{"gene":"PTPN13","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1994,"finding":"PTPN13/PTPL1 is a large cytoplasmic protein tyrosine phosphatase (270 kDa) with a PTP domain at the C-terminus, a band 4.1/FERM domain, five PDZ (GLGF repeat) domains, and a leucine zipper motif; it dephosphorylates 32P-labeled myelin basic protein in vitro, establishing its phosphatase activity.","method":"PCR-based cloning, peptide antisera immunoprecipitation, in vitro phosphatase assay with 32P-labeled substrate","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic assay plus structural domain characterization in original cloning paper, foundational result","pmids":["7929060"],"is_preprint":false},{"year":1997,"finding":"PDZ domains 2 and 4 of PTPN13/PTPL1 interact with high affinity with the C-terminal tail of Fas/CD95; the three C-terminal residues (SLV) of Fas are necessary and sufficient for binding, with specific contributions from residues at positions -2, -3, -4, and -5.","method":"Peptide binding assay, affinity measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical peptide binding assay with systematic mutagenesis of ligand residues, defining binding determinants","pmids":["9261095"],"is_preprint":false},{"year":1997,"finding":"The fourth PDZ domain of PTPN13/PTPL1 interacts with the C-terminal four residues of PARG1, a novel 150 kDa RhoGAP protein; PARG1 shows GAP activity toward Rho, Rac, and Cdc42 in vitro with preference for Rho, suggesting a PTPN13-PARG1 complex as a dual negative regulator of Rho signaling.","method":"Yeast two-hybrid, in vitro GAP assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identifies interaction domain, in vitro GAP activity confirmed; single study","pmids":["9305890"],"is_preprint":false},{"year":1998,"finding":"PDZ domains 2 and 4 of PTPN13/PTP-BL bind the LIM domain of RIL; the RIL LIM domain can be phosphorylated on tyrosine in vitro and in vivo and is dephosphorylated in vitro by the PTPase domain of PTP-BL, placing RIL as a substrate.","method":"Yeast two-hybrid, in vitro kinase and phosphatase assays, immunohistochemistry for colocalization","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphatase assay directly demonstrating dephosphorylation of RIL LIM domain, plus in vivo phosphorylation evidence","pmids":["9487134"],"is_preprint":false},{"year":1999,"finding":"The FERM domain of PTP-BL/PTPN13 is necessary and sufficient for targeting the protein to the apical side of epithelial MDCK cells; the protein shows a submembranous localization ~10-15 nm from the plasma membrane as shown by immuno-electron microscopy, and FRAP experiments show dynamic redistribution via a cytosolic pool. The PTP domains mediate homotypic interactions.","method":"Transient expression of modular domains, immuno-electron microscopy, immunofluorescence, FRAP, yeast two-hybrid","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with domain deletion analysis, FRAP, and EM; multiple orthogonal methods in one study","pmids":["10504335"],"is_preprint":false},{"year":1999,"finding":"The PDZ1 domain of PTPN13/PTP-BAS interacts with IκBα through the N-terminal three ankyrin repeats of IκBα; this interaction was confirmed by co-immunoprecipitation in HeLa cells. Dominant-negative PTP-BAS caused tyrosine phosphorylation of IκBα, suggesting PTPN13 dephosphorylates IκBα to regulate NF-κB activation.","method":"Yeast two-hybrid, co-immunoprecipitation, dominant-negative mutant expression","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP confirmation plus dominant-negative functional evidence; single lab","pmids":["9882613"],"is_preprint":false},{"year":2000,"finding":"PTPN13/PTP-BL PDZ2 domain (specifically the non-spliced variant PDZ2a) binds the extreme C-terminus of the tumor suppressor APC with a dissociation constant of 8.1×10⁻⁹ M; a naturally occurring 5-amino acid splice insertion (PDZ2b) abolishes this binding. Interaction confirmed by co-precipitation in COS cells and colocalization in epithelial cells.","method":"Yeast two-hybrid, surface plasmon resonance, co-precipitation in transfected COS cells, immunofluorescence colocalization","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — surface plasmon resonance provides quantitative KD, co-precipitation confirms in vivo interaction, splice variant abrogation is mechanistic","pmids":["10951583"],"is_preprint":false},{"year":2000,"finding":"PTPN13/PTP-BL PDZ2 domain interacts with the third LIM domain (including the C-terminus) of TRIP6; both proteins colocalize in transfected epithelial cells at F-actin structures, placing PTPN13 in a multiprotein complex with RIL and TRIP6 at actin-based structures.","method":"Yeast two-hybrid, co-precipitation from transfected cells, immunofluorescence colocalization","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-precipitation and colocalization confirmed in multiple interaction partners; single lab","pmids":["10826496"],"is_preprint":false},{"year":2001,"finding":"The PDZ3 domain of PTPN13/PTP-BL interacts with the extreme C-terminus of PRK2 (protein kinase C-related kinase 2), a Rho effector serine/threonine kinase; a conserved C-terminal cysteine of PRK2 is indispensable for this interaction. Both proteins colocalize in lamellipodia-like structures in HeLa cells.","method":"Yeast two-hybrid, co-immunoprecipitation from transfected HeLa cells, site-directed mutagenesis, immunofluorescence colocalization","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP confirmed interaction, mutagenesis identifies critical residue; single lab","pmids":["11356191"],"is_preprint":false},{"year":2002,"finding":"PTPN13/PTP-BL is recruited to ephrinB expression domains with delayed kinetics after EphB receptor engagement and mediates dephosphorylation of ephrinB, acting downstream of Src family kinases which phosphorylate ephrinB. This defines a switch from phosphotyrosine/SFK-dependent signaling to PDZ-dependent signaling.","method":"Co-immunoprecipitation, cell biology/signaling assays, phosphorylation analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, cell-based phosphorylation assays with temporal resolution, establishes substrate relationship and pathway position; well-cited","pmids":["11983165"],"is_preprint":false},{"year":2002,"finding":"NMR solution structure of PDZ2 of PTP-BL/PTPN13 reveals a compact canonical PDZ fold with six β-strands and two α-helices, with a unique flexible L1 loop. PDZ2 binds C-termini of human Fas/CD95 and RIL (including non-canonical E-x-V motif), but murine PDZ2 does not bind murine Fas/CD95, suggesting species-specific differences in substrate recognition.","method":"NMR structure determination, 15N relaxation analysis, peptide binding studies","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional peptide binding validation and negative result for murine Fas","pmids":["11884147"],"is_preprint":false},{"year":2002,"finding":"PTPN13/PTPL1/FAP-1 promotes apoptosis in MCF7 breast cancer cells by inhibiting the IRS-1/PI3K/Akt pathway; antisense abrogation of PTPL1 expression abolished tamoxifen-induced apoptosis, and PTPL1 expression reduced IRS-1 tyrosine phosphorylation by 65%, PI3K activity by 80%, and Akt activation by 55%.","method":"Antisense stable transfection, PI3K activity assay, Akt phosphorylation assay, TUNEL/nucleosome ELISA apoptosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple orthogonal pathway readouts; establishes pathway position with defined biochemical phenotypes","pmids":["12354757"],"is_preprint":false},{"year":2003,"finding":"The FERM domain of PTPN13/PTPL1 is necessary and sufficient for membrane targeting to the apical plasma membrane enriched in dorsal microvilli; two PtdIns(4,5)P2-binding motifs within the FERM domain are required—mutation of both abolishes membrane localization. Direct interaction of the FERM domain with PtdIns(4,5)P2 was demonstrated by protein-lipid overlay assay.","method":"Live imaging of domain constructs in HeLa cells, site-directed mutagenesis of PIP2-binding motifs, protein-lipid overlay, cell fractionation, neomycin treatment","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, lipid overlay, fractionation, pharmacological), direct mechanistic link between FERM-PIP2 interaction and localization","pmids":["12766187"],"is_preprint":false},{"year":2003,"finding":"Endogenous PTPN13/PTPL1 constitutively associates with TAPP1 (a PtdIns(3,4)P2-binding adaptor) primarily through its first PDZ domain; this complex enables PTPN13 association with PtdIns(3,4)P2 in vitro. TAPP1 binding maintains PTPN13 in the cytoplasm; upon H2O2 stimulation (which produces PtdIns(3,4)P2), the PTPN13-TAPP1 complex translocates to the plasma membrane.","method":"Co-immunoprecipitation of endogenous proteins, GST pull-down, RNA interference, lipid binding assay, subcellular fractionation","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — endogenous Co-IP, domain mapping by GST pull-down, RNAi functional consequence, lipid binding assay; multiple orthogonal methods","pmids":["14516276"],"is_preprint":false},{"year":2003,"finding":"PTPN13/PTP-BL localizes to centrosomes during inter- and metaphase, the spindle midzone during anaphase, and concentrates at the midbody during cytokinesis. Targeting to midbody/centrosome requires a specific N-terminal splicing variant (182 aa insertion). The FERM domain associates with the contractile ring and co-sediments with F-actin; the N-terminus co-sediments with microtubules. Overexpression of wild-type or phosphatase-dead PTPN13 causes cytokinesis defects and multinucleate cells.","method":"Immunofluorescence localization of endogenous protein, domain deletion constructs, actin/microtubule co-sedimentation, overexpression functional assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization of endogenous protein with functional consequence (cytokinesis defects), domain mapping by co-sedimentation; multiple orthogonal methods","pmids":["12529439"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of the PTPN13/PTPL1 catalytic domain at 1.8 Å resolution reveals the standard PTP fold with an additional N-terminal helix and an ordered phosphate in the active site. A second positively charged pocket near the active site resembles the second phosphotyrosine-binding site of PTP1B; consistent with this, PTPL1 dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides. Four of five colorectal cancer mutations map to solvent-exposed regions remote from the active site; the fifth (Met2307Thr) is near the active-site cysteine and significantly decreases activity.","method":"X-ray crystallography (1.8 Å), in vitro phosphatase assay with bis- vs mono-phosphorylated peptides, mutant activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay with mutagenesis analysis; single paper with multiple orthogonal methods","pmids":["15611135"],"is_preprint":false},{"year":2004,"finding":"NMR structure of the alternatively spliced PDZ2b (with 5-residue insertion) of PTP-BL/PTPN13 reveals that the insert causes reorientation of a loop that closes the binding site (Lys32 side chain occludes the pocket) and repositions α-helix 2, rendering the binding pocket unable to accommodate APC C-terminus; PDZ2b binds PIP2 and PIP3 with KD ~230 μM via a groove overlapping the APC binding site.","method":"NMR structure determination, NMR titration binding studies, high-affinity chromatography for lipid binding","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with functional binding validation explains splice-dependent specificity change; single rigorous study","pmids":["14596806"],"is_preprint":false},{"year":2007,"finding":"PTPN13/PTPL1 directly dephosphorylates IRS-1 (insulin receptor substrate-1) in vitro and in cells; this is confirmed by dominant-negative mutant and RNAi approaches. PTPN13 expression blocks the IRS-1/PI3K/Akt pathway, inhibits IGF-I-induced cell survival, and induces apoptosis.","method":"In vitro phosphatase assay, co-immunoprecipitation, dominant-negative mutant, RNA interference, PI3K/Akt pathway assays, cell survival assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation assay directly establishing IRS-1 as substrate, confirmed by multiple complementary approaches (DN mutant + RNAi) in cells","pmids":["17638892"],"is_preprint":false},{"year":2007,"finding":"PTPN13 negatively regulates Her2/ErbB2 signaling by dephosphorylating the Her2 signaling domain; siRNA knockdown of PTPN13 augmented Her2 phosphorylation and promoted cancer cell invasiveness. Growth factor-induced phosphorylation of PTPN13 is required for its ability to dephosphorylate Her2, suggesting a negative feedback mechanism. PTPN13 mutations found in human tumors reduced phosphatase activity.","method":"siRNA phosphatase library screen, phosphorylation assays, cell invasion assays, mutant phosphatase activity assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA screen followed by phosphorylation assays and mutant activity measurements establish Her2 as substrate; multiple orthogonal approaches","pmids":["17982484"],"is_preprint":false},{"year":2007,"finding":"PTPN13/PTP-BL dephosphorylates STAT proteins (STAT4, STAT6 confirmed) in vitro and in vivo, attenuating STAT-mediated gene activation. In CD4+ T cells, PTP-BL deficiency leads to increased and prolonged activation of STAT4 and STAT6, and consequently enhanced Th1 and Th2 cell differentiation.","method":"In vitro phosphatase assay, PTP-BL-deficient mouse model, T cell differentiation assays, STAT phosphorylation measurements","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation assay plus genetic knockout model with defined cellular phenotype; multiple orthogonal methods","pmids":["17306571"],"is_preprint":false},{"year":2007,"finding":"PTPN13/PTPL1 dephosphorylates phosphotyrosine-55 of TRIP6 in vitro, inhibiting LPA-induced tyrosine phosphorylation of TRIP6 in cells. This negative regulation requires direct protein-protein interaction and phosphatase activity of PTPL1, preventing TRIP6 turnover at adhesion sites and inhibiting LPA-induced Crk recruitment and cell migration.","method":"In vitro phosphatase assay, co-immunoprecipitation, phosphatase-dead mutant, cell migration/morphology assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro dephosphorylation assay identifies specific substrate site (Tyr-55), confirmed in cells with phosphatase-dead mutant and functional migration readout","pmids":["17591779"],"is_preprint":false},{"year":2007,"finding":"PTPN13/PTPL1 interacts with the TRP channel TRPM2 (confirmed by co-IP and GST pull-down); PTPL1 co-expression reduces TRPM2 tyrosine phosphorylation and inhibits H2O2/TNFα-induced Ca2+ influx and cell death. PTPL1 knockdown increases TRPM2 tyrosine phosphorylation, Ca2+ influx, and cell death susceptibility. Endogenous TRPM2-PTPL1 association confirmed in U937 cells.","method":"PDZ array blot, co-immunoprecipitation, GST pull-down, siRNA knockdown, Ca2+ imaging, cell viability assay","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays plus siRNA and overexpression with specific phosphorylation and functional readouts; endogenous interaction confirmed","pmids":["17251321"],"is_preprint":false},{"year":2007,"finding":"An allosteric intramolecular PDZ1-PDZ2 interaction within PTPN13/PTP-BL modulates PDZ2 binding specificity; structural studies revealed PDZ1 directly contacts a surface on PDZ2 opposite the peptide binding groove, causing long-range allosteric changes in the PDZ2 binding pocket.","method":"Phage display library screening, NMR structural studies, binding specificity assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure combined with phage display functional specificity assay reveals allosteric mechanism","pmids":["17979300"],"is_preprint":false},{"year":2008,"finding":"ICSBP/IRF8 represses PTPN13 gene transcription by binding to a cis element in the proximal PTPN13 promoter in differentiating myeloid cells; this repression is regulated by phosphorylation of conserved tyrosine residues in the ICSBP IRF domain and increases during myeloid differentiation. ICSBP influences Fas-induced apoptosis in a FAP-1/PTPN13-dependent manner.","method":"CpG island microarray with chromatin immunoprecipitation, luciferase reporter assays, ChIP, phosphorylation mutants, Fas-apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirms direct promoter binding, luciferase assays confirm functional repression, phosphorylation mutants establish regulatory mechanism; multiple orthogonal methods","pmids":["18195016"],"is_preprint":false},{"year":2009,"finding":"PTPN13 phosphatase activity inhibits Ras/RAF/MEK/Erk signaling downstream of ErbB2, EGFR, and H-RasV12; co-transfection of wild-type but not enzymatically inactive PTPN13 inhibited this pathway. HPV-negative HNSCCs with PTPN13 phosphatase mutations showed impaired Ras/RAF/MEK/Erk inhibition. MEK inhibitor U0126 blocked anchorage-independent growth in PTPN13-deficient cells, placing PTPN13 upstream of ERK signaling.","method":"Co-transfection assays, phosphatase activity mutants, ERK phosphorylation assays, MEK inhibitor epistasis, anchorage-independent growth assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — enzymatic activity requirement established by catalytic mutant; MEK inhibitor epistasis places PTPN13 in pathway; multiple complementary approaches","pmids":["19734941"],"is_preprint":false},{"year":2010,"finding":"PTPN13/PTPL1 directly dephosphorylates Src at tyrosine 419 (the activating phosphorylation site) as shown by substrate-trapping experiments; PTPL1 knockdown increases Src-Y419 phosphorylation and activates downstream Fak and p130cas. PTPL1 inhibition dramatically increased tumor growth and invasion, identifying PTPL1 as the first phosphatase shown to directly inhibit Src in intact cells.","method":"Substrate-trapping with catalytic mutant, phosphorylation assays, RNA interference, in vivo tumor growth assay, invasion assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — substrate-trapping with catalytic mutant directly identifies Src-Y419 as substrate, confirmed in cells by RNAi with specific phosphorylation readouts","pmids":["20501847"],"is_preprint":false},{"year":2012,"finding":"PTPN13/PTPL1 is a direct transcriptional target of ICSBP; repression requires cooperation of ICSBP with Tel and HDAC3 forming a multiprotein complex at the PTPN13 cis element. The leukemia fusion protein Tel-PdgfRβ disrupts this repressive complex by competing with the Tel component, resulting in increased PTPN13 expression and Fas-resistance.","method":"ChIP, promoter reporter assays, knockdown of Tel/HDAC3, co-immunoprecipitation of repressor complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP confirms complex at promoter, knockdown experiments establish functional requirement, co-IP identifies complex composition; multiple orthogonal methods","pmids":["22262849"],"is_preprint":false},{"year":2012,"finding":"SDCCAG3 forms a complex with PTPN13 (co-immunoprecipitation) and both colocalize at the midbody during cytokinesis; SDCCAG3 is an endosomal protein (early/recycling endosome) that interacts with the ArfGAP GIT1. Overexpression or downregulation of SDCCAG3 causes multinucleate cells, linking PTPN13's cytokinesis function to endosomal trafficking via SDCCAG3-GIT1.","method":"Co-immunoprecipitation, immunofluorescence colocalization, overexpression/knockdown functional assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms complex, functional assays establish cytokinesis role; single lab","pmids":["23108400"],"is_preprint":false},{"year":2013,"finding":"PTPN13/PTPL1 dephosphorylates p85β (PI3K regulatory subunit) at Tyr-655, which stimulates p85β binding to and degradation through the SCF-FBXL2 ubiquitin ligase complex; this controls PI3K signaling by reducing the pool of free p85β that competes with p85-p110 heterodimers for IRS1.","method":"Protein purification (FBXL2 complex), co-immunoprecipitation, ubiquitylation assays, phosphorylation site mutants, PI3K signaling assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification identifies complex, phosphorylation site mutagenesis, functional signaling consequence established; single rigorous paper with multiple orthogonal methods","pmids":["23604317"],"is_preprint":false},{"year":2014,"finding":"PTEN binds to PDZ2 of PTPN13 in a manner dependent on the PTEN PDZ-binding motif and the specific PDZ domain arrangement including the PDZ1-PDZ2 interdomain region; this was shown by yeast two-hybrid and GST pull-down with mutational analysis of the PTEN PDZ-BM.","method":"Yeast two-hybrid, GST pull-down, site-directed mutagenesis of PTEN PDZ-BM","journal":"Methods (San Diego, Calif.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two complementary binding assays with mutagenesis; single study, no functional consequence demonstrated beyond binding","pmids":["25448478"],"is_preprint":false},{"year":2014,"finding":"PTPN13 co-immunoprecipitates and colocalizes with β-catenin; PTPN13 regulates β-catenin phosphorylation, stability, and transcriptional activity during megakaryocytic differentiation. PTPN13 is stabilized upon Wnt signaling, and its silencing triggers megakaryocytic differentiation through effects on ERK and STAT signaling and β-catenin.","method":"Co-immunoprecipitation, colocalization, siRNA silencing, differentiation assays, phosphorylation/stability assays","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms interaction, RNAi with differentiation phenotype; single lab with multiple assays","pmids":["25193362"],"is_preprint":false},{"year":2017,"finding":"PTPN13/FAP-1 is a PDZ-domain-mediated binding partner of calpain-2; PTPN13 is cleaved by calpain-2, which inactivates its phosphatase activity and generates stable breakdown products (P13BPs). PTPN13 dephosphorylates and inhibits c-Abl; after TBI, calpain-2-mediated PTPN13 cleavage activates c-Abl and triggers tau tyrosine phosphorylation and oligomer accumulation. Post-TBI calpain-2 inhibitor treatment prevented this cascade.","method":"PDZ binding partner identification, co-immunoprecipitation, in vitro cleavage and phosphatase activity assays, calpain-2 selective inhibitor in vivo","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical assays (cleavage, phosphatase inactivation, c-Abl as substrate), in vivo pharmacological validation with calpain-2 inhibitor; multiple orthogonal methods","pmids":["28924170"],"is_preprint":false},{"year":2018,"finding":"PTPN13/PTPL1 interacts with PTEN, and this interaction is necessary for apical membrane enrichment of PTEN in polarized epithelial cells; PTPL1 depletion (CRISPR/Cas9) causes enlarged brush border similar to PTEN loss. PTPL1 functions as a scaffolding anchor for PTEN in this process—its phosphatase activity is NOT required.","method":"CRISPR/Cas9 knockout, live imaging of brush border formation, co-immunoprecipitation, domain mapping","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with specific phenotypic readout, Co-IP confirms interaction, catalytically-inactive rescue distinguishes scaffolding from enzymatic function; multiple orthogonal methods","pmids":["29581186"],"is_preprint":false},{"year":2018,"finding":"NMR solution structures of the PDZ3 domain of murine PTPN13 in apo form and in complex with the C-terminal peptide of PRK2 reveal classical compact globular fold; PRK2 binds via an elongated peptide in the canonical groove between β-strand and α-helix, with P0 cysteine and P-2 aspartate facing the groove (class III ligand recognition).","method":"Multidimensional NMR spectroscopy, structure determination","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution NMR structure of protein-ligand complex with physiological ligand PRK2","pmids":["30189200"],"is_preprint":false},{"year":2019,"finding":"The tandem PDZ2/3 domain of PTPN13 shows allosterically modulated binding to APC; PDZ3 presence alters PDZ2 binding affinity for APC, and PRK2 is identified as a weak binding partner of PDZ2. HADDOCK molecular modeling and NMR spectroscopy support an allosteric effect from PDZ3 on PDZ2's ligand binding site.","method":"NMR spectroscopy, HADDOCK molecular modeling, binding affinity measurements of isolated vs tandem domains","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR-based structural and binding analysis; single lab, allosteric effect supported by computational model","pmids":["31286859"],"is_preprint":false},{"year":2020,"finding":"PTPN13 phosphatase activity is required to inhibit breast cancer cell motility and invasion; PTPN13 overexpression in MDA-MB-231 cells inhibited invasion and induced mesenchymal-to-epithelial transition in vivo. Phosphoproteomic and GO analyses revealed a role for PTPN13 in regulation of intercellular junction proteins; PTPN13 stabilizes intercellular adhesion and promotes desmosome formation.","method":"Transgenic mouse crossing (HER2×PTPN13-ΔP), isogenic cell clones with WT vs catalytically inactive PTPN13, phosphoproteomics, wound healing, Boyden chamber, videomicroscopy, immunofluorescence","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model plus phosphoproteomics plus isogenic cell clones with catalytic mutant; multiple orthogonal methods in single rigorous study","pmids":["31938048"],"is_preprint":false},{"year":2020,"finding":"PTPN13 competitively binds IGF2BP1 to decrease functional IGF2BP1 levels, thereby promoting c-Myc mRNA degradation and suppressing metabolic reprogramming; this function is independent of PTPN13 phosphatase activity. HBx inhibits PTPN13 expression by upregulating DNMT3A, which binds the PTPN13 promoter (-343 to -313 bp) and increases DNA methylation to suppress transcription.","method":"Co-immunoprecipitation, competitive binding assays, c-Myc mRNA stability assays, ChIP on PTPN13 promoter, DNMT3A knockdown","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and competitive binding establish PTPN13-IGF2BP1 interaction, ChIP confirms DNMT3A promoter binding; single lab","pmids":["33051595"],"is_preprint":false},{"year":2021,"finding":"PTPN13/PTPL1 suppresses TGF-β1-induced EMT in lung cancer cells by counteracting activation of canonical Smad2/3 and non-canonical p38 MAPK signaling pathways; immunoprecipitation demonstrated direct binding of PTPL1 to p38 MAPK, suggesting p38 MAPK as a direct substrate.","method":"siRNA knockdown, immunoprecipitation for PTPL1-p38 MAPK interaction, EMT marker analysis, Smad2/3 and p38 phosphorylation assays, xenograft model","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP for substrate identification; functional consequence shown in cells and in vivo; single lab","pmids":["33536603"],"is_preprint":false},{"year":2022,"finding":"PTPL1/PTPN13 suppresses lung cancer cell proliferation by counteracting the Src/ERK pathway; PTPL1 knockdown induced activation of Src/ERK signaling and promoted YAP1 nuclear translocation and activation. YAP1 co-knockdown reversed the proliferation increase caused by PTPL1 knockdown, placing PTPL1 upstream of Src/ERK/YAP1.","method":"shRNA knockdown, signaling pathway assays, xenograft model, double knockdown epistasis","journal":"Thoracic cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (double knockdown) places PTPL1 upstream of Src/ERK/YAP1; single lab","pmids":["36193770"],"is_preprint":false},{"year":2025,"finding":"PTPN13 directly dephosphorylates STAT1, suppressing interferon-stimulated MHC class I antigen presentation and CD8+ T cell infiltration; peptides containing the last 11 C-terminal residues of APC (APC11) bind directly to PTPN13, block PTPN13-STAT1 interaction, restore STAT1 phosphorylation and IRF1 expression, and enhance anti-tumor immunity in CRC. APC loss thus drives immune evasion via PTPN13-dependent STAT1 dephosphorylation independently of β-catenin.","method":"APC knockout models, Co-immunoprecipitation for PTPN13-STAT1 interaction, STAT1 phosphorylation assays, APC11 peptide competition assay, in vivo tumor/immune infiltration assays, anti-PD1 combination experiments","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifies PTPN13-STAT1 complex, peptide competition directly blocks the interaction with functional consequence, multiple in vivo and in vitro readouts; single rigorous paper with multiple orthogonal methods","pmids":["41486293"],"is_preprint":false},{"year":2025,"finding":"PDLIM4 acts as an adaptor that recruits PTP-BL/PTPN13 through its LIM domain to facilitate dephosphorylation of STAT3, STAT4, and STAT6; a disease-associated PDLIM4 nsSNP in the LIM domain reduces PTP-BL binding and impairs STAT3 dephosphorylation, linking this complex to regulation of Th1, Th2, and Th17 differentiation.","method":"Co-immunoprecipitation, STAT phosphorylation assays, PDLIM4-deficient T cells, LIM domain nsSNP mutant binding assay","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifies PDLIM4 as adaptor recruiting PTPN13, genetic deficiency model with cellular phenotype, disease SNP validates mechanism; multiple orthogonal methods","pmids":["42028851"],"is_preprint":false},{"year":2025,"finding":"PTPN13 pathogenic mutations (identified in ALL/anemia/IBMF families) impair the PTPN13-β-catenin interaction; PTPN13 silencing reduces Bruton's tyrosine kinase (BTK) activation and β-catenin levels after B-cell receptor (BCR) stimulation, indicating PTPN13 modulates BCR signaling and lymphoid cell homeostasis through β-catenin.","method":"Co-immunoprecipitation of endogenous proteins, PTPN13 silencing with BCR activation assays, surface marker analysis (CD25, CD38)","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RNAi with defined signaling readouts; single lab, functional consequence shown for BTK/β-catenin but mechanism of dephosphorylation not directly demonstrated","pmids":["41422331"],"is_preprint":false}],"current_model":"PTPN13 (PTPL1/PTP-BL/FAP-1) is a large (~270 kDa) non-receptor protein tyrosine phosphatase whose FERM domain targets it to the apical plasma membrane via PtdIns(4,5)P2 binding and whose five PDZ domains assemble multi-protein complexes; its established direct substrates include ephrinB, IRS-1, Src (at Y419), Her2/ErbB2, TRIP6 (at Y55), STAT1/4/6, p85β (at Y655), and c-Abl, through which it negatively regulates PI3K/Akt, Ras/RAF/MEK/ERK, Src/FAK, STAT, and interferon/antigen-presentation pathways, and it also functions as a phosphatase-independent scaffold anchoring PTEN to the apical membrane and recruiting PDLIM4-directed STAT dephosphorylation."},"narrative":{"mechanistic_narrative":"PTPN13 (PTPL1/PTP-BL/FAP-1) is a large cytoplasmic protein tyrosine phosphatase that integrates an N-terminal FERM domain, five PDZ domains, and a C-terminal PTP catalytic domain to act as a membrane-anchored scaffold and negative regulator of tyrosine-kinase signaling [PMID:7929060, PMID:15611135]. Its FERM domain binds PtdIns(4,5)P2 directly and is necessary and sufficient to target the protein to the apical plasma membrane and dorsal microvilli of epithelial cells, while a TAPP1/PtdIns(3,4)P2-dependent route mediates inducible membrane recruitment upon oxidative stimulation [PMID:12766187, PMID:14516276]. The tandem PDZ array assembles multiprotein complexes through C-terminal-motif recognition, with binding specificity tuned by alternative splicing and intramolecular PDZ1–PDZ2 allostery [PMID:9261095, PMID:10951583, PMID:14596806, PMID:17979300]. Through these PDZ-anchored complexes and its catalytic domain, PTPN13 dephosphorylates a broad set of phosphotyrosine substrates—including ephrinB, IRS-1, Her2/ErbB2, Src at the activating Tyr419, TRIP6 at Tyr55, the PI3K regulatory subunit p85β at Tyr655, STAT family proteins, and c-Abl—thereby restraining PI3K/Akt, Ras/RAF/MEK/ERK, Src/FAK, and STAT signaling and promoting apoptosis while suppressing tumor cell invasion and migration [PMID:11983165, PMID:12354757, PMID:17638892, PMID:17982484, PMID:17591779, PMID:19734941, PMID:20501847, PMID:23604317, PMID:17306571, PMID:28924170, PMID:31938048]. Beyond catalysis, PTPN13 also functions as a phosphatase-independent scaffold: it anchors PTEN at the apical membrane and competitively sequesters IGF2BP1 to destabilize c-Myc mRNA [PMID:29581186, PMID:33051595]. PTPN13 localizes to the centrosome, spindle midzone, and midbody, where its activity is required for faithful cytokinesis [PMID:12529439, PMID:23108400]. By dephosphorylating STAT1, PTPN13 suppresses interferon-stimulated MHC class I antigen presentation and CD8+ T cell infiltration, a circuit engaged by APC loss in colorectal cancer [PMID:41486293]. Pathogenic PTPN13 mutations in families with ALL/anemia/inherited bone marrow failure impair the PTPN13–β-catenin interaction and BCR-driven BTK/β-catenin signaling, linking the gene to lymphoid homeostasis [PMID:41422331].","teleology":[{"year":1994,"claim":"Establishing that PTPN13 is a bona fide tyrosine phosphatase with a distinctive multidomain architecture defined the gene as a candidate scaffolding phosphatase rather than a simple enzyme.","evidence":"PCR cloning, immunoprecipitation, and in vitro phosphatase assay on 32P-myelin basic protein","pmids":["7929060"],"confidence":"High","gaps":["No physiological substrate identified at this stage","Roles of the FERM, PDZ, and leucine-zipper modules unassigned"]},{"year":1997,"claim":"Mapping PDZ2/PDZ4 binding to the Fas/CD95 C-terminus and PDZ4 to the RhoGAP PARG1 showed PTPN13 selects partners via C-terminal motifs, framing it as a multi-complex organizer.","evidence":"Peptide binding/affinity assays for Fas; yeast two-hybrid and in vitro GAP assay for PARG1","pmids":["9261095","9305890"],"confidence":"High","gaps":["Functional consequence of Fas binding not resolved here","PARG1 complex link to Rho signaling inferred from in vitro GAP, not cellular readout"]},{"year":1998,"claim":"Identifying RIL as both a PDZ-binding partner and an in vitro substrate connected PTPN13's scaffolding and catalytic functions at actin-based structures.","evidence":"Yeast two-hybrid, in vitro kinase/phosphatase assays, colocalization","pmids":["9487134"],"confidence":"High","gaps":["Physiological relevance of RIL dephosphorylation in cells not established","Cellular pathway controlled by RIL phosphorylation unknown"]},{"year":1999,"claim":"Demonstrating that the FERM domain alone targets PTPN13 to the apical membrane, and IκBα binds PDZ1, defined how the phosphatase is positioned and added an NF-κB-regulatory link.","evidence":"Modular domain expression, immuno-EM, FRAP for localization; yeast two-hybrid, Co-IP, dominant-negative for IκBα","pmids":["10504335","9882613"],"confidence":"High","gaps":["Direct molecular driver of FERM targeting not yet identified (resolved later)","IκBα as a direct substrate inferred from dominant-negative, not in vitro dephosphorylation"]},{"year":2000,"claim":"Quantifying high-affinity PDZ2 binding to the APC tumor suppressor and its abolition by a 5-residue splice insertion revealed splicing as a switch controlling PTPN13 partner selection.","evidence":"Yeast two-hybrid, surface plasmon resonance, co-precipitation, colocalization; additional TRIP6 PDZ2 mapping","pmids":["10951583","10826496"],"confidence":"High","gaps":["Functional output of the PTPN13-APC complex not defined here","Physiological regulation of the splicing switch unknown"]},{"year":2002,"claim":"Defining ephrinB dephosphorylation downstream of Src family kinases, and solving the PDZ2 structure, established PTPN13 as a temporally-controlled signaling switch with structurally rationalized specificity.","evidence":"Reciprocal Co-IP and temporal phosphorylation assays (ephrinB); NMR structure with peptide binding (PDZ2); FEBS PRK2 PDZ3 interaction mapping","pmids":["11983165","11884147","11356191"],"confidence":"High","gaps":["Species-specific PDZ2 recognition complicates extrapolation across organisms","In vivo ephrinB regulation by endogenous PTPN13 not tested"]},{"year":2002,"claim":"Showing PTPN13 localizes to centrosome, midzone, and midbody and its overexpression causes multinucleation established a direct role in cytokinesis.","evidence":"Immunofluorescence of endogenous protein, domain co-sedimentation with actin/microtubules, overexpression phenotype","pmids":["12529439"],"confidence":"High","gaps":["Substrate dephosphorylated during cytokinesis not identified","Mechanism linking phosphatase activity to abscission unclear"]},{"year":2003,"claim":"Identifying the FERM–PtdIns(4,5)P2 interaction and TAPP1/PtdIns(3,4)P2-dependent recruitment defined the lipid logic of constitutive versus stimulus-induced membrane targeting.","evidence":"Mutagenesis of PIP2-binding motifs, protein-lipid overlay, fractionation (FERM); endogenous Co-IP, GST pull-down, RNAi, lipid binding (TAPP1)","pmids":["12766187","14516276"],"confidence":"High","gaps":["How membrane recruitment is coupled to substrate access not resolved","Relative contribution of constitutive vs inducible routes in vivo unknown"]},{"year":2004,"claim":"The catalytic domain crystal structure and the spliced PDZ2b NMR structure provided atomic-level explanations for substrate preference and splice-dependent specificity loss.","evidence":"X-ray crystallography of PTP domain with bis-phospho-peptide assay; NMR of PDZ2b with binding studies","pmids":["15611135","14596806"],"confidence":"High","gaps":["Physiological bis-phosphorylated substrates not identified","Functional consequence of PDZ2b lipid binding in cells untested"]},{"year":2007,"claim":"A burst of substrate-identification studies established PTPN13 as a broad negative regulator of growth/survival signaling and immune differentiation by directly dephosphorylating IRS-1, Her2, TRIP6, STATs, and regulating TRPM2.","evidence":"In vitro phosphatase assays, Co-IP, dominant-negative/RNAi, knockout mouse (STATs), substrate-site mapping (TRIP6 Tyr55), Ca2+/viability assays (TRPM2)","pmids":["17638892","17982484","17591779","17306571","17251321"],"confidence":"High","gaps":["Hierarchy/coordination among multiple substrates within a single cell unresolved","Determinants of substrate selection by individual PDZ domains incompletely mapped"]},{"year":2007,"claim":"Discovering an allosteric PDZ1–PDZ2 interaction and transcriptional repression by ICSBP/IRF8 revealed both intramolecular and gene-expression-level control of PTPN13 function.","evidence":"Phage display, NMR (PDZ1-PDZ2 allostery); ChIP, luciferase reporters, phospho-mutants (ICSBP)","pmids":["17979300","18195016"],"confidence":"High","gaps":["In vivo relevance of allosteric specificity modulation unknown","Signals controlling ICSBP-mediated repression beyond myeloid differentiation unclear"]},{"year":2009,"claim":"Placing PTPN13 phosphatase activity upstream of Ras/RAF/MEK/ERK extended its tumor-suppressive scope to a major mitogenic cascade and linked cancer-associated catalytic mutations to pathway dysregulation.","evidence":"Co-transfection with catalytic mutants, ERK phosphorylation assays, MEK-inhibitor epistasis, anchorage-independent growth in HNSCC","pmids":["19734941"],"confidence":"High","gaps":["Direct ERK-pathway substrate not pinpointed in this study","Mechanism connecting PTPN13 to upstream receptors incompletely defined"]},{"year":2010,"claim":"Substrate-trapping identification of Src Tyr419 as a direct target established PTPN13 as the first phosphatase shown to directly inactivate Src in intact cells, with strong tumor-suppressive consequences.","evidence":"Substrate-trapping catalytic mutant, RNAi, downstream FAK/p130cas readouts, in vivo tumor growth/invasion","pmids":["20501847"],"confidence":"High","gaps":["Spatial coupling of PTPN13 to Src pools not defined","Whether membrane anchoring is required for Src dephosphorylation untested"]},{"year":2012,"claim":"Defining an ICSBP–Tel–HDAC3 repressor complex at the PTPN13 promoter and its disruption by Tel-PdgfRβ, plus the SDCCAG3 cytokinesis link, connected PTPN13 regulation to leukemogenesis and trafficking.","evidence":"ChIP, reporter assays, Tel/HDAC3 knockdown, complex Co-IP (transcription); Co-IP, colocalization, knockdown (SDCCAG3)","pmids":["22262849","23108400"],"confidence":"High","gaps":["How increased PTPN13 confers Fas-resistance mechanistically unresolved","SDCCAG3-GIT1 endosomal contribution to cytokinesis defined only by Co-IP and phenotype"]},{"year":2013,"claim":"Identifying p85β Tyr655 dephosphorylation that triggers SCF-FBXL2-mediated p85β degradation revealed an indirect route by which PTPN13 tunes PI3K subunit stoichiometry.","evidence":"FBXL2 complex purification, Co-IP, ubiquitylation assays, phospho-site mutants, PI3K signaling readouts","pmids":["23604317"],"confidence":"High","gaps":["Integration with direct IRS-1 dephosphorylation in regulating PI3K not fully reconciled","Cell-type dependence of the p85β degradation axis unknown"]},{"year":2014,"claim":"Demonstrating PTEN binding to PDZ2 and PTPN13 control of β-catenin phosphorylation/stability expanded the scaffolding and Wnt-linked functions of the protein.","evidence":"Yeast two-hybrid/GST pull-down with PTEN PDZ-BM mutagenesis; Co-IP, RNAi, differentiation/stability assays (β-catenin)","pmids":["25448478","25193362"],"confidence":"Medium","gaps":["PTEN interaction shown without functional consequence in this study","Whether β-catenin is a direct substrate not demonstrated"]},{"year":2017,"claim":"Showing calpain-2 cleaves and inactivates PTPN13, de-repressing c-Abl and driving tau pathology after TBI, revealed regulated proteolysis as an off-switch with neuropathological consequence.","evidence":"PDZ partner ID, Co-IP, in vitro cleavage and phosphatase assays, c-Abl substrate identification, in vivo calpain-2 inhibitor","pmids":["28924170"],"confidence":"High","gaps":["Generalizability of the calpain-PTPN13-cAbl-tau axis beyond TBI unclear","Other substrates de-repressed by PTPN13 cleavage not catalogued"]},{"year":2018,"claim":"CRISPR knockout established PTPN13 as a phosphatase-independent scaffold required for apical PTEN enrichment, and PDZ3 structure with PRK2 refined ligand-recognition rules.","evidence":"CRISPR/Cas9 KO with brush-border phenotype, catalytically-dead rescue, Co-IP (PTEN); NMR of PDZ3-PRK2 complex","pmids":["29581186","30189200"],"confidence":"High","gaps":["How PTEN anchoring is coordinated with PTPN13 catalytic substrates unknown","Functional output of the PDZ3-PRK2 interaction in cells not defined"]},{"year":2020,"claim":"Catalytic-activity-dependent suppression of breast cancer motility/invasion and phosphatase-independent IGF2BP1/c-Myc control demonstrated that PTPN13 acts both enzymatically and as a scaffold to restrain tumor progression.","evidence":"Transgenic mouse, isogenic WT vs catalytic-dead clones, phosphoproteomics (invasion); Co-IP/competitive binding, c-Myc mRNA stability, ChIP/DNMT3A (IGF2BP1)","pmids":["31938048","33051595"],"confidence":"High","gaps":["Direct junction-protein substrates not individually validated","Coordination between catalytic and scaffolding tumor-suppressive arms unresolved"]},{"year":2022,"claim":"Epistasis placing PTPN13 upstream of Src/ERK/YAP1 and counteraction of TGF-β1/Smad/p38 EMT signaling consolidated its role as a brake on multiple oncogenic cascades in lung cancer.","evidence":"shRNA/siRNA knockdown, double-knockdown epistasis, Co-IP (p38), EMT marker and xenograft assays","pmids":["36193770","33536603"],"confidence":"Medium","gaps":["p38 MAPK as a direct substrate rests on a single Co-IP","Direct vs indirect control of YAP1 not distinguished"]},{"year":2025,"claim":"Identifying STAT1 dephosphorylation as the basis of APC-loss-driven immune evasion, PDLIM4 as a STAT-recruiting adaptor, and β-catenin-linked pathogenic mutations integrated PTPN13 into antigen presentation, T-cell differentiation, and inherited hematologic disease.","evidence":"APC-KO models, Co-IP, APC11 peptide competition, immune-infiltration/anti-PD1 assays (STAT1); Co-IP, PDLIM4-deficient T cells, nsSNP binding (adaptor); Co-IP, silencing, BCR-activation/surface markers (β-catenin/BTK in ALL/IBMF families)","pmids":["41486293","42028851","41422331"],"confidence":"High","gaps":["β-catenin pathogenic-mutation study (Medium) does not directly demonstrate dephosphorylation mechanism","How PDLIM4-recruited STAT dephosphorylation integrates with direct STAT1/4/6 substrate activity unresolved"]},{"year":null,"claim":"How PTPN13's distinct PDZ-anchored complexes, lipid-dependent membrane targeting, and broad substrate set are coordinated within a single cell to produce context-specific outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated model of substrate prioritization across tissues","In vivo phenotypes of full-length human PTPN13 loss incompletely mapped","Relationship between scaffolding and catalytic functions not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,9,17,18,19,20,25,28,39]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,15]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,6,32,36,40]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[12,13,16]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[14,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,12,13,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,4,13]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[7,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,24,25,28,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,39,40]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,17,23,26]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14,27]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,24,39,41]}],"complexes":["PTPN13-TAPP1 complex","PTPN13-PDLIM4-STAT complex","SCF-FBXL2 (functional partner in p85β degradation)"],"partners":["FAS","APC","PTEN","TRIP6","TAPP1","PRK2","SDCCAG3","IGF2BP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12923","full_name":"Tyrosine-protein phosphatase non-receptor type 13","aliases":["Fas-associated protein-tyrosine phosphatase 1","FAP-1","PTP-BAS","Protein-tyrosine phosphatase 1E","PTP-E1","hPTPE1","Protein-tyrosine phosphatase PTPL1"],"length_aa":2485,"mass_kda":276.9,"function":"Tyrosine phosphatase which negatively regulates FAS-induced apoptosis and NGFR-mediated pro-apoptotic signaling (PubMed:15611135). May regulate phosphoinositide 3-kinase (PI3K) signaling through dephosphorylation of PIK3R2 (PubMed:23604317)","subcellular_location":"Cytoplasm, cytoskeleton; Nucleus; Cell projection, lamellipodium","url":"https://www.uniprot.org/uniprotkb/Q12923/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPN13","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"STK26","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PTPN13","total_profiled":1310},"omim":[{"mim_id":"618489","title":"BROMODOMAIN-CONTAINING PROTEIN 7; BRD7","url":"https://www.omim.org/entry/618489"},{"mim_id":"618289","title":"ENDOSOME-ASSOCIATED TRAFFICKING REGULATOR 1; ENTR1","url":"https://www.omim.org/entry/618289"},{"mim_id":"613323","title":"FERM AND PDZ DOMAINS-CONTAINING PROTEIN 2; FRMPD2","url":"https://www.omim.org/entry/613323"},{"mim_id":"610496","title":"RHO GTPase-ACTIVATING PROTEIN 29; ARHGAP29","url":"https://www.omim.org/entry/610496"},{"mim_id":"608712","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, T; PTPRT","url":"https://www.omim.org/entry/608712"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Primary cilium transition zone","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":115.1}],"url":"https://www.proteinatlas.org/search/PTPN13"},"hgnc":{"alias_symbol":["PTP1E","PTP-BAS","PTPL1","PTP-BL"],"prev_symbol":[]},"alphafold":{"accession":"Q12923","domains":[{"cath_id":"1.10.510.10","chopping":"2-179","consensus_level":"medium","plddt":83.3394,"start":2,"end":179},{"cath_id":"3.10.20.90","chopping":"539-642_652-662","consensus_level":"medium","plddt":84.2117,"start":539,"end":662},{"cath_id":"2.30.29.30","chopping":"779-880","consensus_level":"medium","plddt":85.5759,"start":779,"end":880},{"cath_id":"2.30.42.10","chopping":"1091-1178","consensus_level":"high","plddt":81.472,"start":1091,"end":1178},{"cath_id":"2.30.42.10","chopping":"1367-1451","consensus_level":"high","plddt":85.4451,"start":1367,"end":1451},{"cath_id":"2.30.42.10","chopping":"1500-1587","consensus_level":"high","plddt":81.5655,"start":1500,"end":1587},{"cath_id":"2.30.42.10","chopping":"1785-1869","consensus_level":"medium","plddt":82.3036,"start":1785,"end":1869},{"cath_id":"3.90.190.10","chopping":"2174-2478","consensus_level":"medium","plddt":90.1041,"start":2174,"end":2478}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12923","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12923-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12923-F1-predicted_aligned_error_v6.png","plddt_mean":60.03},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPN13","jax_strain_url":"https://www.jax.org/strain/search?query=PTPN13"},"sequence":{"accession":"Q12923","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12923.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12923/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12923"}},"corpus_meta":[{"pmid":"11983165","id":"PMC_11983165","title":"EphrinB 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with ras for invasive growth.","date":"2007","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/18160445","citation_count":113,"is_preprint":false},{"pmid":"23604317","id":"PMC_23604317","title":"FBXL2- and PTPL1-mediated degradation of p110-free p85β regulatory subunit controls the PI(3)K signalling cascade.","date":"2013","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23604317","citation_count":109,"is_preprint":false},{"pmid":"7929060","id":"PMC_7929060","title":"Cloning and characterization of PTPL1, a protein tyrosine phosphatase with similarities to cytoskeletal-associated proteins.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7929060","citation_count":93,"is_preprint":false},{"pmid":"21061268","id":"PMC_21061268","title":"Curcumin suppresses human papillomavirus oncoproteins, restores p53, Rb, and PTPN13 proteins and inhibits benzo[a]pyrene-induced upregulation of HPV 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immunoprecipitation, in vitro phosphatase assay with 32P-labeled substrate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic assay plus structural domain characterization in original cloning paper, foundational result\",\n      \"pmids\": [\"7929060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PDZ domains 2 and 4 of PTPN13/PTPL1 interact with high affinity with the C-terminal tail of Fas/CD95; the three C-terminal residues (SLV) of Fas are necessary and sufficient for binding, with specific contributions from residues at positions -2, -3, -4, and -5.\",\n      \"method\": \"Peptide binding assay, affinity measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical peptide binding assay with systematic mutagenesis of ligand residues, defining binding determinants\",\n      \"pmids\": [\"9261095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The fourth PDZ domain of PTPN13/PTPL1 interacts with the C-terminal four residues of PARG1, a novel 150 kDa RhoGAP protein; PARG1 shows GAP activity toward Rho, Rac, and Cdc42 in vitro with preference for Rho, suggesting a PTPN13-PARG1 complex as a dual negative regulator of Rho signaling.\",\n      \"method\": \"Yeast two-hybrid, in vitro GAP assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identifies interaction domain, in vitro GAP activity confirmed; single study\",\n      \"pmids\": [\"9305890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PDZ domains 2 and 4 of PTPN13/PTP-BL bind the LIM domain of RIL; the RIL LIM domain can be phosphorylated on tyrosine in vitro and in vivo and is dephosphorylated in vitro by the PTPase domain of PTP-BL, placing RIL as a substrate.\",\n      \"method\": \"Yeast two-hybrid, in vitro kinase and phosphatase assays, immunohistochemistry for colocalization\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphatase assay directly demonstrating dephosphorylation of RIL LIM domain, plus in vivo phosphorylation evidence\",\n      \"pmids\": [\"9487134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The FERM domain of PTP-BL/PTPN13 is necessary and sufficient for targeting the protein to the apical side of epithelial MDCK cells; the protein shows a submembranous localization ~10-15 nm from the plasma membrane as shown by immuno-electron microscopy, and FRAP experiments show dynamic redistribution via a cytosolic pool. The PTP domains mediate homotypic interactions.\",\n      \"method\": \"Transient expression of modular domains, immuno-electron microscopy, immunofluorescence, FRAP, yeast two-hybrid\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with domain deletion analysis, FRAP, and EM; multiple orthogonal methods in one study\",\n      \"pmids\": [\"10504335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The PDZ1 domain of PTPN13/PTP-BAS interacts with IκBα through the N-terminal three ankyrin repeats of IκBα; this interaction was confirmed by co-immunoprecipitation in HeLa cells. Dominant-negative PTP-BAS caused tyrosine phosphorylation of IκBα, suggesting PTPN13 dephosphorylates IκBα to regulate NF-κB activation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, dominant-negative mutant expression\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP confirmation plus dominant-negative functional evidence; single lab\",\n      \"pmids\": [\"9882613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTPN13/PTP-BL PDZ2 domain (specifically the non-spliced variant PDZ2a) binds the extreme C-terminus of the tumor suppressor APC with a dissociation constant of 8.1×10⁻⁹ M; a naturally occurring 5-amino acid splice insertion (PDZ2b) abolishes this binding. Interaction confirmed by co-precipitation in COS cells and colocalization in epithelial cells.\",\n      \"method\": \"Yeast two-hybrid, surface plasmon resonance, co-precipitation in transfected COS cells, immunofluorescence colocalization\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — surface plasmon resonance provides quantitative KD, co-precipitation confirms in vivo interaction, splice variant abrogation is mechanistic\",\n      \"pmids\": [\"10951583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTPN13/PTP-BL PDZ2 domain interacts with the third LIM domain (including the C-terminus) of TRIP6; both proteins colocalize in transfected epithelial cells at F-actin structures, placing PTPN13 in a multiprotein complex with RIL and TRIP6 at actin-based structures.\",\n      \"method\": \"Yeast two-hybrid, co-precipitation from transfected cells, immunofluorescence colocalization\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-precipitation and colocalization confirmed in multiple interaction partners; single lab\",\n      \"pmids\": [\"10826496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The PDZ3 domain of PTPN13/PTP-BL interacts with the extreme C-terminus of PRK2 (protein kinase C-related kinase 2), a Rho effector serine/threonine kinase; a conserved C-terminal cysteine of PRK2 is indispensable for this interaction. Both proteins colocalize in lamellipodia-like structures in HeLa cells.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation from transfected HeLa cells, site-directed mutagenesis, immunofluorescence colocalization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP confirmed interaction, mutagenesis identifies critical residue; single lab\",\n      \"pmids\": [\"11356191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PTPN13/PTP-BL is recruited to ephrinB expression domains with delayed kinetics after EphB receptor engagement and mediates dephosphorylation of ephrinB, acting downstream of Src family kinases which phosphorylate ephrinB. This defines a switch from phosphotyrosine/SFK-dependent signaling to PDZ-dependent signaling.\",\n      \"method\": \"Co-immunoprecipitation, cell biology/signaling assays, phosphorylation analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, cell-based phosphorylation assays with temporal resolution, establishes substrate relationship and pathway position; well-cited\",\n      \"pmids\": [\"11983165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NMR solution structure of PDZ2 of PTP-BL/PTPN13 reveals a compact canonical PDZ fold with six β-strands and two α-helices, with a unique flexible L1 loop. PDZ2 binds C-termini of human Fas/CD95 and RIL (including non-canonical E-x-V motif), but murine PDZ2 does not bind murine Fas/CD95, suggesting species-specific differences in substrate recognition.\",\n      \"method\": \"NMR structure determination, 15N relaxation analysis, peptide binding studies\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional peptide binding validation and negative result for murine Fas\",\n      \"pmids\": [\"11884147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PTPN13/PTPL1/FAP-1 promotes apoptosis in MCF7 breast cancer cells by inhibiting the IRS-1/PI3K/Akt pathway; antisense abrogation of PTPL1 expression abolished tamoxifen-induced apoptosis, and PTPL1 expression reduced IRS-1 tyrosine phosphorylation by 65%, PI3K activity by 80%, and Akt activation by 55%.\",\n      \"method\": \"Antisense stable transfection, PI3K activity assay, Akt phosphorylation assay, TUNEL/nucleosome ELISA apoptosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple orthogonal pathway readouts; establishes pathway position with defined biochemical phenotypes\",\n      \"pmids\": [\"12354757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The FERM domain of PTPN13/PTPL1 is necessary and sufficient for membrane targeting to the apical plasma membrane enriched in dorsal microvilli; two PtdIns(4,5)P2-binding motifs within the FERM domain are required—mutation of both abolishes membrane localization. Direct interaction of the FERM domain with PtdIns(4,5)P2 was demonstrated by protein-lipid overlay assay.\",\n      \"method\": \"Live imaging of domain constructs in HeLa cells, site-directed mutagenesis of PIP2-binding motifs, protein-lipid overlay, cell fractionation, neomycin treatment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis, lipid overlay, fractionation, pharmacological), direct mechanistic link between FERM-PIP2 interaction and localization\",\n      \"pmids\": [\"12766187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Endogenous PTPN13/PTPL1 constitutively associates with TAPP1 (a PtdIns(3,4)P2-binding adaptor) primarily through its first PDZ domain; this complex enables PTPN13 association with PtdIns(3,4)P2 in vitro. TAPP1 binding maintains PTPN13 in the cytoplasm; upon H2O2 stimulation (which produces PtdIns(3,4)P2), the PTPN13-TAPP1 complex translocates to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, GST pull-down, RNA interference, lipid binding assay, subcellular fractionation\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — endogenous Co-IP, domain mapping by GST pull-down, RNAi functional consequence, lipid binding assay; multiple orthogonal methods\",\n      \"pmids\": [\"14516276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTPN13/PTP-BL localizes to centrosomes during inter- and metaphase, the spindle midzone during anaphase, and concentrates at the midbody during cytokinesis. Targeting to midbody/centrosome requires a specific N-terminal splicing variant (182 aa insertion). The FERM domain associates with the contractile ring and co-sediments with F-actin; the N-terminus co-sediments with microtubules. Overexpression of wild-type or phosphatase-dead PTPN13 causes cytokinesis defects and multinucleate cells.\",\n      \"method\": \"Immunofluorescence localization of endogenous protein, domain deletion constructs, actin/microtubule co-sedimentation, overexpression functional assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization of endogenous protein with functional consequence (cytokinesis defects), domain mapping by co-sedimentation; multiple orthogonal methods\",\n      \"pmids\": [\"12529439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of the PTPN13/PTPL1 catalytic domain at 1.8 Å resolution reveals the standard PTP fold with an additional N-terminal helix and an ordered phosphate in the active site. A second positively charged pocket near the active site resembles the second phosphotyrosine-binding site of PTP1B; consistent with this, PTPL1 dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides. Four of five colorectal cancer mutations map to solvent-exposed regions remote from the active site; the fifth (Met2307Thr) is near the active-site cysteine and significantly decreases activity.\",\n      \"method\": \"X-ray crystallography (1.8 Å), in vitro phosphatase assay with bis- vs mono-phosphorylated peptides, mutant activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus in vitro enzymatic assay with mutagenesis analysis; single paper with multiple orthogonal methods\",\n      \"pmids\": [\"15611135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NMR structure of the alternatively spliced PDZ2b (with 5-residue insertion) of PTP-BL/PTPN13 reveals that the insert causes reorientation of a loop that closes the binding site (Lys32 side chain occludes the pocket) and repositions α-helix 2, rendering the binding pocket unable to accommodate APC C-terminus; PDZ2b binds PIP2 and PIP3 with KD ~230 μM via a groove overlapping the APC binding site.\",\n      \"method\": \"NMR structure determination, NMR titration binding studies, high-affinity chromatography for lipid binding\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with functional binding validation explains splice-dependent specificity change; single rigorous study\",\n      \"pmids\": [\"14596806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13/PTPL1 directly dephosphorylates IRS-1 (insulin receptor substrate-1) in vitro and in cells; this is confirmed by dominant-negative mutant and RNAi approaches. PTPN13 expression blocks the IRS-1/PI3K/Akt pathway, inhibits IGF-I-induced cell survival, and induces apoptosis.\",\n      \"method\": \"In vitro phosphatase assay, co-immunoprecipitation, dominant-negative mutant, RNA interference, PI3K/Akt pathway assays, cell survival assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation assay directly establishing IRS-1 as substrate, confirmed by multiple complementary approaches (DN mutant + RNAi) in cells\",\n      \"pmids\": [\"17638892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 negatively regulates Her2/ErbB2 signaling by dephosphorylating the Her2 signaling domain; siRNA knockdown of PTPN13 augmented Her2 phosphorylation and promoted cancer cell invasiveness. Growth factor-induced phosphorylation of PTPN13 is required for its ability to dephosphorylate Her2, suggesting a negative feedback mechanism. PTPN13 mutations found in human tumors reduced phosphatase activity.\",\n      \"method\": \"siRNA phosphatase library screen, phosphorylation assays, cell invasion assays, mutant phosphatase activity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA screen followed by phosphorylation assays and mutant activity measurements establish Her2 as substrate; multiple orthogonal approaches\",\n      \"pmids\": [\"17982484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13/PTP-BL dephosphorylates STAT proteins (STAT4, STAT6 confirmed) in vitro and in vivo, attenuating STAT-mediated gene activation. In CD4+ T cells, PTP-BL deficiency leads to increased and prolonged activation of STAT4 and STAT6, and consequently enhanced Th1 and Th2 cell differentiation.\",\n      \"method\": \"In vitro phosphatase assay, PTP-BL-deficient mouse model, T cell differentiation assays, STAT phosphorylation measurements\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation assay plus genetic knockout model with defined cellular phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"17306571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13/PTPL1 dephosphorylates phosphotyrosine-55 of TRIP6 in vitro, inhibiting LPA-induced tyrosine phosphorylation of TRIP6 in cells. This negative regulation requires direct protein-protein interaction and phosphatase activity of PTPL1, preventing TRIP6 turnover at adhesion sites and inhibiting LPA-induced Crk recruitment and cell migration.\",\n      \"method\": \"In vitro phosphatase assay, co-immunoprecipitation, phosphatase-dead mutant, cell migration/morphology assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro dephosphorylation assay identifies specific substrate site (Tyr-55), confirmed in cells with phosphatase-dead mutant and functional migration readout\",\n      \"pmids\": [\"17591779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13/PTPL1 interacts with the TRP channel TRPM2 (confirmed by co-IP and GST pull-down); PTPL1 co-expression reduces TRPM2 tyrosine phosphorylation and inhibits H2O2/TNFα-induced Ca2+ influx and cell death. PTPL1 knockdown increases TRPM2 tyrosine phosphorylation, Ca2+ influx, and cell death susceptibility. Endogenous TRPM2-PTPL1 association confirmed in U937 cells.\",\n      \"method\": \"PDZ array blot, co-immunoprecipitation, GST pull-down, siRNA knockdown, Ca2+ imaging, cell viability assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays plus siRNA and overexpression with specific phosphorylation and functional readouts; endogenous interaction confirmed\",\n      \"pmids\": [\"17251321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"An allosteric intramolecular PDZ1-PDZ2 interaction within PTPN13/PTP-BL modulates PDZ2 binding specificity; structural studies revealed PDZ1 directly contacts a surface on PDZ2 opposite the peptide binding groove, causing long-range allosteric changes in the PDZ2 binding pocket.\",\n      \"method\": \"Phage display library screening, NMR structural studies, binding specificity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure combined with phage display functional specificity assay reveals allosteric mechanism\",\n      \"pmids\": [\"17979300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ICSBP/IRF8 represses PTPN13 gene transcription by binding to a cis element in the proximal PTPN13 promoter in differentiating myeloid cells; this repression is regulated by phosphorylation of conserved tyrosine residues in the ICSBP IRF domain and increases during myeloid differentiation. ICSBP influences Fas-induced apoptosis in a FAP-1/PTPN13-dependent manner.\",\n      \"method\": \"CpG island microarray with chromatin immunoprecipitation, luciferase reporter assays, ChIP, phosphorylation mutants, Fas-apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirms direct promoter binding, luciferase assays confirm functional repression, phosphorylation mutants establish regulatory mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"18195016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTPN13 phosphatase activity inhibits Ras/RAF/MEK/Erk signaling downstream of ErbB2, EGFR, and H-RasV12; co-transfection of wild-type but not enzymatically inactive PTPN13 inhibited this pathway. HPV-negative HNSCCs with PTPN13 phosphatase mutations showed impaired Ras/RAF/MEK/Erk inhibition. MEK inhibitor U0126 blocked anchorage-independent growth in PTPN13-deficient cells, placing PTPN13 upstream of ERK signaling.\",\n      \"method\": \"Co-transfection assays, phosphatase activity mutants, ERK phosphorylation assays, MEK inhibitor epistasis, anchorage-independent growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enzymatic activity requirement established by catalytic mutant; MEK inhibitor epistasis places PTPN13 in pathway; multiple complementary approaches\",\n      \"pmids\": [\"19734941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTPN13/PTPL1 directly dephosphorylates Src at tyrosine 419 (the activating phosphorylation site) as shown by substrate-trapping experiments; PTPL1 knockdown increases Src-Y419 phosphorylation and activates downstream Fak and p130cas. PTPL1 inhibition dramatically increased tumor growth and invasion, identifying PTPL1 as the first phosphatase shown to directly inhibit Src in intact cells.\",\n      \"method\": \"Substrate-trapping with catalytic mutant, phosphorylation assays, RNA interference, in vivo tumor growth assay, invasion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — substrate-trapping with catalytic mutant directly identifies Src-Y419 as substrate, confirmed in cells by RNAi with specific phosphorylation readouts\",\n      \"pmids\": [\"20501847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPN13/PTPL1 is a direct transcriptional target of ICSBP; repression requires cooperation of ICSBP with Tel and HDAC3 forming a multiprotein complex at the PTPN13 cis element. The leukemia fusion protein Tel-PdgfRβ disrupts this repressive complex by competing with the Tel component, resulting in increased PTPN13 expression and Fas-resistance.\",\n      \"method\": \"ChIP, promoter reporter assays, knockdown of Tel/HDAC3, co-immunoprecipitation of repressor complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP confirms complex at promoter, knockdown experiments establish functional requirement, co-IP identifies complex composition; multiple orthogonal methods\",\n      \"pmids\": [\"22262849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SDCCAG3 forms a complex with PTPN13 (co-immunoprecipitation) and both colocalize at the midbody during cytokinesis; SDCCAG3 is an endosomal protein (early/recycling endosome) that interacts with the ArfGAP GIT1. Overexpression or downregulation of SDCCAG3 causes multinucleate cells, linking PTPN13's cytokinesis function to endosomal trafficking via SDCCAG3-GIT1.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, overexpression/knockdown functional assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms complex, functional assays establish cytokinesis role; single lab\",\n      \"pmids\": [\"23108400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTPN13/PTPL1 dephosphorylates p85β (PI3K regulatory subunit) at Tyr-655, which stimulates p85β binding to and degradation through the SCF-FBXL2 ubiquitin ligase complex; this controls PI3K signaling by reducing the pool of free p85β that competes with p85-p110 heterodimers for IRS1.\",\n      \"method\": \"Protein purification (FBXL2 complex), co-immunoprecipitation, ubiquitylation assays, phosphorylation site mutants, PI3K signaling assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification identifies complex, phosphorylation site mutagenesis, functional signaling consequence established; single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"23604317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTEN binds to PDZ2 of PTPN13 in a manner dependent on the PTEN PDZ-binding motif and the specific PDZ domain arrangement including the PDZ1-PDZ2 interdomain region; this was shown by yeast two-hybrid and GST pull-down with mutational analysis of the PTEN PDZ-BM.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, site-directed mutagenesis of PTEN PDZ-BM\",\n      \"journal\": \"Methods (San Diego, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two complementary binding assays with mutagenesis; single study, no functional consequence demonstrated beyond binding\",\n      \"pmids\": [\"25448478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN13 co-immunoprecipitates and colocalizes with β-catenin; PTPN13 regulates β-catenin phosphorylation, stability, and transcriptional activity during megakaryocytic differentiation. PTPN13 is stabilized upon Wnt signaling, and its silencing triggers megakaryocytic differentiation through effects on ERK and STAT signaling and β-catenin.\",\n      \"method\": \"Co-immunoprecipitation, colocalization, siRNA silencing, differentiation assays, phosphorylation/stability assays\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms interaction, RNAi with differentiation phenotype; single lab with multiple assays\",\n      \"pmids\": [\"25193362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPN13/FAP-1 is a PDZ-domain-mediated binding partner of calpain-2; PTPN13 is cleaved by calpain-2, which inactivates its phosphatase activity and generates stable breakdown products (P13BPs). PTPN13 dephosphorylates and inhibits c-Abl; after TBI, calpain-2-mediated PTPN13 cleavage activates c-Abl and triggers tau tyrosine phosphorylation and oligomer accumulation. Post-TBI calpain-2 inhibitor treatment prevented this cascade.\",\n      \"method\": \"PDZ binding partner identification, co-immunoprecipitation, in vitro cleavage and phosphatase activity assays, calpain-2 selective inhibitor in vivo\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical assays (cleavage, phosphatase inactivation, c-Abl as substrate), in vivo pharmacological validation with calpain-2 inhibitor; multiple orthogonal methods\",\n      \"pmids\": [\"28924170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPN13/PTPL1 interacts with PTEN, and this interaction is necessary for apical membrane enrichment of PTEN in polarized epithelial cells; PTPL1 depletion (CRISPR/Cas9) causes enlarged brush border similar to PTEN loss. PTPL1 functions as a scaffolding anchor for PTEN in this process—its phosphatase activity is NOT required.\",\n      \"method\": \"CRISPR/Cas9 knockout, live imaging of brush border formation, co-immunoprecipitation, domain mapping\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with specific phenotypic readout, Co-IP confirms interaction, catalytically-inactive rescue distinguishes scaffolding from enzymatic function; multiple orthogonal methods\",\n      \"pmids\": [\"29581186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NMR solution structures of the PDZ3 domain of murine PTPN13 in apo form and in complex with the C-terminal peptide of PRK2 reveal classical compact globular fold; PRK2 binds via an elongated peptide in the canonical groove between β-strand and α-helix, with P0 cysteine and P-2 aspartate facing the groove (class III ligand recognition).\",\n      \"method\": \"Multidimensional NMR spectroscopy, structure determination\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution NMR structure of protein-ligand complex with physiological ligand PRK2\",\n      \"pmids\": [\"30189200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The tandem PDZ2/3 domain of PTPN13 shows allosterically modulated binding to APC; PDZ3 presence alters PDZ2 binding affinity for APC, and PRK2 is identified as a weak binding partner of PDZ2. HADDOCK molecular modeling and NMR spectroscopy support an allosteric effect from PDZ3 on PDZ2's ligand binding site.\",\n      \"method\": \"NMR spectroscopy, HADDOCK molecular modeling, binding affinity measurements of isolated vs tandem domains\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR-based structural and binding analysis; single lab, allosteric effect supported by computational model\",\n      \"pmids\": [\"31286859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN13 phosphatase activity is required to inhibit breast cancer cell motility and invasion; PTPN13 overexpression in MDA-MB-231 cells inhibited invasion and induced mesenchymal-to-epithelial transition in vivo. Phosphoproteomic and GO analyses revealed a role for PTPN13 in regulation of intercellular junction proteins; PTPN13 stabilizes intercellular adhesion and promotes desmosome formation.\",\n      \"method\": \"Transgenic mouse crossing (HER2×PTPN13-ΔP), isogenic cell clones with WT vs catalytically inactive PTPN13, phosphoproteomics, wound healing, Boyden chamber, videomicroscopy, immunofluorescence\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model plus phosphoproteomics plus isogenic cell clones with catalytic mutant; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"31938048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN13 competitively binds IGF2BP1 to decrease functional IGF2BP1 levels, thereby promoting c-Myc mRNA degradation and suppressing metabolic reprogramming; this function is independent of PTPN13 phosphatase activity. HBx inhibits PTPN13 expression by upregulating DNMT3A, which binds the PTPN13 promoter (-343 to -313 bp) and increases DNA methylation to suppress transcription.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assays, c-Myc mRNA stability assays, ChIP on PTPN13 promoter, DNMT3A knockdown\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and competitive binding establish PTPN13-IGF2BP1 interaction, ChIP confirms DNMT3A promoter binding; single lab\",\n      \"pmids\": [\"33051595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTPN13/PTPL1 suppresses TGF-β1-induced EMT in lung cancer cells by counteracting activation of canonical Smad2/3 and non-canonical p38 MAPK signaling pathways; immunoprecipitation demonstrated direct binding of PTPL1 to p38 MAPK, suggesting p38 MAPK as a direct substrate.\",\n      \"method\": \"siRNA knockdown, immunoprecipitation for PTPL1-p38 MAPK interaction, EMT marker analysis, Smad2/3 and p38 phosphorylation assays, xenograft model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP for substrate identification; functional consequence shown in cells and in vivo; single lab\",\n      \"pmids\": [\"33536603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPL1/PTPN13 suppresses lung cancer cell proliferation by counteracting the Src/ERK pathway; PTPL1 knockdown induced activation of Src/ERK signaling and promoted YAP1 nuclear translocation and activation. YAP1 co-knockdown reversed the proliferation increase caused by PTPL1 knockdown, placing PTPL1 upstream of Src/ERK/YAP1.\",\n      \"method\": \"shRNA knockdown, signaling pathway assays, xenograft model, double knockdown epistasis\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (double knockdown) places PTPL1 upstream of Src/ERK/YAP1; single lab\",\n      \"pmids\": [\"36193770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN13 directly dephosphorylates STAT1, suppressing interferon-stimulated MHC class I antigen presentation and CD8+ T cell infiltration; peptides containing the last 11 C-terminal residues of APC (APC11) bind directly to PTPN13, block PTPN13-STAT1 interaction, restore STAT1 phosphorylation and IRF1 expression, and enhance anti-tumor immunity in CRC. APC loss thus drives immune evasion via PTPN13-dependent STAT1 dephosphorylation independently of β-catenin.\",\n      \"method\": \"APC knockout models, Co-immunoprecipitation for PTPN13-STAT1 interaction, STAT1 phosphorylation assays, APC11 peptide competition assay, in vivo tumor/immune infiltration assays, anti-PD1 combination experiments\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifies PTPN13-STAT1 complex, peptide competition directly blocks the interaction with functional consequence, multiple in vivo and in vitro readouts; single rigorous paper with multiple orthogonal methods\",\n      \"pmids\": [\"41486293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDLIM4 acts as an adaptor that recruits PTP-BL/PTPN13 through its LIM domain to facilitate dephosphorylation of STAT3, STAT4, and STAT6; a disease-associated PDLIM4 nsSNP in the LIM domain reduces PTP-BL binding and impairs STAT3 dephosphorylation, linking this complex to regulation of Th1, Th2, and Th17 differentiation.\",\n      \"method\": \"Co-immunoprecipitation, STAT phosphorylation assays, PDLIM4-deficient T cells, LIM domain nsSNP mutant binding assay\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifies PDLIM4 as adaptor recruiting PTPN13, genetic deficiency model with cellular phenotype, disease SNP validates mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"42028851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN13 pathogenic mutations (identified in ALL/anemia/IBMF families) impair the PTPN13-β-catenin interaction; PTPN13 silencing reduces Bruton's tyrosine kinase (BTK) activation and β-catenin levels after B-cell receptor (BCR) stimulation, indicating PTPN13 modulates BCR signaling and lymphoid cell homeostasis through β-catenin.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, PTPN13 silencing with BCR activation assays, surface marker analysis (CD25, CD38)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RNAi with defined signaling readouts; single lab, functional consequence shown for BTK/β-catenin but mechanism of dephosphorylation not directly demonstrated\",\n      \"pmids\": [\"41422331\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN13 (PTPL1/PTP-BL/FAP-1) is a large (~270 kDa) non-receptor protein tyrosine phosphatase whose FERM domain targets it to the apical plasma membrane via PtdIns(4,5)P2 binding and whose five PDZ domains assemble multi-protein complexes; its established direct substrates include ephrinB, IRS-1, Src (at Y419), Her2/ErbB2, TRIP6 (at Y55), STAT1/4/6, p85β (at Y655), and c-Abl, through which it negatively regulates PI3K/Akt, Ras/RAF/MEK/ERK, Src/FAK, STAT, and interferon/antigen-presentation pathways, and it also functions as a phosphatase-independent scaffold anchoring PTEN to the apical membrane and recruiting PDLIM4-directed STAT dephosphorylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPN13 (PTPL1/PTP-BL/FAP-1) is a large cytoplasmic protein tyrosine phosphatase that integrates an N-terminal FERM domain, five PDZ domains, and a C-terminal PTP catalytic domain to act as a membrane-anchored scaffold and negative regulator of tyrosine-kinase signaling [#0, #15]. Its FERM domain binds PtdIns(4,5)P2 directly and is necessary and sufficient to target the protein to the apical plasma membrane and dorsal microvilli of epithelial cells, while a TAPP1/PtdIns(3,4)P2-dependent route mediates inducible membrane recruitment upon oxidative stimulation [#12, #13]. The tandem PDZ array assembles multiprotein complexes through C-terminal-motif recognition, with binding specificity tuned by alternative splicing and intramolecular PDZ1–PDZ2 allostery [#1, #6, #16, #22]. Through these PDZ-anchored complexes and its catalytic domain, PTPN13 dephosphorylates a broad set of phosphotyrosine substrates—including ephrinB, IRS-1, Her2/ErbB2, Src at the activating Tyr419, TRIP6 at Tyr55, the PI3K regulatory subunit p85β at Tyr655, STAT family proteins, and c-Abl—thereby restraining PI3K/Akt, Ras/RAF/MEK/ERK, Src/FAK, and STAT signaling and promoting apoptosis while suppressing tumor cell invasion and migration [#9, #11, #17, #18, #20, #24, #25, #28, #19, #31, #35]. Beyond catalysis, PTPN13 also functions as a phosphatase-independent scaffold: it anchors PTEN at the apical membrane and competitively sequesters IGF2BP1 to destabilize c-Myc mRNA [#32, #36]. PTPN13 localizes to the centrosome, spindle midzone, and midbody, where its activity is required for faithful cytokinesis [#14, #27]. By dephosphorylating STAT1, PTPN13 suppresses interferon-stimulated MHC class I antigen presentation and CD8+ T cell infiltration, a circuit engaged by APC loss in colorectal cancer [#39]. Pathogenic PTPN13 mutations in families with ALL/anemia/inherited bone marrow failure impair the PTPN13–β-catenin interaction and BCR-driven BTK/β-catenin signaling, linking the gene to lymphoid homeostasis [#41].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that PTPN13 is a bona fide tyrosine phosphatase with a distinctive multidomain architecture defined the gene as a candidate scaffolding phosphatase rather than a simple enzyme.\",\n      \"evidence\": \"PCR cloning, immunoprecipitation, and in vitro phosphatase assay on 32P-myelin basic protein\",\n      \"pmids\": [\"7929060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified at this stage\", \"Roles of the FERM, PDZ, and leucine-zipper modules unassigned\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Mapping PDZ2/PDZ4 binding to the Fas/CD95 C-terminus and PDZ4 to the RhoGAP PARG1 showed PTPN13 selects partners via C-terminal motifs, framing it as a multi-complex organizer.\",\n      \"evidence\": \"Peptide binding/affinity assays for Fas; yeast two-hybrid and in vitro GAP assay for PARG1\",\n      \"pmids\": [\"9261095\", \"9305890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Fas binding not resolved here\", \"PARG1 complex link to Rho signaling inferred from in vitro GAP, not cellular readout\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying RIL as both a PDZ-binding partner and an in vitro substrate connected PTPN13's scaffolding and catalytic functions at actin-based structures.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro kinase/phosphatase assays, colocalization\",\n      \"pmids\": [\"9487134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of RIL dephosphorylation in cells not established\", \"Cellular pathway controlled by RIL phosphorylation unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that the FERM domain alone targets PTPN13 to the apical membrane, and IκBα binds PDZ1, defined how the phosphatase is positioned and added an NF-κB-regulatory link.\",\n      \"evidence\": \"Modular domain expression, immuno-EM, FRAP for localization; yeast two-hybrid, Co-IP, dominant-negative for IκBα\",\n      \"pmids\": [\"10504335\", \"9882613\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular driver of FERM targeting not yet identified (resolved later)\", \"IκBα as a direct substrate inferred from dominant-negative, not in vitro dephosphorylation\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Quantifying high-affinity PDZ2 binding to the APC tumor suppressor and its abolition by a 5-residue splice insertion revealed splicing as a switch controlling PTPN13 partner selection.\",\n      \"evidence\": \"Yeast two-hybrid, surface plasmon resonance, co-precipitation, colocalization; additional TRIP6 PDZ2 mapping\",\n      \"pmids\": [\"10951583\", \"10826496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of the PTPN13-APC complex not defined here\", \"Physiological regulation of the splicing switch unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defining ephrinB dephosphorylation downstream of Src family kinases, and solving the PDZ2 structure, established PTPN13 as a temporally-controlled signaling switch with structurally rationalized specificity.\",\n      \"evidence\": \"Reciprocal Co-IP and temporal phosphorylation assays (ephrinB); NMR structure with peptide binding (PDZ2); FEBS PRK2 PDZ3 interaction mapping\",\n      \"pmids\": [\"11983165\", \"11884147\", \"11356191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Species-specific PDZ2 recognition complicates extrapolation across organisms\", \"In vivo ephrinB regulation by endogenous PTPN13 not tested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showing PTPN13 localizes to centrosome, midzone, and midbody and its overexpression causes multinucleation established a direct role in cytokinesis.\",\n      \"evidence\": \"Immunofluorescence of endogenous protein, domain co-sedimentation with actin/microtubules, overexpression phenotype\",\n      \"pmids\": [\"12529439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate dephosphorylated during cytokinesis not identified\", \"Mechanism linking phosphatase activity to abscission unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying the FERM–PtdIns(4,5)P2 interaction and TAPP1/PtdIns(3,4)P2-dependent recruitment defined the lipid logic of constitutive versus stimulus-induced membrane targeting.\",\n      \"evidence\": \"Mutagenesis of PIP2-binding motifs, protein-lipid overlay, fractionation (FERM); endogenous Co-IP, GST pull-down, RNAi, lipid binding (TAPP1)\",\n      \"pmids\": [\"12766187\", \"14516276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How membrane recruitment is coupled to substrate access not resolved\", \"Relative contribution of constitutive vs inducible routes in vivo unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"The catalytic domain crystal structure and the spliced PDZ2b NMR structure provided atomic-level explanations for substrate preference and splice-dependent specificity loss.\",\n      \"evidence\": \"X-ray crystallography of PTP domain with bis-phospho-peptide assay; NMR of PDZ2b with binding studies\",\n      \"pmids\": [\"15611135\", \"14596806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological bis-phosphorylated substrates not identified\", \"Functional consequence of PDZ2b lipid binding in cells untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A burst of substrate-identification studies established PTPN13 as a broad negative regulator of growth/survival signaling and immune differentiation by directly dephosphorylating IRS-1, Her2, TRIP6, STATs, and regulating TRPM2.\",\n      \"evidence\": \"In vitro phosphatase assays, Co-IP, dominant-negative/RNAi, knockout mouse (STATs), substrate-site mapping (TRIP6 Tyr55), Ca2+/viability assays (TRPM2)\",\n      \"pmids\": [\"17638892\", \"17982484\", \"17591779\", \"17306571\", \"17251321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy/coordination among multiple substrates within a single cell unresolved\", \"Determinants of substrate selection by individual PDZ domains incompletely mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovering an allosteric PDZ1–PDZ2 interaction and transcriptional repression by ICSBP/IRF8 revealed both intramolecular and gene-expression-level control of PTPN13 function.\",\n      \"evidence\": \"Phage display, NMR (PDZ1-PDZ2 allostery); ChIP, luciferase reporters, phospho-mutants (ICSBP)\",\n      \"pmids\": [\"17979300\", \"18195016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of allosteric specificity modulation unknown\", \"Signals controlling ICSBP-mediated repression beyond myeloid differentiation unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Placing PTPN13 phosphatase activity upstream of Ras/RAF/MEK/ERK extended its tumor-suppressive scope to a major mitogenic cascade and linked cancer-associated catalytic mutations to pathway dysregulation.\",\n      \"evidence\": \"Co-transfection with catalytic mutants, ERK phosphorylation assays, MEK-inhibitor epistasis, anchorage-independent growth in HNSCC\",\n      \"pmids\": [\"19734941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ERK-pathway substrate not pinpointed in this study\", \"Mechanism connecting PTPN13 to upstream receptors incompletely defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Substrate-trapping identification of Src Tyr419 as a direct target established PTPN13 as the first phosphatase shown to directly inactivate Src in intact cells, with strong tumor-suppressive consequences.\",\n      \"evidence\": \"Substrate-trapping catalytic mutant, RNAi, downstream FAK/p130cas readouts, in vivo tumor growth/invasion\",\n      \"pmids\": [\"20501847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial coupling of PTPN13 to Src pools not defined\", \"Whether membrane anchoring is required for Src dephosphorylation untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defining an ICSBP–Tel–HDAC3 repressor complex at the PTPN13 promoter and its disruption by Tel-PdgfRβ, plus the SDCCAG3 cytokinesis link, connected PTPN13 regulation to leukemogenesis and trafficking.\",\n      \"evidence\": \"ChIP, reporter assays, Tel/HDAC3 knockdown, complex Co-IP (transcription); Co-IP, colocalization, knockdown (SDCCAG3)\",\n      \"pmids\": [\"22262849\", \"23108400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How increased PTPN13 confers Fas-resistance mechanistically unresolved\", \"SDCCAG3-GIT1 endosomal contribution to cytokinesis defined only by Co-IP and phenotype\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identifying p85β Tyr655 dephosphorylation that triggers SCF-FBXL2-mediated p85β degradation revealed an indirect route by which PTPN13 tunes PI3K subunit stoichiometry.\",\n      \"evidence\": \"FBXL2 complex purification, Co-IP, ubiquitylation assays, phospho-site mutants, PI3K signaling readouts\",\n      \"pmids\": [\"23604317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration with direct IRS-1 dephosphorylation in regulating PI3K not fully reconciled\", \"Cell-type dependence of the p85β degradation axis unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating PTEN binding to PDZ2 and PTPN13 control of β-catenin phosphorylation/stability expanded the scaffolding and Wnt-linked functions of the protein.\",\n      \"evidence\": \"Yeast two-hybrid/GST pull-down with PTEN PDZ-BM mutagenesis; Co-IP, RNAi, differentiation/stability assays (β-catenin)\",\n      \"pmids\": [\"25448478\", \"25193362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PTEN interaction shown without functional consequence in this study\", \"Whether β-catenin is a direct substrate not demonstrated\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing calpain-2 cleaves and inactivates PTPN13, de-repressing c-Abl and driving tau pathology after TBI, revealed regulated proteolysis as an off-switch with neuropathological consequence.\",\n      \"evidence\": \"PDZ partner ID, Co-IP, in vitro cleavage and phosphatase assays, c-Abl substrate identification, in vivo calpain-2 inhibitor\",\n      \"pmids\": [\"28924170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generalizability of the calpain-PTPN13-cAbl-tau axis beyond TBI unclear\", \"Other substrates de-repressed by PTPN13 cleavage not catalogued\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CRISPR knockout established PTPN13 as a phosphatase-independent scaffold required for apical PTEN enrichment, and PDZ3 structure with PRK2 refined ligand-recognition rules.\",\n      \"evidence\": \"CRISPR/Cas9 KO with brush-border phenotype, catalytically-dead rescue, Co-IP (PTEN); NMR of PDZ3-PRK2 complex\",\n      \"pmids\": [\"29581186\", \"30189200\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PTEN anchoring is coordinated with PTPN13 catalytic substrates unknown\", \"Functional output of the PDZ3-PRK2 interaction in cells not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Catalytic-activity-dependent suppression of breast cancer motility/invasion and phosphatase-independent IGF2BP1/c-Myc control demonstrated that PTPN13 acts both enzymatically and as a scaffold to restrain tumor progression.\",\n      \"evidence\": \"Transgenic mouse, isogenic WT vs catalytic-dead clones, phosphoproteomics (invasion); Co-IP/competitive binding, c-Myc mRNA stability, ChIP/DNMT3A (IGF2BP1)\",\n      \"pmids\": [\"31938048\", \"33051595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct junction-protein substrates not individually validated\", \"Coordination between catalytic and scaffolding tumor-suppressive arms unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epistasis placing PTPN13 upstream of Src/ERK/YAP1 and counteraction of TGF-β1/Smad/p38 EMT signaling consolidated its role as a brake on multiple oncogenic cascades in lung cancer.\",\n      \"evidence\": \"shRNA/siRNA knockdown, double-knockdown epistasis, Co-IP (p38), EMT marker and xenograft assays\",\n      \"pmids\": [\"36193770\", \"33536603\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p38 MAPK as a direct substrate rests on a single Co-IP\", \"Direct vs indirect control of YAP1 not distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identifying STAT1 dephosphorylation as the basis of APC-loss-driven immune evasion, PDLIM4 as a STAT-recruiting adaptor, and β-catenin-linked pathogenic mutations integrated PTPN13 into antigen presentation, T-cell differentiation, and inherited hematologic disease.\",\n      \"evidence\": \"APC-KO models, Co-IP, APC11 peptide competition, immune-infiltration/anti-PD1 assays (STAT1); Co-IP, PDLIM4-deficient T cells, nsSNP binding (adaptor); Co-IP, silencing, BCR-activation/surface markers (β-catenin/BTK in ALL/IBMF families)\",\n      \"pmids\": [\"41486293\", \"42028851\", \"41422331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"β-catenin pathogenic-mutation study (Medium) does not directly demonstrate dephosphorylation mechanism\", \"How PDLIM4-recruited STAT dephosphorylation integrates with direct STAT1/4/6 substrate activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTPN13's distinct PDZ-anchored complexes, lipid-dependent membrane targeting, and broad substrate set are coordinated within a single cell to produce context-specific outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated model of substrate prioritization across tissues\", \"In vivo phenotypes of full-length human PTPN13 loss incompletely mapped\", \"Relationship between scaffolding and catalytic functions not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 9, 17, 18, 19, 20, 25, 28, 39]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 6, 32, 36, 40]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [12, 13, 16]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [14, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 12, 13, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 4, 13]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [7, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 24, 25, 28, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 39, 40]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 17, 23, 26]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 24, 39, 41]}\n    ],\n    \"complexes\": [\n      \"PTPN13-TAPP1 complex\",\n      \"PTPN13-PDLIM4-STAT complex\",\n      \"SCF-FBXL2 (functional partner in p85\\u03b2 degradation)\"\n    ],\n    \"partners\": [\n      \"FAS\",\n      \"APC\",\n      \"PTEN\",\n      \"TRIP6\",\n      \"TAPP1\",\n      \"PRK2\",\n      \"SDCCAG3\",\n      \"IGF2BP1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}