumor suppression by showing it controls E-cadherin trafficking and restrains SRC/β-catenin-driven invasion.","evidence":"RNAi loss-of-function screen, substrate phosphorylation assays, invasion assays, and SRC-inhibitor epistasis in mammary epithelial cells","pmids":["21724833"],"confidence":"High","gaps":["Reconciliation with catalytic inactivity (substrate dephosphorylation claim) not addressed","Direct versus trafficking-mediated effects on substrates not separated"]},{"year":2015,"claim":"Demonstrated PTPN23 can substitute for ESCRT-II/VPS20 as a non-canonical ESCRT-I–ESCRT-III bridge, generalizing its adaptor role to virally ubiquitinated MHC class I.","evidence":"Systematic RNAi of individual ESCRT components with WT/mutant rescue and flow cytometry","pmids":["26221024"],"confidence":"High","gaps":["Did not define when the non-canonical versus canonical route is selected","Structural basis of ESCRT-I bridging not resolved here"]},{"year":2016,"claim":"Provided the atomic basis for ESCRT-0 engagement, showing STAM2 binds the Bro1 hydrophobic pocket in an orientation opposite to CHMP4B with Thr145 as the determinant residue.","evidence":"X-ray crystallography of the Bro1–STAM2 complex with mutagenesis","pmids":["26866605"],"confidence":"High","gaps":["Full-length complex architecture not captured","Dynamics of STAM2/CHMP4B exchange not directly observed"]},{"year":2016,"claim":"Linked PTPN23 dosage to in vivo tumor suppression and integrin recycling, validating its physiological role in restraining migration and invasion.","evidence":"Ptpn23+/- mouse tumor monitoring with integrin trafficking and migration assays","pmids":["27210750"],"confidence":"High","gaps":["Cell-type origin of tumors not dissected","Direct integrin sorting mechanism in vivo not shown"]},{"year":2017,"claim":"Defined the conformational logic enabling simultaneous multi-ESCRT engagement, showing PTPN23 is extended and open unlike compact Alix.","evidence":"SAXS, hydrodynamic analysis, and binding assays with cellular partners","pmids":["28831121"],"confidence":"High","gaps":["High-resolution full-length structure absent","Conformational regulation on membranes untested"]},{"year":2017,"claim":"Identified SARA and endofin as HD-PTP-specific Bro1 ligands competing with CHMP4 at the same site, revealing a unique neighboring pocket distinguishing PTPN23.","evidence":"Crystal structures of Bro1 with SARA, endofin, and three CHMP4 isoforms plus competition assays","pmids":["28602823"],"confidence":"High","gaps":["Cellular role of SARA/endofin competition not resolved here","How competing ligands are ordered in time unknown"]},{"year":2021,"claim":"Placed endofin as a functional partner linking PTPN23 to ESCRT-0 (Hrs) for sorting of ubiquitinated integrin α5 and EGFR.","evidence":"BioID, co-IP, RNAi with mutant complementation, and receptor trafficking/migration assays","pmids":["34761192"],"confidence":"High","gaps":["Whether endofin is universally required or cargo-selective unclear","Quantitative contribution versus direct STAM2/TSG101 routes not partitioned"]},{"year":2014,"claim":"Extended PTPN23 function to the nucleus, showing it shuttles and regulates SMN phosphorylation and Cajal body localization.","evidence":"Phosphatase RNAi screen, Cajal body accumulation assay, co-IP, phosphorylation analysis, fractionation","pmids":["25392300"],"confidence":"Medium","gaps":["Mechanism linking endosomal scaffold to nuclear SMN regulation unknown","Whether effect is direct given catalytic inactivity unresolved"]},{"year":2007,"claim":"Implicated PTPN23 in adhesion signaling by showing it binds FAK and restrains FAK tyrosine phosphorylation and migration in endothelial cells.","evidence":"siRNA, co-IP, immunofluorescence, and migration assays","pmids":["17959146"],"confidence":"Medium","gaps":["Direct dephosphorylation excluded by later catalytic-dead finding","Mechanism of FAK regulation (scaffold versus trafficking) unclear"]},{"year":2008,"claim":"Showed reciprocal regulation by Src, which phosphorylates and inhibits PTPN23, positioning it downstream of growth-factor signaling.","evidence":"Co-IP, in vitro phosphorylation, phosphatase activity assay, RNAi, Src inhibition","pmids":["18762272","18835089"],"confidence":"Medium","gaps":["Reconciliation with catalytic inactivity of the PTP domain","Phosphosites on PTPN23 not mapped"]},{"year":2019,"claim":"Established a role in neuronal receptor signaling, showing PTPN23 sustains EphB2 clustering/activation and controls axon guidance.","evidence":"BioID, co-IP, RNAi, collapse assay, in vivo chick motor neuron axon guidance","pmids":["31420572"],"confidence":"High","gaps":["How PTPN23 promotes clustering rather than only degradation unclear","Direct versus ESCRT-mediated effect on EphB2 not separated"]},{"year":2020,"claim":"Identified PTPN23 as a regulator of neurotrophin receptor (p75NTR/TrkB) endocytic sorting through interaction with the dynein adaptor BICD1.","evidence":"BICD1 interactome MS, domain mapping, RNAi, fluorescence microscopy in motor neurons","pmids":["32079660"],"confidence":"Medium","gaps":["Functional significance of BICD1 binding (non-cargo) undefined","Link to motor transport versus sorting not resolved"]},{"year":2024,"claim":"Revealed an unanticipated structural role in cardiac muscle, with PTPN23 required for T-tubule formation and DGC assembly at costameres via α-actinin and dystrophin interactions.","evidence":"Cardiomyocyte conditional/CRISPR knockout mice, AAV9 mosaics, fractionation, co-IP, EM, T-tubule imaging","pmids":["38214189"],"confidence":"High","gaps":["Whether ESCRT activity underlies the costamere role unclear","Mechanism of membrane tubule shaping at Z-discs not defined"]},{"year":2024,"claim":"Defined PTPN23/ESCRT as a cell-death checkpoint by sorting death receptors and TLRs, with NAP1 facilitating TNFR1 endosomal sorting.","evidence":"CRISPR screen in AML cells, BioID, co-IP, receptor imaging, cell death assays","pmids":["39609437"],"confidence":"High","gaps":["Whether NAP1 acts on cargoes beyond TNFR1 unknown","Selectivity of death-receptor versus other cargo sorting not resolved"]},{"year":2025,"claim":"Showed PTPN23 mediates endosomal microautophagy of tau aggregates by bridging TSG101-recognized polyubiquitinated tau to ESCRT-III, linking it to disease via UBAP1.","evidence":"Genome-wide CRISPR screen, co-IP, domain mapping, microscopy, tau degradation assay","pmids":["40197510"],"confidence":"High","gaps":["In vivo relevance to tauopathy clearance not tested","Distinction between microautophagy and canonical ILV pathway not fully resolved"]},{"year":2025,"claim":"Uncovered a catalysis-independent signaling output: PTPN23 drives WNK3-dependent PI3KC2α phosphorylation to fuel PI(3,4)P2/AKT2 survival signaling at endosomes.","evidence":"RNAi/CRISPR, in vitro kinase assay, PI lipidomics, co-IP, mouse melanoma models","pmids":["39841180"],"confidence":"High","gaps":["How PTPN23 induces WNK3 activity mechanistically unclear","Relationship of this axis to ESCRT sorting unresolved"]},{"year":2026,"claim":"Extended ESCRT-dependent PTPN23 function to the secretory pathway, showing it is required for trans-Golgi tubule fission and constitutive secretion.","evidence":"Post-Golgi carrier affinity-MS, pooled CRISPR screen, live-cell TGN imaging, secretion assays","pmids":["41848521"],"confidence":"High","gaps":["Direct membrane-fission contacts at the TGN not defined","Whether the same Bro1 contacts operate at the Golgi unknown"]},{"year":2023,"claim":"Identified the upstream control of PTPN23 abundance, showing WDR4–Cullin 4 ubiquitinates PTPN23 to restrain EGFR/c-MET degradation.","evidence":"Ubiquitylome MS, co-IP, proteasome inhibition, degradation assays, competitive peptide","pmids":["37821451"],"confidence":"High","gaps":["Physiological context regulating WDR4 activity unknown","Ubiquitination sites on PTPN23 not detailed"]},{"year":null,"claim":"How PTPN23's many roles — endosomal sorting, costamere assembly, TGN secretion, nuclear SMN regulation, and the catalysis-independent WNK3–PI3KC2α axis — are coordinated and selectively deployed in different tissues remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unifying model linking endosomal scaffolding to non-endosomal functions","Tissue-specific partner repertoire not mapped","No human Mendelian disease directly attributed to PTPN23 in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,7,8,9,17,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,21,23]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[20]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,5,17,21,28]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,7,22,24]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,24]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,15,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[21]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,20,22]}],"complexes":["ESCRT machinery","dystrophin-glycoprotein complex (DGC)"],"partners":["STAM2","TSG101","CHMP4B","USP8","UBAP1","PI3KC2A","ACTN2","DMD"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H3S7","full_name":"Tyrosine-protein phosphatase non-receptor type 23","aliases":["His domain-containing protein tyrosine phosphatase","HD-PTP","Protein tyrosine phosphatase TD14","PTP-TD14"],"length_aa":1636,"mass_kda":179.0,"function":"Plays a role in sorting of endocytic ubiquitinated cargos into multivesicular bodies (MVBs) via its interaction with the ESCRT-I complex (endosomal sorting complex required for transport I), and possibly also other ESCRT complexes (PubMed:18434552, PubMed:21757351). May act as a negative regulator of Ras-mediated mitogenic activity (PubMed:18434552). Plays a role in ciliogenesis (PubMed:20393563)","subcellular_location":"Nucleus; Cytoplasm; Cytoplasmic vesicle; Endosome; Cytoplasm, cytoskeleton, cilium basal body; Early endosome","url":"https://www.uniprot.org/uniprotkb/Q9H3S7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPN23","classification":"Common Essential","n_dependent_lines":1145,"n_total_lines":1208,"dependency_fraction":0.9478476821192053},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"MIF","stoichiometry":0.2},{"gene":"SLK","stoichiometry":0.2},{"gene":"SNX12","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PTPN23","total_profiled":1310},"omim":[{"mim_id":"618890","title":"NEURODEVELOPMENTAL DISORDER AND STRUCTURAL BRAIN ANOMALIES WITH OR WITHOUT SEIZURES AND SPASTICITY; NEDBASS","url":"https://www.omim.org/entry/618890"},{"mim_id":"609787","title":"UBIQUITIN-ASSOCIATED PROTEIN 1; UBAP1","url":"https://www.omim.org/entry/609787"},{"mim_id":"606584","title":"PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 23; PTPN23","url":"https://www.omim.org/entry/606584"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPN23"},"hgnc":{"alias_symbol":["DKFZP564F0923","KIAA1471","HD-PTP"],"prev_symbol":[]},"alphafold":{"accession":"Q9H3S7","domains":[{"cath_id":"1.25.40.280","chopping":"2-198","consensus_level":"medium","plddt":94.7697,"start":2,"end":198},{"cath_id":"1.25.40.280","chopping":"199-338","consensus_level":"medium","plddt":96.2519,"start":199,"end":338},{"cath_id":"3.90.190.10","chopping":"1188-1461","consensus_level":"high","plddt":92.5132,"start":1188,"end":1461}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3S7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3S7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H3S7-F1-predicted_aligned_error_v6.png","plddt_mean":69.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPN23","jax_strain_url":"https://www.jax.org/strain/search?query=PTPN23"},"sequence":{"accession":"Q9H3S7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H3S7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H3S7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H3S7"}},"corpus_meta":[{"pmid":"18434552","id":"PMC_18434552","title":"The 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endosomal cargo sorting and multivesicular body morphogenesis; its Bro1 domain is essential for function, and ESCRT-III binding correlates with full biological activity. Depletion causes accumulation of ubiquitinated proteins on endosomal compartments and disrupts MVB morphogenesis.\",\n      \"method\": \"RNAi depletion in mammalian cells, RNAi-resistant rescue with HD-PTP mutants, fluorescence microscopy, electron microscopy\",\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 rescue experiments with domain mutants, multiple orthogonal readouts, replicated by subsequent studies\",\n      \"pmids\": [\"18434552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HD-PTP acts as a central coordinator of the ESCRT pathway for EGFR sorting: (1) the HD-PTP Bro1 domain binds the core domain of STAM2 (ESCRT-0), competed by CHMP4B (ESCRT-III) at an overlapping site; (2) a proline-rich peptide in HD-PTP binds the SH3 domain of STAM2; (3) HD-PTP recruits UBPY/USP8 to deubiquitinate EGFR, with UBPY interacting with HD-PTP-bound CHMP4B and with HD-PTP directly; concerted CHMP4B/UBPY recruitment displaces ESCRT-0 from cargo in favor of ESCRT-III.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, RNAi depletion, fluorescence microscopy, EGFR trafficking assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal binding and functional assays, mechanistic model validated with domain-specific interactions and competition experiments\",\n      \"pmids\": [\"23477725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTPN23 suppression in mammary epithelial cells increases E-cadherin internalization, impairs early endosome trafficking of E-cadherin, elevates SRC and β-catenin activity, and promotes cell invasion. SRC, E-cadherin, and β-catenin were identified as direct substrates of PTPN23. Inhibition of SRC blocked the invasive effects of PTPN23 depletion.\",\n      \"method\": \"RNAi loss-of-function screen, shRNA knockdown, phosphorylation assays, migration/invasion assays, SRC inhibitor epistasis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic loss-of-function with substrate identification, epistasis with SRC inhibitor, multiple orthogonal readouts\",\n      \"pmids\": [\"21724833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HD-PTP interacts with CHMP4b/Shax1 (ESCRT-III), TSG101 (ESCRT-I), endophilin A1, and ALG-2 via its Bro1 domain and proline-rich region. Interaction with ALG-2 is Ca2+-dependent; interaction with TSG101 is Ca2+-independent (unlike Alix). HD-PTP does not interact with CIN85.\",\n      \"method\": \"Yeast two-hybrid, Strep-tag pulldown from HEK293T cell lysates, Western blotting\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown and Y2H, two orthogonal methods, single lab\",\n      \"pmids\": [\"17174262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HD-PTP is catalytically inactive as a tyrosine phosphatase due to evolutionary divergence of a key catalytic residue in its phosphatase domain; back-mutation of this residue restores tyrosine phosphatase activity. HD-PTP also lacks lipid phosphatase activity. Its colony growth reduction activity is independent of catalytic PTP activity.\",\n      \"method\": \"In vitro enzymatic assay using DiFMUP substrate and phosphoinositide phosphates, site-directed mutagenesis, colony formation assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro enzymatic analysis with mutagenesis rescue, single lab with multiple substrates tested\",\n      \"pmids\": [\"19340315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Myopic (Drosophila HD-PTP ortholog) regulates the Salvador/Warts/Hippo pathway by binding Yorkie via PPxY motifs interacting with Yorkie WW domains; Myopic colocalizes with Yorkie at endosomes and controls Yorkie endosomal association and protein levels, influencing expression of some Yorkie target genes.\",\n      \"method\": \"Genetic screen, co-immunoprecipitation, colocalization by fluorescence microscopy, in vivo Drosophila genetics\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Drosophila combined with co-IP and colocalization, single lab\",\n      \"pmids\": [\"21571226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Haploinsufficiency of HD-PTP/PTPN23 in mice promotes tumor formation (lung adenoma, B cell lymphoma) and enhances integrin β1-dependent lymphoma survival and dissemination, consistent with a role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion.\",\n      \"method\": \"Mouse Ptpn23+/- heterozygous knockout model, tumor monitoring, integrin trafficking assays, cell migration assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function with defined tumor phenotype, integrin trafficking readout, single lab with multiple models\",\n      \"pmids\": [\"27210750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HD-PTP acts as an alternative to ESCRT-II and VPS20/CHMP6 as a link between ESCRT-I and ESCRT-III in the non-canonical ESCRT pathway used for sorting virally ubiquitinated (K63-linked) MHC class I into MVBs for lysosomal degradation.\",\n      \"method\": \"RNAi-mediated depletion of individual ESCRT proteins, rescue experiments with WT and mutant HD-PTP, flow cytometry for cell-surface MHC class I\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNAi depletion of multiple ESCRT components with defined epistatic relationship, rescue with mutants, single lab\",\n      \"pmids\": [\"26221024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structure of the HD-PTP Bro1 domain in complex with the STAM2 core region revealed that STAM2 binds the hydrophobic concave pocket of the Bro1 domain in the opposite orientation compared to CHMP4B binding to Alix/Brox. Thr145 of HD-PTP (vs. Lys151 of Alix) is a determinant residue enabling STAM2 binding; Alix- or Brox-mimicking mutations at this position abolish STAM2 interaction.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with mutagenesis validation, single lab but rigorous structural and biochemical analysis\",\n      \"pmids\": [\"26866605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HD-PTP adopts an open and extended conformation (determined by SAXS and hydrodynamic analysis), optimal for simultaneous interactions with multiple ESCRTs, contrasting with the compact conformation of Alix. This open conformation is functionally competent for binding cellular ESCRT partners.\",\n      \"method\": \"Small angle X-ray scattering (SAXS), hydrodynamic analyses, binding assays with cellular partners\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural analysis by SAXS with functional binding validation, single lab\",\n      \"pmids\": [\"28831121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SARA and endofin bind with high affinity to the conserved hydrophobic region of the HD-PTP Bro1 domain (the same site as CHMP4/ESCRT-III) and compete with CHMP4 for this site. The interaction is specific to HD-PTP among Bro1 proteins due to a neighboring pocket unique to HD-PTP. Crystal structures of HD-PTPBro1 with SARA, endofin, and three CHMP4 isoforms were determined.\",\n      \"method\": \"X-ray crystallography, mutagenesis, binding/competition assays, co-immunoprecipitation\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures plus mutagenesis and competition binding, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"28602823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN23/HD-PTP interacts with SMN and regulates SMN complex localization: PTPN23 knockdown reduces SMN accumulation in Cajal bodies and alters the phosphorylation pattern of SMN without affecting SMN complex assembly. PTPN23 shuttles between nucleus and cytoplasm.\",\n      \"method\": \"Systematic phosphatase RNAi screen, SMN-Cajal body accumulation assay, co-immunoprecipitation, phosphorylation analysis, subcellular fractionation/imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic screen plus co-IP and phosphorylation readout, single lab, two orthogonal methods\",\n      \"pmids\": [\"25392300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HD-PTP binds Focal Adhesion Kinase (FAK) in endothelial cells; this interaction is inhibited by bFGF treatment. In cells depleted of HD-PTP, FAK is hyperphosphorylated on tyrosine residues and localizes in focal adhesions at the leading edge, promoting cell migration.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, immunofluorescence, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus functional migration readout and localization, single lab, two orthogonal methods\",\n      \"pmids\": [\"17959146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Src binds HD-PTP in endothelial cells; this interaction is enhanced by bFGF. Src phosphorylates HD-PTP on tyrosine residues, which inhibits HD-PTP's enzymatic (phosphatase) activity. HD-PTP does not modulate Src phosphorylation levels.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphorylation assay, tyrosine phosphatase activity assay, RNAi, pharmacological Src inhibition\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase and phosphatase assays plus co-IP and functional readout, single lab\",\n      \"pmids\": [\"18762272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In T24 bladder carcinoma cells, Src binds and phosphorylates HD-PTP on tyrosine residues upon EGF stimulation; FAK also binds and phosphorylates HD-PTP, reducing the HD-PTP–FAK interaction. HD-PTP depletion enhances FAK phosphorylation and its localization in focal complexes, promoting migration in a Src-dependent manner.\",\n      \"method\": \"RNAi, co-immunoprecipitation, phosphorylation assays, pharmacological Src inhibition, immunofluorescence, migration assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and phosphorylation assays with functional epistasis using Src inhibitor, single lab\",\n      \"pmids\": [\"18835089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HD-PTP is required for ephrin-B2:EphB2 signaling: HD-PTP associates with EphB2 (identified by BioID and confirmed by co-IP). HD-PTP loss attenuates ephrin-B2-induced EphB2 clustering and EphB2/Src family kinase activation, accelerates ligand-induced EphB2 degradation, and impairs axonal growth cone collapse and spinal motor neuron axon guidance in vivo.\",\n      \"method\": \"BioID proximity labeling, co-immunoprecipitation, RNAi knockdown, cell collapse assay, in vivo chick spinal motor neuron axon guidance\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID plus co-IP plus in vivo axon guidance phenotype, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"31420572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN23 binds the N-terminus of the dynein adaptor BICD1 (not as canonical cargo); loss of PTPN23 leads to accumulation of BDNF-activated p75NTR and TrkB in swollen vacuole-like compartments, identifying PTPN23 as a regulator of endocytic sorting of neurotrophin receptors in motor neurons.\",\n      \"method\": \"Proteomics/mass spectrometry of BICD1 interactome, molecular mapping, RNAi knockdown, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS interactome identification with domain mapping and loss-of-function cellular phenotype, single lab\",\n      \"pmids\": [\"32079660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Endofin forms a complex with ESCRT constituents including HD-PTP and is required for HD-PTP/ESCRT-0-interdependent sorting of ubiquitinated transmembrane cargoes (integrin α5, EGFR). Mutants with impaired Endofin/HD-PTP association or cytosolic Endofin fail to restore EGFR lysosomal delivery. Endofin also promotes indirect interaction between Hrs (ESCRT-0) and HD-PTP.\",\n      \"method\": \"Proximity biotinylation (BioID), co-immunoprecipitation, RNAi depletion, complementation with mutants, receptor trafficking assays, cell migration assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID plus co-IP plus rescue with mutants plus trafficking readout, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"34761192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HD-PTP Bro1 domain directly interacts with the HAV capsid pX export signal (confirmed by co-IP with recombinant proteins and biotin-tagged peptides). RNAi-mediated depletion of HD-PTP impedes quasi-enveloped HAV (eHAV) release. HD-PTP and ALIX activities are non-redundant and both required for eHAV release.\",\n      \"method\": \"Co-immunoprecipitation with recombinant proteins, biotin-tagged peptide pulldown, RNAi depletion, super-resolution fluorescence microscopy, quantitative virus release assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct binding with recombinant proteins, multiple binding assays, functional RNAi readout, single lab with orthogonal methods\",\n      \"pmids\": [\"35969644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WDR4-based Cullin 4 ubiquitin ligase ubiquitinates PTPN23, leading to its proteasomal degradation, thereby suppressing lysosomal trafficking and degradation of EGFR (WT, mutant) and c-MET. A competing peptide blocking PTPN23–WDR4 interaction restores EGFR/c-MET degradation.\",\n      \"method\": \"Unbiased ubiquitylome mass spectrometry, co-immunoprecipitation, proteasome inhibitor assays, receptor trafficking/degradation assays, competitive peptide intervention\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ubiquitylome MS identification with mechanistic follow-up, co-IP, and functional rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37821451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPN23 is essential for cardiac T-tubule formation and maintenance along Z-discs. PTPN23 interacts with sarcomeric α-actinin and dystrophin and promotes assembly of the dystrophin-glycoprotein complex (DGC) at costameres. Deletion of α-actinin alters PTPN23 subcellular localization; genetic inactivation of dystrophin causes similar T-tubule defects without affecting PTPN23 localization at Z-discs.\",\n      \"method\": \"Cardiomyocyte-specific Cre/LoxP and CRISPR/Cas9 knockout mice, AAV9-mediated mosaic mutagenesis, glycerol-gradient fractionation, co-immunoprecipitation, electron microscopy, T-tubule fluorescence staining\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple genetic mouse models, biochemical fractionation, and structural imaging with multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"38214189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPN23-dependent ESCRT machinery functions as a cell death checkpoint: loss of PTPN23 causes accumulation of death receptors (TNFR1) and TLRs in endosomes, activating NF-κB, apoptotic, necroptotic, and pyroptotic pathways. NAK-associated protein 1 (NAP1) interacts with PTPN23 to facilitate endosomal sorting of TNFR1, sensitizing cells to TNF-α-induced cytotoxicity.\",\n      \"method\": \"CRISPR screen in AML cells, proximity-dependent biotin labeling (BioID), co-immunoprecipitation, receptor localization imaging, cell death assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen plus BioID interactomics plus co-IP plus functional cell death assays, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39609437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN23 bridges ESCRT-I and ESCRT-III (instead of ESCRT-II) to mediate endosomal microautophagy of ubiquitylated tau (tauRD) aggregates. ESCRT-I subunit TSG101 recognizes polyubiquitinated tauRD via its UEV domain; PTPN23 acts as the adaptor linking ESCRT-I to ESCRT-III for microautophagic engulfment. A disease-associated UBAP1 mutation disrupts UBAP1–PTPN23 interaction and impairs tau clearance.\",\n      \"method\": \"Genome-wide CRISPR knockout screen, co-immunoprecipitation, domain mapping, fluorescence microscopy, tau aggregate degradation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased genome-wide CRISPR screen with mechanistic co-IP and domain-mapping follow-up, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40197510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN23 activates PI3KC2α by inducing WNK3-mediated phosphorylation of PI3KC2α at Ser329, enhancing PI3KC2α catalytic activity at endosomes, increasing PI(3,4)P2 production and subsequent AKT2 activation to support BRAF-mutant cancer cell survival. PTPN23 catalytic activity is not required for this function.\",\n      \"method\": \"RNAi/CRISPR knockdown, in vitro kinase assay, PI lipid mass spectrometry, co-immunoprecipitation, mouse melanoma models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus lipidomics plus co-IP plus in vivo validation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"39841180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTPN23 is required for constitutive secretion from the trans-Golgi network: loss of PTPN23 (and ESCRT subunits CHMP1 and VPS4) disrupts tubule fission from the trans-Golgi and impairs delivery of cargo to the plasma membrane, as well as constitutive secretion of soluble cargoes and endogenous hormones/antibodies in specialized cells.\",\n      \"method\": \"Affinity isolation of post-Golgi carriers with mass spectrometry, pooled CRISPR-KO screen, live-cell imaging of trans-Golgi tubules, cargo secretion assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pooled CRISPR screen with mechanistic live-imaging and secretion assay validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"41848521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HD-PTP undergoes calcium-dependent proteolytic degradation by calpains in T24 bladder carcinoma cells; calpain inhibition prevents this degradation and causes redistribution of HD-PTP to the cell periphery.\",\n      \"method\": \"Calpain inhibitor treatment, calcium manipulation, Western blotting, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological inhibitor evidence plus redistribution readout, single lab, two orthogonal readouts\",\n      \"pmids\": [\"22510412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HD-PTP protein is degraded via the proteasome system in response to FGF-2 in endothelial cells; VEGF does not affect HD-PTP protein levels.\",\n      \"method\": \"Proteasome inhibitor treatment, Western blotting, growth factor stimulation\",\n      \"journal\": \"Frontiers in bioscience : a journal and virtual library\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (pharmacological inhibitor + Western blot), no mechanistic detail of ubiquitin ligase\",\n      \"pmids\": [\"16720300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A PTPN23 variant (rs6780013, p.Thr) binds EGFR and modulates its phosphorylation at Thr699, substantially inhibiting ESCC cell proliferation in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo proliferation assays, phosphorylation analysis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP plus functional assay showing variant-specific EGFR phosphorylation, single lab, limited mechanistic detail\",\n      \"pmids\": [\"38704135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Myopic (HD-PTP/PTPN23 Drosophila ortholog) selectively inhibits activity-induced Ca2+-dependent neuropeptide (DCV) release at the NMJ without affecting small synaptic vesicle (SSV) release. This function does not require interaction with ESCRT-III protein CHMP4/Shrub. Presynaptic Myopic is abundant at early endosomes.\",\n      \"method\": \"Transgenic overexpression/knockdown in Drosophila NMJ, optical imaging of synaptic neuropeptide release, DCV counting, genetic rescue with CHMP4-interaction mutants\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Drosophila gain/loss-of-function with functional secretion readout and domain-specific rescue, single lab\",\n      \"pmids\": [\"29378961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTPN23 acts as a cofactor for HIV-1 Vpu-directed degradation of BST-2 and decrease of CD4 at the cell surface by supporting ESCRT-dependent sorting at multivesicular bodies; identified as part of the Vpu proximal proteome by APEX2 proximity labeling.\",\n      \"method\": \"APEX2 proximity proteomics, hierarchical clustering, RNAi depletion, flow cytometry for cell-surface protein levels\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics with functional RNAi validation, single lab\",\n      \"pmids\": [\"34843601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HD-PTP hypomorphic mice with reduced protein expression develop lipodystrophy, decreased receptor-mediated EGFR signaling in white adipose tissue (decreased trans-autophosphorylation and downstream effector activation despite normal EGF binding), decreased plasma membrane cholesterol, and increased lysosomal cholesterol, attributable to defective endosomal maturation and cholesterol trafficking.\",\n      \"method\": \"Hypomorphic mouse model, adipose tissue signaling assays, cholesterol fractionation, in vitro EGFR assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model with biochemical dissection of signaling and cholesterol trafficking, single lab\",\n      \"pmids\": [\"39155850\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN23/HD-PTP is a catalytically inactive pseudophosphatase that functions as a master coordinator of the ESCRT pathway: its open, extended Bro1 domain simultaneously engages ESCRT-0 (via STAM2), ESCRT-I (via TSG101), and ESCRT-III (via CHMP4B) to drive ubiquitinated cargo (EGFR, integrins, death receptors, neurotrophin receptors, tau aggregates) from early endosomes into multivesicular body intraluminal vesicles for lysosomal degradation; it recruits the deubiquitinase UBPY/USP8 to transfer cargo from ESCRT-0 to ESCRT-III, acts as a non-canonical ESCRT-II substitute bridging ESCRT-I to ESCRT-III, mediates endosomal microautophagy of ubiquitylated aggregates, and also functions at the trans-Golgi to enable constitutive secretion; beyond endosomes, PTPN23 promotes DGC assembly at cardiac costameres, controls SMN phosphorylation and Cajal body localization, activates a WNK3–PI3KC2α–AKT2 survival axis at endosomes, and is itself regulated by WDR4-mediated ubiquitination/proteasomal degradation and by calpain-dependent calcium-regulated proteolysis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPN23/HD-PTP is a catalytically inactive pseudophosphatase that serves as a central coordinator of the ESCRT pathway, driving the endosomal sorting of ubiquitinated transmembrane cargo into multivesicular bodies for lysosomal degradation [#0, #4]. Its Bro1 domain is the functional hub: it adopts an open, extended conformation optimal for simultaneous engagement of multiple ESCRT components [#9], binding ESCRT-0 (STAM2 core, via a hydrophobic pocket that orients STAM2 oppositely to CHMP4B on Alix/Brox), ESCRT-I (TSG101), and ESCRT-III (CHMP4B), with overlapping binding sites enabling competitive handoff [#1, #3, #8]. PTPN23 recruits the deubiquitinase UBPY/USP8 and coordinately displaces ESCRT-0 in favor of ESCRT-III to transfer cargo such as EGFR [#1], and it can act as a non-canonical substitute for ESCRT-II, bridging ESCRT-I directly to ESCRT-III for sorting of cargoes including MHC class I and ubiquitylated tau aggregates [#7, #22]. Through this machinery PTPN23 governs the fate of diverse receptors — EGFR, integrins, death receptors (TNFR1) and TLRs, and neurotrophin receptors — thereby attenuating downstream signaling, suppressing invasion and tumorigenesis, and acting as a cell-death checkpoint [#2, #6, #21, #16]. PTPN23 also functions beyond endosomes: it is essential for cardiac T-tubule formation, interacting with sarcomeric α-actinin and dystrophin to promote dystrophin-glycoprotein complex assembly at costameres [#20], is required for constitutive secretion via tubule fission at the trans-Golgi network [#24], and activates a WNK3–PI3KC2α–AKT2 endosomal survival axis independently of its catalytic activity [#23]. PTPN23 levels are controlled by WDR4–Cullin 4-mediated ubiquitination and proteasomal degradation, which restrains EGFR and c-MET turnover [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established PTPN23 as a required factor for endosomal cargo sorting and MVB morphogenesis, defining its core cellular role and the indispensability of its Bro1 domain.\",\n      \"evidence\": \"RNAi depletion with domain-mutant rescue and EM/fluorescence imaging in mammalian cells\",\n      \"pmids\": [\"18434552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which ESCRT contacts are direct versus indirect\", \"Catalytic status of the phosphatase domain not yet defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the paradox of a phosphatase-named protein lacking enzymatic activity by showing PTPN23 is a catalytically dead pseudophosphatase whose biological activity is catalysis-independent.\",\n      \"evidence\": \"In vitro DiFMUP and phosphoinositide assays with catalytic back-mutation and colony formation assay\",\n      \"pmids\": [\"19340315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish what the divergent phosphatase domain does instead\", \"No structural basis for the scaffolding function\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped the first Bro1-domain interaction network, distinguishing PTPN23 from Alix by Ca2+-independent TSG101 binding and lack of CIN85 interaction.\",\n      \"evidence\": \"Yeast two-hybrid and Strep-tag pulldowns from HEK293T lysates\",\n      \"pmids\": [\"17174262\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinities and stoichiometry not quantified\", \"Functional consequence of ALG-2 Ca2+-dependence untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Built the mechanistic model of PTPN23 as a coordinator that hands EGFR cargo from ESCRT-0 to ESCRT-III, including recruitment of the deubiquitinase UBPY/USP8.\",\n      \"evidence\": \"Co-IP, pulldowns, competition assays, RNAi, and EGFR trafficking readouts\",\n      \"pmids\": [\"23477725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Temporal order of competition events on endosomes not directly visualized\", \"Did not address cargoes other than EGFR\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected PTPN23 endosomal function to tumor suppression by showing it controls E-cadherin trafficking and restrains SRC/β-catenin-driven invasion.\",\n      \"evidence\": \"RNAi loss-of-function screen, substrate phosphorylation assays, invasion assays, and SRC-inhibitor epistasis in mammary epithelial cells\",\n      \"pmids\": [\"21724833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with catalytic inactivity (substrate dephosphorylation claim) not addressed\", \"Direct versus trafficking-mediated effects on substrates not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated PTPN23 can substitute for ESCRT-II/VPS20 as a non-canonical ESCRT-I–ESCRT-III bridge, generalizing its adaptor role to virally ubiquitinated MHC class I.\",\n      \"evidence\": \"Systematic RNAi of individual ESCRT components with WT/mutant rescue and flow cytometry\",\n      \"pmids\": [\"26221024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define when the non-canonical versus canonical route is selected\", \"Structural basis of ESCRT-I bridging not resolved here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the atomic basis for ESCRT-0 engagement, showing STAM2 binds the Bro1 hydrophobic pocket in an orientation opposite to CHMP4B with Thr145 as the determinant residue.\",\n      \"evidence\": \"X-ray crystallography of the Bro1–STAM2 complex with mutagenesis\",\n      \"pmids\": [\"26866605\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length complex architecture not captured\", \"Dynamics of STAM2/CHMP4B exchange not directly observed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked PTPN23 dosage to in vivo tumor suppression and integrin recycling, validating its physiological role in restraining migration and invasion.\",\n      \"evidence\": \"Ptpn23+/- mouse tumor monitoring with integrin trafficking and migration assays\",\n      \"pmids\": [\"27210750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type origin of tumors not dissected\", \"Direct integrin sorting mechanism in vivo not shown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the conformational logic enabling simultaneous multi-ESCRT engagement, showing PTPN23 is extended and open unlike compact Alix.\",\n      \"evidence\": \"SAXS, hydrodynamic analysis, and binding assays with cellular partners\",\n      \"pmids\": [\"28831121\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution full-length structure absent\", \"Conformational regulation on membranes untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified SARA and endofin as HD-PTP-specific Bro1 ligands competing with CHMP4 at the same site, revealing a unique neighboring pocket distinguishing PTPN23.\",\n      \"evidence\": \"Crystal structures of Bro1 with SARA, endofin, and three CHMP4 isoforms plus competition assays\",\n      \"pmids\": [\"28602823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular role of SARA/endofin competition not resolved here\", \"How competing ligands are ordered in time unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed endofin as a functional partner linking PTPN23 to ESCRT-0 (Hrs) for sorting of ubiquitinated integrin α5 and EGFR.\",\n      \"evidence\": \"BioID, co-IP, RNAi with mutant complementation, and receptor trafficking/migration assays\",\n      \"pmids\": [\"34761192\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endofin is universally required or cargo-selective unclear\", \"Quantitative contribution versus direct STAM2/TSG101 routes not partitioned\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended PTPN23 function to the nucleus, showing it shuttles and regulates SMN phosphorylation and Cajal body localization.\",\n      \"evidence\": \"Phosphatase RNAi screen, Cajal body accumulation assay, co-IP, phosphorylation analysis, fractionation\",\n      \"pmids\": [\"25392300\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking endosomal scaffold to nuclear SMN regulation unknown\", \"Whether effect is direct given catalytic inactivity unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Implicated PTPN23 in adhesion signaling by showing it binds FAK and restrains FAK tyrosine phosphorylation and migration in endothelial cells.\",\n      \"evidence\": \"siRNA, co-IP, immunofluorescence, and migration assays\",\n      \"pmids\": [\"17959146\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation excluded by later catalytic-dead finding\", \"Mechanism of FAK regulation (scaffold versus trafficking) unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed reciprocal regulation by Src, which phosphorylates and inhibits PTPN23, positioning it downstream of growth-factor signaling.\",\n      \"evidence\": \"Co-IP, in vitro phosphorylation, phosphatase activity assay, RNAi, Src inhibition\",\n      \"pmids\": [\"18762272\", \"18835089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with catalytic inactivity of the PTP domain\", \"Phosphosites on PTPN23 not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a role in neuronal receptor signaling, showing PTPN23 sustains EphB2 clustering/activation and controls axon guidance.\",\n      \"evidence\": \"BioID, co-IP, RNAi, collapse assay, in vivo chick motor neuron axon guidance\",\n      \"pmids\": [\"31420572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PTPN23 promotes clustering rather than only degradation unclear\", \"Direct versus ESCRT-mediated effect on EphB2 not separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified PTPN23 as a regulator of neurotrophin receptor (p75NTR/TrkB) endocytic sorting through interaction with the dynein adaptor BICD1.\",\n      \"evidence\": \"BICD1 interactome MS, domain mapping, RNAi, fluorescence microscopy in motor neurons\",\n      \"pmids\": [\"32079660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of BICD1 binding (non-cargo) undefined\", \"Link to motor transport versus sorting not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed an unanticipated structural role in cardiac muscle, with PTPN23 required for T-tubule formation and DGC assembly at costameres via α-actinin and dystrophin interactions.\",\n      \"evidence\": \"Cardiomyocyte conditional/CRISPR knockout mice, AAV9 mosaics, fractionation, co-IP, EM, T-tubule imaging\",\n      \"pmids\": [\"38214189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ESCRT activity underlies the costamere role unclear\", \"Mechanism of membrane tubule shaping at Z-discs not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined PTPN23/ESCRT as a cell-death checkpoint by sorting death receptors and TLRs, with NAP1 facilitating TNFR1 endosomal sorting.\",\n      \"evidence\": \"CRISPR screen in AML cells, BioID, co-IP, receptor imaging, cell death assays\",\n      \"pmids\": [\"39609437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NAP1 acts on cargoes beyond TNFR1 unknown\", \"Selectivity of death-receptor versus other cargo sorting not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed PTPN23 mediates endosomal microautophagy of tau aggregates by bridging TSG101-recognized polyubiquitinated tau to ESCRT-III, linking it to disease via UBAP1.\",\n      \"evidence\": \"Genome-wide CRISPR screen, co-IP, domain mapping, microscopy, tau degradation assay\",\n      \"pmids\": [\"40197510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to tauopathy clearance not tested\", \"Distinction between microautophagy and canonical ILV pathway not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a catalysis-independent signaling output: PTPN23 drives WNK3-dependent PI3KC2α phosphorylation to fuel PI(3,4)P2/AKT2 survival signaling at endosomes.\",\n      \"evidence\": \"RNAi/CRISPR, in vitro kinase assay, PI lipidomics, co-IP, mouse melanoma models\",\n      \"pmids\": [\"39841180\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PTPN23 induces WNK3 activity mechanistically unclear\", \"Relationship of this axis to ESCRT sorting unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Extended ESCRT-dependent PTPN23 function to the secretory pathway, showing it is required for trans-Golgi tubule fission and constitutive secretion.\",\n      \"evidence\": \"Post-Golgi carrier affinity-MS, pooled CRISPR screen, live-cell TGN imaging, secretion assays\",\n      \"pmids\": [\"41848521\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct membrane-fission contacts at the TGN not defined\", \"Whether the same Bro1 contacts operate at the Golgi unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified the upstream control of PTPN23 abundance, showing WDR4–Cullin 4 ubiquitinates PTPN23 to restrain EGFR/c-MET degradation.\",\n      \"evidence\": \"Ubiquitylome MS, co-IP, proteasome inhibition, degradation assays, competitive peptide\",\n      \"pmids\": [\"37821451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological context regulating WDR4 activity unknown\", \"Ubiquitination sites on PTPN23 not detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPN23's many roles — endosomal sorting, costamere assembly, TGN secretion, nuclear SMN regulation, and the catalysis-independent WNK3–PI3KC2α axis — are coordinated and selectively deployed in different tissues remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unifying model linking endosomal scaffolding to non-endosomal functions\", \"Tissue-specific partner repertoire not mapped\", \"No human Mendelian disease directly attributed to PTPN23 in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 7, 8, 9, 17, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 21, 23]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 5, 17, 21, 28]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 7, 22, 24]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 24]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 15, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 20, 22]}\n    ],\n    \"complexes\": [\"ESCRT machinery\", \"dystrophin-glycoprotein complex (DGC)\"],\n    \"partners\": [\"STAM2\", \"TSG101\", \"CHMP4B\", \"USP8\", \"UBAP1\", \"PI3KC2A\", \"ACTN2\", \"DMD\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":6,"faith_total":6,"faith_pct":100.0}}