{"gene":"PTPN13","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1994,"finding":"PTPN13 (PTPL1) was identified as a novel cytoplasmic protein tyrosine phosphatase with a PTP domain, a FERM domain (band 4.1 homology), five GLGF/PDZ repeats, and a leucine zipper motif; its catalytic activity was confirmed by dephosphorylation of 32P-labeled myelin basic protein in vitro.","method":"PCR-based cloning, in vitro phosphatase assay with MBP substrate","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with direct in vitro enzymatic assay","pmids":["7929060"],"is_preprint":false},{"year":1997,"finding":"The PDZ2 and PDZ4 domains of PTPN13 bind with high affinity to the C-terminal tail of Fas/CD95; the three C-terminal residues (SLV) of Fas are necessary and sufficient for high-affinity interaction with both PDZ2 and PDZ4.","method":"Peptide binding assay (affinity chromatography), systematic mutagenesis of Fas C-terminus","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical binding assay with mutagenesis defining binding determinants","pmids":["9261095"],"is_preprint":false},{"year":1997,"finding":"PTPN13 PDZ4 domain interacts with the C-terminal four residues of PARG1 (PTPL1-associated RhoGAP 1), a novel 150-kDa protein whose GAP domain is active on Rho, Rac, and Cdc42 in vitro (preferring Rho), suggesting PTPN13 can scaffold a potent negative regulator of Rho signaling.","method":"Yeast two-hybrid, in vitro GAP activity assay, pulldown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — biochemical interaction and enzymatic activity of the complex characterized in vitro","pmids":["9305890"],"is_preprint":false},{"year":1998,"finding":"PTPN13 PDZ2 and PDZ4 domains interact with the LIM domain of the adaptor protein RIL; the RIL LIM domain is phosphorylated on tyrosine in vivo and is dephosphorylated in vitro by the PTPN13 PTP domain, establishing RIL-LIM as a direct substrate.","method":"Yeast two-hybrid, in vitro phosphatase assay, co-immunoprecipitation, immunohistochemistry","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro dephosphorylation assay with multiple orthogonal methods","pmids":["9487134"],"is_preprint":false},{"year":1999,"finding":"PTPN13 PDZ1 domain binds to the N-terminal ankyrin repeats of IκBα; expression of dominant-negative PTPN13 leads to tyrosine phosphorylation of IκBα, indicating PTPN13 dephosphorylates IκBα and thereby modulates NF-κB activation under oxidative stress.","method":"Yeast two-hybrid, co-immunoprecipitation in HeLa cells, dominant-negative expression","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal interaction confirmed and functional consequence shown by dominant-negative, but direct dephosphorylation not reconstituted","pmids":["9882613"],"is_preprint":false},{"year":1999,"finding":"The FERM domain of PTPN13 is necessary and sufficient for targeting the protein to the apical membrane of polarized epithelial (MDCK) cells; this apical confinement is dynamic (as shown by FRAP, with full redistribution within 20 min via a cytosolic pool) and the PTP domains mediate homotypic interactions.","method":"Transient expression of domain constructs in MDCK cells, immuno-electron microscopy, FRAP, yeast two-hybrid","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiment with functional domain dissection and FRAP in live cells","pmids":["10504335"],"is_preprint":false},{"year":2000,"finding":"PTPN13 PDZ2 (but not the alternatively spliced PDZ2b with a 5-aa insertion) binds the extreme C-terminus of the tumor suppressor APC with nanomolar affinity (KD = 8.1 nM); in vivo interaction confirmed by co-precipitation in COS cells and co-localization at cell extensions and nucleus in epithelial cells.","method":"Yeast two-hybrid, surface plasmon resonance, co-precipitation in COS cells, immunofluorescence in MDCK cells","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — interaction quantified by SPR, confirmed by co-IP in cells, domain specificity defined","pmids":["10951583"],"is_preprint":false},{"year":2000,"finding":"PTPN13 PDZ2 domain interacts with the zyxin-related focal adhesion protein TRIP6 (via its third LIM domain and C-terminus); co-precipitation and co-localization of TRIP6 with PTP-BL at F-actin structures in epithelial cells links PTPN13 to actin-based subcellular complexes.","method":"Yeast two-hybrid, co-immunoprecipitation in transfected epithelial cells, immunofluorescence","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP confirmed but no direct functional consequence of the PTPN13-TRIP6 interaction demonstrated","pmids":["10826496"],"is_preprint":false},{"year":2001,"finding":"PTPN13 PDZ3 domain interacts with the C-terminus of the Rho effector kinase PRK2; a conserved C-terminal cysteine of PRK2 is indispensable for the interaction; the two proteins co-localize at lamellipodia in HeLa cells, linking PTPN13 to actin cytoskeleton regulation.","method":"Yeast two-hybrid, co-immunoprecipitation in HeLa cells, immunofluorescence, mutagenesis of PRK2 C-terminus","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP with mutagenesis defining binding determinant and co-localization in cells","pmids":["11356191"],"is_preprint":false},{"year":2002,"finding":"PTPN13 (PTP-BL) is recruited to ephrinB expression domains with delayed kinetics following EphB receptor engagement, dephosphorylates phospho-ephrinB ligands, and serves as part of a phosphotyrosine/SFK → PDZ-signaling switch during reverse signaling.","method":"Co-immunoprecipitation, phosphorylation assays in transfected cells, dominant-negative PTPN13 expression","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches, replicated in different cell systems; highly cited foundational paper","pmids":["11983165"],"is_preprint":false},{"year":2002,"finding":"NMR solution structure of PTPN13 PDZ2 was determined; PDZ2 displays a canonical fold with a unique extended flexible loop (L1) at the base of the binding pocket; PDZ2 binds the C-terminus of RIL (with non-canonical E-x-V motif) but does not bind the murine Fas C-terminus, clarifying target selectivity.","method":"NMR structure determination, 15N relaxation, peptide binding titration","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution structure with functional binding validation","pmids":["11884147"],"is_preprint":false},{"year":2002,"finding":"PTPN13 (PTPL1/FAP-1) triggers apoptosis in human breast cancer cells by inhibiting the IRS-1/PI3K/Akt survival pathway; antisense abrogation of PTPN13 abolished 4-hydroxytamoxifen-induced apoptosis, and overexpression of PTPN13 reduced PI3K activity (~80%), Akt activation (~55%), and IRS-1 tyrosine phosphorylation (~65%).","method":"Stable antisense transfection, timed PTPN13 expression, PI3K activity assay, Akt phosphorylation assay, TUNEL/nucleosome ELISA for apoptosis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, loss- and gain-of-function in same cell system","pmids":["12354757"],"is_preprint":false},{"year":2003,"finding":"PTPN13 FERM domain is necessary and sufficient for targeting the phosphatase to the apical plasma membrane (dorsal microvilli) of HeLa cells; two PtdIns(4,5)P2-binding motifs within the FERM domain mediate membrane binding, demonstrated by mutation of both sites and protein-lipid overlay assays.","method":"Overexpression of full-length vs. domain constructs in HeLa cells, PtdIns(4,5)P2 mutation analysis, protein-lipid overlay, cell fractionation, neomycin masking experiment","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — direct biochemical lipid binding assay plus mutagenesis and fractionation confirming FERM-PIP2 interaction as membrane anchor","pmids":["12766187"],"is_preprint":false},{"year":2003,"finding":"PTPN13 (PTPL1) associates with the PtdIns(3,4)P2-binding adaptor TAPP1 (and TAPP2) primarily through its PDZ1 domain; this interaction maintains PTPL1 in the cytoplasm under basal conditions, and following H2O2 stimulation (which generates PtdIns(3,4)P2), the PTPL1-TAPP1 complex translocates to the plasma membrane; TAPP1 knockdown enhances PKB activation after IGF1 stimulation.","method":"Co-immunoprecipitation of endogenous proteins, GST pulldown, subcellular fractionation, siRNA knockdown, Akt phosphorylation assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — endogenous co-IP, domain mapping, functional rescue/knockdown, multiple orthogonal methods","pmids":["14516276"],"is_preprint":false},{"year":2003,"finding":"PTPN13 (PTP-BL) localizes to centrosomes and the spindle midzone during mitosis, and concentrates at the midbody during cytokinesis; overexpression of wild-type or phosphatase-inactive PTPN13 causes defects in cytokinesis and generation of multinucleate cells; the FERM domain co-sediments with F-actin and an N-terminal splicing variant (182-aa insertion) targets PTPN13 to the midbody and centrosome.","method":"Immunofluorescence of endogenous protein, co-sedimentation with F-actin and microtubules, overexpression of WT and catalytically-inactive mutants, analysis of multinucleation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — direct localization experiments with functional phenotype (cytokinesis defect) and domain dissection","pmids":["12529439"],"is_preprint":false},{"year":2004,"finding":"Crystal structure of the PTPN13 catalytic domain at 1.8 Å resolution revealed a standard PTP fold with an additional N-terminal helix and a second positively charged pocket near the active site reminiscent of PTP1B's second phosphotyrosine binding site; PTPN13, like PTP1B, dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than a monophosphorylated one; the M2307T tumor mutation near the active site cysteine significantly reduces phosphatase activity.","method":"X-ray crystallography (1.8 Å), in vitro phosphatase assay with insulin receptor peptides, mutagenesis of tumor-derived mutations","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus in vitro enzymatic characterization with mutagenesis","pmids":["15611135"],"is_preprint":false},{"year":2007,"finding":"PTPN13 directly dephosphorylates IRS-1, thereby blocking the IRS-1/PI3K/Akt signaling pathway and inducing apoptosis; shown by in vitro dephosphorylation of IRS-1 by PTPN13, dominant-negative PTPN13 preventing IRS-1 dephosphorylation, and siRNA confirming PTPL1's crucial role in IRS-1 dephosphorylation in cells.","method":"In vitro phosphatase assay with immunoprecipitated IRS-1, dominant-negative PTPN13 expression, siRNA knockdown, PI3K/Akt activity assays, apoptosis assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro dephosphorylation of identified substrate, confirmed by multiple orthogonal methods in cells","pmids":["17638892"],"is_preprint":false},{"year":2007,"finding":"PTPN13 negatively regulates Her2/ErbB2 by dephosphorylating the Her2 signaling domain; growth factor-induced phosphorylation of PTPN13 is required for this dephosphorylation (negative feedback); tumor-derived PTPN13 mutations reduce its phosphatase activity and elevate Her2 oncogenic signaling and cell invasiveness.","method":"siRNA phosphatase library screen, growth factor stimulation with phosphorylation assays, invasion assays, comparison of WT vs. tumor-mutant PTPN13 phosphatase activity","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — functional screen plus mechanistic validation including mutant phosphatase activity and invasion phenotype","pmids":["17982484"],"is_preprint":false},{"year":2007,"finding":"PTPN13 dephosphorylates STAT proteins (STAT4 and STAT6) in vitro and in vivo; PTP-BL deficiency leads to increased and prolonged STAT4/STAT6 activation in CD4+ T cells, resulting in enhanced Th1 and Th2 differentiation.","method":"In vitro dephosphorylation assay, PTP-BL knockout mouse model, flow cytometry for Th1/Th2 differentiation, STAT phosphorylation measurements","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro dephosphorylation assay plus genetic knockout with defined cellular phenotype","pmids":["17306571"],"is_preprint":false},{"year":2007,"finding":"PTPN13 dephosphorylates phosphotyrosine-55 of TRIP6 in vitro and inhibits LPA-induced TRIP6 tyrosine phosphorylation in cells; this requires a direct protein-protein interaction and PTPN13 phosphatase activity, resulting in inhibition of TRIP6-Crk association and LPA-induced cell migration.","method":"In vitro phosphatase assay (dephosphorylation of pTyr-55 TRIP6), co-immunoprecipitation, TRIP6 focal adhesion dynamics, cell migration assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro dephosphorylation of identified substrate site plus functional migration phenotype","pmids":["17591779"],"is_preprint":false},{"year":2007,"finding":"HPV16 E6 oncoprotein interacts with PTPN13 via its PDZ binding motif and induces loss of PTPN13 protein; PTPN13 loss allows anchorage-independent growth and synergizes with Ras(v12) for invasive growth in vivo; restoring PTPN13 expression reverses anchorage-independent growth.","method":"Co-immunoprecipitation, shRNA knockdown, E6 PDZBM mutant, soft-agar assay, in vivo xenograft invasion model, rescue experiment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches, loss-of-function with clear phenotypic rescue, in vivo confirmation","pmids":["18160445"],"is_preprint":false},{"year":2008,"finding":"ICSBP/IRF8 represses PTPN13 transcription by binding a cis element in the proximal PTPN13 promoter; this interaction requires phosphorylation of conserved tyrosine residues in the ICSBP IRF domain and increases during myeloid differentiation, thereby reducing Fap-1 (PTPN13) levels and sensitizing cells to Fas-induced apoptosis.","method":"CpG island microarray chromatin immunoprecipitation, luciferase reporter, ChIP, ICSBP mutants, Fas apoptosis assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — ChIP and reporter assay identify direct transcriptional repression mechanism; functional apoptosis readout","pmids":["18195016"],"is_preprint":false},{"year":2009,"finding":"PTPN13 phosphatase activity inhibits Ras/RAF/MEK/ERK (MAP kinase) signaling; wild-type PTPN13 suppresses MAPK signaling in cells overexpressing ErbB2, EGFR, or H-Ras(V12), while a catalytically-inactive PTPN13 does not; MEK inhibitor U0126 blocks anchorage-independent growth in PTPN13-null cells; 20% of HPV-negative HNSCCs harbor PTPN13 phosphatase mutations that fail to inhibit MAPK signaling.","method":"Co-transfection of WT vs. catalytically-inactive PTPN13, MAPK phosphorylation assays, MEK inhibitor rescue, soft-agar assay, sequencing of patient tumors","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — catalytic mutant comparison, pharmacological rescue, and clinical mutation validation; multiple orthogonal approaches","pmids":["19734941"],"is_preprint":false},{"year":2010,"finding":"PTPN13 directly dephosphorylates Src at tyrosine 419 (activating phosphorylation), established by substrate-trapping experiments; PTPN13 silencing increases pY419-Src, activating downstream FAK and p130cas; PTPN13 loss increases tumor growth and invasion in vivo.","method":"Substrate-trapping mutant PTPN13, co-immunoprecipitation, siRNA knockdown, Src/FAK/p130cas phosphorylation assays, mouse xenograft tumor model, invasion assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — substrate-trapping (classic method for PTP substrate identification) plus in vivo tumor model; replicated in multiple cell lines","pmids":["20501847"],"is_preprint":false},{"year":2007,"finding":"PTPN13 (PTPL1) interacts with TRPM2 calcium channel via PDZ domain binding; PTPN13 co-expression reduces TRPM2 tyrosine phosphorylation and inhibits H2O2/TNFα-induced calcium influx and cell death; PTPN13 knockdown increases TRPM2 phosphorylation and susceptibility to oxidative stress-induced death.","method":"PDZ domain array blot, co-immunoprecipitation, GST pulldown, PTPN13 overexpression/siRNA knockdown, intracellular calcium measurement, cell viability assays","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — interaction confirmed by multiple methods; functional consequence demonstrated, but direct dephosphorylation of TRPM2 not reconstituted in vitro","pmids":["17251321"],"is_preprint":false},{"year":2012,"finding":"The serologically defined colon cancer antigen-3 (SDCCAG3) forms a complex with PTPN13 at the midbody during cytokinesis; both proteins regulate cytokinesis, as overexpression or downregulation of SDCCAG3 causes multinucleation; SDCCAG3 also interacts with ArfGAP GIT1, linking PTPN13 complex to vesicular trafficking during cell division.","method":"Co-immunoprecipitation, immunofluorescence localization, overexpression/RNAi of SDCCAG3, multinucleation quantification","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP confirmed, localization at midbody shown, but the direct mechanistic role of PTPN13 in this complex not fully dissected","pmids":["23108400"],"is_preprint":false},{"year":2012,"finding":"PTPN13 regulates a signaling complex involving ErbB2, Src kinase, and EphrinB1 in breast cancer; EphrinB1 (a PTPN13 substrate) interacts with ErbB2; Src mediates EphrinB1 phosphorylation and subsequent MAP kinase signaling; decreased PTPN13 function enhances this signaling.","method":"Co-immunoprecipitation, localization studies, EphrinB1 phosphorylation assays, PTPN13 siRNA knockdown, MAP kinase assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and phosphorylation assays demonstrate the complex, but mechanistic dissection is partial","pmids":["22279592"],"is_preprint":false},{"year":2013,"finding":"PTPN13 (PTPL1) dephosphorylates p85β regulatory subunit of PI3K at Tyr-655 (adjacent to its degron), enabling p85β binding to the F-box protein FBXL2 and subsequent ubiquitylation and proteasomal degradation; this mechanism controls PI3K signaling cascade and, when defective, promotes autophagy.","method":"Purification of FBXL2 complex, co-immunoprecipitation, ubiquitylation assay, p85β phosphorylation assays, PTPL1 knockdown, in vitro dephosphorylation, autophagy readout","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical reconstitution of the dephosphorylation-ubiquitylation cascade, multiple orthogonal methods in one study","pmids":["23604317"],"is_preprint":false},{"year":2012,"finding":"Valosin-containing protein (VCP/p97) was identified as a direct substrate of PTPN13 by substrate-trapping mass spectrometry; VCP tyrosine phosphorylation may be important for its midbody localization during cytokinesis.","method":"Substrate-trapping PTPN13 mutant, mass spectrometry, co-immunoprecipitation, overexpression and localization studies","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — substrate-trapping MS is a validated PTP substrate identification approach; functional link to midbody is suggestive but not fully demonstrated","pmids":["23018179"],"is_preprint":false},{"year":2014,"finding":"PTPN13 PDZ2 domain binds the C-terminal PDZ-binding motif of PTEN in a manner dependent on the PDZ1-PDZ2 interdomain arrangement; yeast two-hybrid and GST pull-down with mutational analysis of PTEN PDZ-BM define binding specificity.","method":"Yeast two-hybrid, GST pulldown, mutational analysis of PTEN C-terminal PDZ-binding motif","journal":"Methods (San Diego, Calif.)","confidence":"Medium","confidence_rationale":"Tier 3 — interaction confirmed but functional consequence of PTPN13-PTEN interaction not established","pmids":["25448478"],"is_preprint":false},{"year":2017,"finding":"PTPN13 is a PDZ-binding partner of calpain-2 and is cleaved/inactivated by calpain-2, generating stable breakdown products (P13BPs); PTPN13 dephosphorylates and inhibits c-Abl; following TBI, calpain-2 activation cleaves PTPN13, activates c-Abl, and triggers tau tyrosine phosphorylation and tau oligomer accumulation; calpain-2 inhibitor post-TBI blocks this pathway.","method":"Co-immunoprecipitation (calpain-2/PTPN13), in vitro calpain cleavage assay, c-Abl phosphorylation assays, calpain-2 selective inhibitor treatment in TBI mouse model, tau oligomer quantification","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — multiple biochemical assays, in vivo pharmacological intervention, and defined substrate (c-Abl) for PTPN13","pmids":["28924170"],"is_preprint":false},{"year":2018,"finding":"NMR solution structure of PTPN13 PDZ3 domain (apo and in complex with PRK2 C-terminus) reveals that PDZ3 binds the five C-terminal amino acids of PRK2 in the canonical β-groove, with P0 (Cys) and P-2 (Asp) side chains facing the groove and P-1 (Trp) and P-3 (Ala) pointing away — providing a structural basis for class III ligand recognition.","method":"Multidimensional NMR spectroscopy (structure determination of apo and ligand-bound PDZ3)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — atomic-resolution NMR structure of a physiologically relevant complex","pmids":["30189200"],"is_preprint":false},{"year":2018,"finding":"PTPN13 (PTPL1) functions as an apical membrane anchor for PTEN, requiring a direct protein-protein interaction; this anchoring is necessary for PTEN's role in regulating apical membrane size in polarized intestinal epithelial cells; notably, PTPN13 phosphatase activity is dispensable for this scaffolding function.","method":"CRISPR/Cas9 deletion of PTPN13 and PTEN, co-immunoprecipitation, immunofluorescence, brush border phenotype quantification in Ls174T:W4 cells","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic deletion with clear cellular phenotype, direct interaction confirmed, catalytic-independence established","pmids":["29581186"],"is_preprint":false},{"year":2019,"finding":"The PTPN13 tandem PDZ2/3 domain allosterically modulates PDZ2 binding to APC; the presence of PDZ3 alters PDZ2's affinity for APC (12 C-terminal APC residues); PRK2 is a weak binding partner of PDZ2; NMR-based HADDOCK model of the PDZ2/3 tandem domain supports allosteric communication from PDZ3 to the PDZ2 ligand-binding site.","method":"Heteronuclear multidimensional NMR spectroscopy, NMR titration, HADDOCK molecular modeling","journal":"BMC molecular and cell biology","confidence":"Medium","confidence_rationale":"Tier 1–2 — NMR-based structural analysis, but functional consequence of allosteric modulation not directly tested in cells","pmids":["31286859"],"is_preprint":false},{"year":2020,"finding":"PTPN13 inhibits cell motility and invasion via its phosphatase activity; phosphoproteomic analysis of breast cancer cells revealed that PTPN13 regulates intercellular junction-related proteins; in vivo, PTPN13 phosphatase activity deletion in HER2-overexpressing mice strongly increases breast tumor development and invasiveness associated with a loss of mesenchymal-to-epithelial transition phenotype and desmosome disruption.","method":"Transgenic mouse model (PTPN13 phosphatase domain deletion × HER2-overexpression), phosphoproteomics, gene ontology analysis, wound healing and invasion assays, immunofluorescence for cell junctions and desmosomes, xenograft model","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse model with clear in vivo phenotype, phosphoproteomics for mechanism, multiple orthogonal approaches","pmids":["31938048"],"is_preprint":false},{"year":2020,"finding":"HBx protein promotes PTPN13 promoter methylation by upregulating and interacting with DNMT3A, which binds the PTPN13 promoter (-343 to -313 bp) to suppress transcription; PTPN13 inhibits tumor growth through competitive binding to IGF2BP1, reducing functional IGF2BP1 levels and promoting c-Myc mRNA degradation independent of PTPN13 phosphatase activity.","method":"Co-immunoprecipitation (HBx-DNMT3A, PTPN13-IGF2BP1), ChIP of DNMT3A at PTPN13 promoter, methylation analysis, overexpression/knockdown functional assays, c-Myc mRNA stability assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple mechanisms defined but some aspects (phosphatase-independent IGF2BP1 sequestration) are novel and await independent replication","pmids":["33051595"],"is_preprint":false},{"year":2021,"finding":"PTPN13 suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer cells by counteracting canonical Smad2/3 and non-canonical p38 MAPK signaling pathways; immunoprecipitation demonstrated direct binding of PTPN13 to p38 MAPK, suggesting p38 MAPK is a direct substrate.","method":"siRNA knockdown, co-immunoprecipitation (PTPN13-p38 MAPK), Smad2/3 and p38 phosphorylation assays, cell migration/invasion assays, xenograft lung metastasis model","journal":"Acta pharmacologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2–3 — interaction demonstrated by co-IP, functional phenotype shown, but direct dephosphorylation of p38 not reconstituted in vitro","pmids":["33536603"],"is_preprint":false},{"year":2025,"finding":"PTPN13 modulates BCR signaling: PTPN13 and β-catenin are stabilized upon B-cell receptor activation; PTPN13 silencing reduces Bruton's tyrosine kinase (BTK) activation and β-catenin levels; pathogenic PTPN13 mutations (found in families with ALL/anemia/IBMF) impair the PTPN13-β-catenin interaction; PTPN13 co-immunoprecipitates with β-catenin.","method":"Co-immunoprecipitation (PTPN13-β-catenin), siRNA knockdown, BCR stimulation assays, BTK phosphorylation measurement, flow cytometry for CD25/CD38 markers","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP and functional readouts demonstrated, but mechanism of PTPN13 action on BTK/β-catenin not fully reconstituted","pmids":["41422331"],"is_preprint":false},{"year":2026,"finding":"PTPN13 directly dephosphorylates STAT1, and loss of APC (common in CRC) leads to PTPN13-mediated STAT1 dephosphorylation, reducing MHC class I antigen presentation and CD8+ T cell infiltration; APC C-terminal 11-aa peptides (APC11) compete for PTPN13 binding, block PTPN13-STAT1 interaction, restore STAT1 phosphorylation and IRF1/MHC-I expression, and enhance anti-PD1 efficacy in vivo.","method":"Co-immunoprecipitation (PTPN13-STAT1), STAT1 phosphorylation assays, in vitro dephosphorylation, direct peptide binding assay, mouse CRC models, tumor-infiltrating lymphocyte quantification, combination anti-PD1 therapy","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical dephosphorylation, in vivo rescue with peptide, pharmacological combination; multiple orthogonal methods","pmids":["41486293"],"is_preprint":false},{"year":2026,"finding":"PDLIM4 recruits PTPN13 (PTP-BL) to dephosphorylate STAT3, STAT4, and STAT6 via PDLIM4's LIM domain interaction with PTPN13; a disease-associated nsSNP in PDLIM4 (Gly→Cys in LIM domain) reduces PDLIM4-PTPN13 binding and impairs STAT3 dephosphorylation; PDLIM4-deficient CD4+ T cells show augmented STAT phosphorylation and enhanced Th1, Th2, and Th17 differentiation.","method":"Co-immunoprecipitation, STAT phosphorylation assays, PDLIM4 knockout T cells, mutagenesis of PDLIM4 LIM domain, Th differentiation assays","journal":"International immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with defined cellular phenotype, direct protein interaction with mutagenesis, mechanistic connection to previous STAT-dephosphorylation findings for PTPN13","pmids":["42028851"],"is_preprint":false},{"year":2007,"finding":"PTPN13 allosteric regulation of PDZ2 binding specificity: PDZ1 directly contacts a surface on PDZ2 opposite the peptide-binding groove, causing long-range allosteric structural changes in the PDZ2 binding groove that alter its preference for class III-type ligands, as demonstrated by phage display library screening and structural NMR studies.","method":"Random C-terminal peptide λ phage display library screening, NMR structural studies of PDZ1-PDZ2 interaction","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — NMR structural evidence plus functional binding screen demonstrating allosteric inter-domain regulation","pmids":["17979300"],"is_preprint":false},{"year":2014,"finding":"PTPN13 co-immunoprecipitates with β-catenin, co-localizes with β-catenin in megakaryocytic cell lines, regulates β-catenin phosphorylation and stability, and controls β-catenin transcriptional activity; PTPN13 silencing triggers megakaryocytic differentiation while overexpression inhibits it; PTPN13 is stabilized by Wnt signaling, placing it in the canonical Wnt/β-catenin pathway.","method":"Co-immunoprecipitation, co-localization, siRNA knockdown, β-catenin stability assays, differentiation assays in cell lines and murine hematopoietic progenitors","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 — co-IP and functional knockdown/OE, but direct dephosphorylation of β-catenin not reconstituted in vitro","pmids":["25193362"],"is_preprint":false}],"current_model":"PTPN13 is a large multi-domain non-receptor protein tyrosine phosphatase (270 kDa) that is targeted to the apical plasma membrane via FERM domain binding to PtdIns(4,5)P2, where it assembles multiprotein scaffolds through five PDZ domains (with allosteric inter-domain regulation) and directly dephosphorylates a broad set of substrates including ephrinB ligands, IRS-1, Her2/ErbB2, Src (pY419), TRIP6 (pY55), STAT1/4/6, c-Abl, p85β PI3K regulatory subunit, and p38 MAPK, thereby negatively regulating PI3K/Akt, Ras/RAF/MEK/ERK, JAK/STAT, and Src signaling pathways to suppress cancer cell invasion, promote apoptosis, and maintain epithelial cell junction integrity and polarity; it also functions as a phosphatase-independent scaffold anchoring PTEN to the apical membrane and sequestering IGF2BP1 to destabilize c-Myc mRNA."},"narrative":{"teleology":[{"year":1994,"claim":"Identification of PTPN13 as a novel multi-domain cytoplasmic PTP established the existence of a uniquely large phosphatase combining FERM, PDZ, and catalytic domains, raising the question of how each domain contributes to function.","evidence":"PCR-based cloning and in vitro phosphatase assay on 32P-myelin basic protein","pmids":["7929060"],"confidence":"High","gaps":["No cellular substrates identified","Function of FERM and PDZ domains unknown","No in vivo data"]},{"year":1997,"claim":"Discovery that PDZ domains of PTPN13 bind specific C-terminal motifs (Fas, PARG1) established PTPN13 as a scaffolding hub capable of recruiting apoptotic receptors and Rho-regulatory GTPase-activating proteins.","evidence":"Peptide affinity chromatography with Fas C-terminus mutagenesis; yeast two-hybrid and in vitro GAP assay for PARG1","pmids":["9261095","9305890"],"confidence":"High","gaps":["Functional consequence of Fas–PTPN13 interaction on apoptosis not demonstrated","In vivo relevance of PARG1 scaffolding unclear"]},{"year":1999,"claim":"Demonstrating that the FERM domain targets PTPN13 to the apical membrane of polarized epithelial cells resolved where PTPN13 operates and implied a role in epithelial polarity.","evidence":"Domain constructs in MDCK cells, immuno-EM, and FRAP showing dynamic apical localization","pmids":["10504335"],"confidence":"High","gaps":["Lipid-binding mechanism of FERM domain not yet defined","Functional consequence of apical targeting on signaling not tested"]},{"year":2000,"claim":"High-affinity binding of PTPN13 PDZ2 to the tumor suppressor APC and to the focal adhesion protein TRIP6 expanded the interactome to include Wnt-pathway and cytoskeletal components.","evidence":"SPR (KD = 8.1 nM for APC), co-IP in COS cells, yeast two-hybrid for TRIP6","pmids":["10951583","10826496"],"confidence":"High","gaps":["Functional significance of APC–PTPN13 interaction in Wnt signaling not established","No dephosphorylation of TRIP6 yet shown"]},{"year":2002,"claim":"NMR structure of PDZ2 and the discovery that PTPN13 dephosphorylates ephrinB ligands during reverse signaling provided both atomic-level insight into target selectivity and the first defined signaling pathway regulated by PTPN13 catalytic activity.","evidence":"NMR structure determination with peptide binding titration; co-IP and phosphorylation assays for ephrinB dephosphorylation","pmids":["11884147","11983165"],"confidence":"High","gaps":["In vivo significance of ephrinB dephosphorylation in tissue patterning not shown","Structural basis of PDZ–ephrinB interaction not determined"]},{"year":2002,"claim":"Establishing that PTPN13 triggers apoptosis in breast cancer cells by dephosphorylating IRS-1 and suppressing the PI3K/Akt pathway identified the first direct substrate-to-phenotype link for PTPN13 in cancer.","evidence":"Antisense and overexpression in breast cancer cells with PI3K activity, Akt phosphorylation, and apoptosis assays","pmids":["12354757"],"confidence":"High","gaps":["Specific IRS-1 phosphosites dephosphorylated not mapped","In vivo tumor suppression not yet demonstrated"]},{"year":2003,"claim":"Identification of PtdIns(4,5)P2-binding motifs within the FERM domain and PTPN13 localization to centrosomes/midbody during mitosis revealed dual membrane-targeting mechanisms and an unexpected role in cytokinesis.","evidence":"PIP2 mutation analysis, protein-lipid overlay for FERM-PIP2 binding; endogenous immunofluorescence at centrosomes/midbody, cytokinesis defect upon overexpression","pmids":["12766187","12529439"],"confidence":"High","gaps":["Identity of cytokinesis-relevant substrates unknown","Mechanism linking FERM–actin binding to midbody function unclear"]},{"year":2007,"claim":"A burst of substrate identifications—IRS-1, Src pY419, TRIP6 pY55, STAT4/6, Her2/ErbB2—and the discovery of PDZ1-PDZ2 allosteric regulation established PTPN13 as a broad negative regulator of multiple oncogenic and immune signaling pathways with built-in selectivity control.","evidence":"In vitro dephosphorylation and substrate-trapping for IRS-1/TRIP6; PTP-BL knockout mice for STAT4/6; siRNA screen and tumor mutant analysis for Her2; NMR/phage display for PDZ allostery","pmids":["17638892","17591779","17306571","17982484","17979300"],"confidence":"High","gaps":["How allosteric PDZ regulation translates to substrate selectivity in vivo not tested","Whether STAT dephosphorylation is direct or scaffold-mediated not fully resolved"]},{"year":2007,"claim":"HPV16 E6-mediated degradation of PTPN13 provided direct evidence that PTPN13 loss is selected for during viral oncogenesis, enabling anchorage-independent growth.","evidence":"Co-IP, shRNA, E6 PDZBM mutant, soft-agar and in vivo xenograft invasion models with rescue","pmids":["18160445"],"confidence":"High","gaps":["Mechanism of E6-induced PTPN13 degradation (proteasomal vs. other) not fully defined"]},{"year":2009,"claim":"Demonstrating that PTPN13 phosphatase activity suppresses Ras/RAF/MEK/ERK signaling and that 20% of HPV-negative HNSCCs harbor loss-of-function PTPN13 mutations linked the enzyme to a second major oncogenic pathway.","evidence":"Catalytic-mutant comparison, MEK inhibitor rescue, soft-agar assay, patient tumor sequencing","pmids":["19734941"],"confidence":"High","gaps":["Direct MAPK pathway substrate of PTPN13 not identified in this study","Comprehensive PTPN13 mutation frequency across cancer types not established"]},{"year":2010,"claim":"Substrate-trapping identified Src pY419 as a direct PTPN13 substrate, and in vivo xenograft experiments showed that PTPN13 loss increases tumor growth and invasion through Src/FAK/p130cas hyperactivation.","evidence":"Substrate-trapping mutant co-IP, siRNA, Src/FAK phosphorylation assays, mouse xenograft","pmids":["20501847"],"confidence":"High","gaps":["Whether PTPN13 dephosphorylates Src at the plasma membrane or in a specific compartment unknown"]},{"year":2013,"claim":"Discovery that PTPN13 dephosphorylates p85β at Tyr-655 to license its ubiquitylation by FBXL2 revealed a mechanism coupling phosphatase activity to PI3K subunit turnover and autophagy control.","evidence":"In vitro dephosphorylation, FBXL2 complex purification, ubiquitylation assay, autophagy readout","pmids":["23604317"],"confidence":"High","gaps":["Whether this mechanism operates in all PI3K-dependent tissues not tested","Relative contribution of p85β vs. IRS-1 dephosphorylation to PI3K suppression unclear"]},{"year":2018,"claim":"CRISPR deletion established that PTPN13 anchors PTEN to the apical membrane independently of phosphatase activity, separating PTPN13's scaffolding from catalytic tumor suppressor functions.","evidence":"CRISPR knockout of PTPN13 and PTEN in polarized Ls174T:W4 cells, co-IP, brush border quantification","pmids":["29581186"],"confidence":"High","gaps":["Which PDZ domain mediates PTEN anchoring in vivo not fully resolved","Whether PTEN anchoring contributes to tumor suppression in mouse models not tested"]},{"year":2020,"claim":"Transgenic mouse models with PTPN13 phosphatase domain deletion crossed to HER2-overexpressing mice demonstrated that PTPN13 catalytic activity maintains desmosomes and suppresses breast tumor invasiveness in vivo, with phosphoproteomics implicating junction-related substrates.","evidence":"Genetic mouse model, phosphoproteomics, desmosome immunofluorescence, xenograft","pmids":["31938048"],"confidence":"High","gaps":["Specific desmosomal substrates directly dephosphorylated by PTPN13 not identified","Whether junction maintenance is Src-dependent or involves novel substrates unclear"]},{"year":2020,"claim":"A phosphatase-independent tumor-suppressive mechanism was uncovered: PTPN13 sequesters IGF2BP1 to promote c-Myc mRNA degradation, and HBx-driven DNMT3A methylation silences the PTPN13 promoter in HBV-related hepatocellular carcinoma.","evidence":"Co-IP (PTPN13-IGF2BP1, HBx-DNMT3A), ChIP of DNMT3A at PTPN13 promoter, c-Myc mRNA stability assay","pmids":["33051595"],"confidence":"Medium","gaps":["Phosphatase-independent IGF2BP1 sequestration mechanism awaits independent replication","Structural basis of PTPN13-IGF2BP1 interaction unknown"]},{"year":2026,"claim":"APC loss in colorectal cancer frees PTPN13 to dephosphorylate STAT1, suppressing MHC-I expression and CD8+ T cell immunity; a competitive APC-derived peptide restores anti-tumor immunity and enhances anti-PD1 therapy, establishing PTPN13 as a targetable immune evasion mechanism.","evidence":"In vitro STAT1 dephosphorylation, co-IP, competitive peptide (APC11) binding, mouse CRC models with anti-PD1 combination","pmids":["41486293"],"confidence":"High","gaps":["Whether APC11 peptide has off-target effects on other PDZ-containing proteins not assessed","Applicability beyond APC-mutant CRC not established"]},{"year":2026,"claim":"PDLIM4 was identified as a recruiter of PTPN13 to dephosphorylate STAT3/4/6 in T cells, with a disease-associated PDLIM4 SNP impairing PTPN13 binding and causing augmented Th differentiation, demonstrating adaptor-dependent substrate targeting.","evidence":"Co-IP, PDLIM4 knockout T cells, STAT phosphorylation assays, LIM domain mutagenesis, Th differentiation assays","pmids":["42028851"],"confidence":"High","gaps":["Whether PDLIM4 recruits PTPN13 to STAT substrates in non-immune cell types unknown","Structural basis of PDLIM4 LIM–PTPN13 interaction not determined"]},{"year":null,"claim":"Key open questions include the identity of direct desmosomal/junction substrates, the structural basis of full-length PTPN13 autoinhibition and inter-domain allosteric regulation, and whether PTPN13's diverse functions can be pharmacologically separated to exploit its tumor-suppressive or immune-potentiating activities.","evidence":"","pmids":[],"confidence":"High","gaps":["No full-length structure or cryo-EM model exists","Desmosomal substrates not identified","Pharmacological activators or targeted degraders not developed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,3,9,11,15,16,17,18,19,23,27,30,38,39]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[32,35]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,12,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,5,13]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,16,17,22,23,26,27,34,38]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,38,39]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,16,21]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14,25,28]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[34]}],"complexes":[],"partners":["APC","PTEN","TRIP6","PDLIM4","TAPP1","PRK2","SDCCAG3","IGF2BP1"],"other_free_text":[]},"mechanistic_narrative":"PTPN13 is a large, multi-domain non-receptor protein tyrosine phosphatase that functions as both a catalytic enzyme and a phosphatase-independent scaffold to negatively regulate oncogenic signaling, modulate immune cell differentiation, and maintain epithelial cell polarity. Its FERM domain binds PtdIns(4,5)P2 to anchor the protein at the apical plasma membrane of polarized epithelial cells, while five PDZ domains—subject to allosteric inter-domain regulation—recruit diverse substrates and scaffolding partners including APC, PTEN, ephrinB, TRIP6, and STAT proteins [PMID:10504335, PMID:12766187, PMID:17979300, PMID:29581186]. Catalytically, PTPN13 directly dephosphorylates IRS-1, Her2/ErbB2, Src (pY419), STAT1/4/6, ephrinB ligands, TRIP6 (pY55), p85β, and c-Abl, thereby suppressing PI3K/Akt, Ras/MAPK, JAK/STAT, and Src signaling pathways to inhibit cell invasion, promote apoptosis, sustain intercellular junction integrity, and regulate CD4+ T helper cell differentiation [PMID:17638892, PMID:20501847, PMID:17306571, PMID:23604317, PMID:31938048, PMID:41486293]. Independent of its phosphatase activity, PTPN13 anchors PTEN to the apical membrane to control apical domain size and sequesters IGF2BP1 to destabilize c-Myc mRNA [PMID:29581186, PMID:33051595]."},"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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biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with direct in vitro enzymatic assay\",\n      \"pmids\": [\"7929060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The PDZ2 and PDZ4 domains of PTPN13 bind with high affinity to the C-terminal tail of Fas/CD95; the three C-terminal residues (SLV) of Fas are necessary and sufficient for high-affinity interaction with both PDZ2 and PDZ4.\",\n      \"method\": \"Peptide binding assay (affinity chromatography), systematic mutagenesis of Fas C-terminus\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical binding assay with mutagenesis defining binding determinants\",\n      \"pmids\": [\"9261095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"PTPN13 PDZ4 domain interacts with the C-terminal four residues of PARG1 (PTPL1-associated RhoGAP 1), a novel 150-kDa protein whose GAP domain is active on Rho, Rac, and Cdc42 in vitro (preferring Rho), suggesting PTPN13 can scaffold a potent negative regulator of Rho signaling.\",\n      \"method\": \"Yeast two-hybrid, in vitro GAP activity assay, pulldown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical interaction and enzymatic activity of the complex characterized in vitro\",\n      \"pmids\": [\"9305890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PTPN13 PDZ2 and PDZ4 domains interact with the LIM domain of the adaptor protein RIL; the RIL LIM domain is phosphorylated on tyrosine in vivo and is dephosphorylated in vitro by the PTPN13 PTP domain, establishing RIL-LIM as a direct substrate.\",\n      \"method\": \"Yeast two-hybrid, in vitro phosphatase assay, co-immunoprecipitation, immunohistochemistry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro dephosphorylation assay with multiple orthogonal methods\",\n      \"pmids\": [\"9487134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PTPN13 PDZ1 domain binds to the N-terminal ankyrin repeats of IκBα; expression of dominant-negative PTPN13 leads to tyrosine phosphorylation of IκBα, indicating PTPN13 dephosphorylates IκBα and thereby modulates NF-κB activation under oxidative stress.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in HeLa cells, dominant-negative expression\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed and functional consequence shown by dominant-negative, but direct dephosphorylation not reconstituted\",\n      \"pmids\": [\"9882613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The FERM domain of PTPN13 is necessary and sufficient for targeting the protein to the apical membrane of polarized epithelial (MDCK) cells; this apical confinement is dynamic (as shown by FRAP, with full redistribution within 20 min via a cytosolic pool) and the PTP domains mediate homotypic interactions.\",\n      \"method\": \"Transient expression of domain constructs in MDCK cells, immuno-electron microscopy, FRAP, yeast two-hybrid\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment with functional domain dissection and FRAP in live cells\",\n      \"pmids\": [\"10504335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTPN13 PDZ2 (but not the alternatively spliced PDZ2b with a 5-aa insertion) binds the extreme C-terminus of the tumor suppressor APC with nanomolar affinity (KD = 8.1 nM); in vivo interaction confirmed by co-precipitation in COS cells and co-localization at cell extensions and nucleus in epithelial cells.\",\n      \"method\": \"Yeast two-hybrid, surface plasmon resonance, co-precipitation in COS cells, immunofluorescence in MDCK cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — interaction quantified by SPR, confirmed by co-IP in cells, domain specificity defined\",\n      \"pmids\": [\"10951583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PTPN13 PDZ2 domain interacts with the zyxin-related focal adhesion protein TRIP6 (via its third LIM domain and C-terminus); co-precipitation and co-localization of TRIP6 with PTP-BL at F-actin structures in epithelial cells links PTPN13 to actin-based subcellular complexes.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in transfected epithelial cells, immunofluorescence\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP confirmed but no direct functional consequence of the PTPN13-TRIP6 interaction demonstrated\",\n      \"pmids\": [\"10826496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PTPN13 PDZ3 domain interacts with the C-terminus of the Rho effector kinase PRK2; a conserved C-terminal cysteine of PRK2 is indispensable for the interaction; the two proteins co-localize at lamellipodia in HeLa cells, linking PTPN13 to actin cytoskeleton regulation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in HeLa cells, immunofluorescence, mutagenesis of PRK2 C-terminus\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with mutagenesis defining binding determinant and co-localization in cells\",\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 following EphB receptor engagement, dephosphorylates phospho-ephrinB ligands, and serves as part of a phosphotyrosine/SFK → PDZ-signaling switch during reverse signaling.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays in transfected cells, dominant-negative PTPN13 expression\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches, replicated in different cell systems; highly cited foundational paper\",\n      \"pmids\": [\"11983165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NMR solution structure of PTPN13 PDZ2 was determined; PDZ2 displays a canonical fold with a unique extended flexible loop (L1) at the base of the binding pocket; PDZ2 binds the C-terminus of RIL (with non-canonical E-x-V motif) but does not bind the murine Fas C-terminus, clarifying target selectivity.\",\n      \"method\": \"NMR structure determination, 15N relaxation, peptide binding titration\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution structure with functional binding validation\",\n      \"pmids\": [\"11884147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"PTPN13 (PTPL1/FAP-1) triggers apoptosis in human breast cancer cells by inhibiting the IRS-1/PI3K/Akt survival pathway; antisense abrogation of PTPN13 abolished 4-hydroxytamoxifen-induced apoptosis, and overexpression of PTPN13 reduced PI3K activity (~80%), Akt activation (~55%), and IRS-1 tyrosine phosphorylation (~65%).\",\n      \"method\": \"Stable antisense transfection, timed PTPN13 expression, PI3K activity assay, Akt phosphorylation assay, TUNEL/nucleosome ELISA for apoptosis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, loss- and gain-of-function in same cell system\",\n      \"pmids\": [\"12354757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTPN13 FERM domain is necessary and sufficient for targeting the phosphatase to the apical plasma membrane (dorsal microvilli) of HeLa cells; two PtdIns(4,5)P2-binding motifs within the FERM domain mediate membrane binding, demonstrated by mutation of both sites and protein-lipid overlay assays.\",\n      \"method\": \"Overexpression of full-length vs. domain constructs in HeLa cells, PtdIns(4,5)P2 mutation analysis, protein-lipid overlay, cell fractionation, neomycin masking experiment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct biochemical lipid binding assay plus mutagenesis and fractionation confirming FERM-PIP2 interaction as membrane anchor\",\n      \"pmids\": [\"12766187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTPN13 (PTPL1) associates with the PtdIns(3,4)P2-binding adaptor TAPP1 (and TAPP2) primarily through its PDZ1 domain; this interaction maintains PTPL1 in the cytoplasm under basal conditions, and following H2O2 stimulation (which generates PtdIns(3,4)P2), the PTPL1-TAPP1 complex translocates to the plasma membrane; TAPP1 knockdown enhances PKB activation after IGF1 stimulation.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, GST pulldown, subcellular fractionation, siRNA knockdown, Akt phosphorylation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — endogenous co-IP, domain mapping, functional rescue/knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"14516276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTPN13 (PTP-BL) localizes to centrosomes and the spindle midzone during mitosis, and concentrates at the midbody during cytokinesis; overexpression of wild-type or phosphatase-inactive PTPN13 causes defects in cytokinesis and generation of multinucleate cells; the FERM domain co-sediments with F-actin and an N-terminal splicing variant (182-aa insertion) targets PTPN13 to the midbody and centrosome.\",\n      \"method\": \"Immunofluorescence of endogenous protein, co-sedimentation with F-actin and microtubules, overexpression of WT and catalytically-inactive mutants, analysis of multinucleation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional phenotype (cytokinesis defect) and domain dissection\",\n      \"pmids\": [\"12529439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Crystal structure of the PTPN13 catalytic domain at 1.8 Å resolution revealed a standard PTP fold with an additional N-terminal helix and a second positively charged pocket near the active site reminiscent of PTP1B's second phosphotyrosine binding site; PTPN13, like PTP1B, dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than a monophosphorylated one; the M2307T tumor mutation near the active site cysteine significantly reduces phosphatase activity.\",\n      \"method\": \"X-ray crystallography (1.8 Å), in vitro phosphatase assay with insulin receptor peptides, mutagenesis of tumor-derived mutations\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus in vitro enzymatic characterization with mutagenesis\",\n      \"pmids\": [\"15611135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 directly dephosphorylates IRS-1, thereby blocking the IRS-1/PI3K/Akt signaling pathway and inducing apoptosis; shown by in vitro dephosphorylation of IRS-1 by PTPN13, dominant-negative PTPN13 preventing IRS-1 dephosphorylation, and siRNA confirming PTPL1's crucial role in IRS-1 dephosphorylation in cells.\",\n      \"method\": \"In vitro phosphatase assay with immunoprecipitated IRS-1, dominant-negative PTPN13 expression, siRNA knockdown, PI3K/Akt activity assays, apoptosis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro dephosphorylation of identified substrate, confirmed by multiple orthogonal methods in cells\",\n      \"pmids\": [\"17638892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 negatively regulates Her2/ErbB2 by dephosphorylating the Her2 signaling domain; growth factor-induced phosphorylation of PTPN13 is required for this dephosphorylation (negative feedback); tumor-derived PTPN13 mutations reduce its phosphatase activity and elevate Her2 oncogenic signaling and cell invasiveness.\",\n      \"method\": \"siRNA phosphatase library screen, growth factor stimulation with phosphorylation assays, invasion assays, comparison of WT vs. tumor-mutant PTPN13 phosphatase activity\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — functional screen plus mechanistic validation including mutant phosphatase activity and invasion phenotype\",\n      \"pmids\": [\"17982484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 dephosphorylates STAT proteins (STAT4 and STAT6) in vitro and in vivo; PTP-BL deficiency leads to increased and prolonged STAT4/STAT6 activation in CD4+ T cells, resulting in enhanced Th1 and Th2 differentiation.\",\n      \"method\": \"In vitro dephosphorylation assay, PTP-BL knockout mouse model, flow cytometry for Th1/Th2 differentiation, STAT phosphorylation measurements\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro dephosphorylation assay plus genetic knockout with defined cellular phenotype\",\n      \"pmids\": [\"17306571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 dephosphorylates phosphotyrosine-55 of TRIP6 in vitro and inhibits LPA-induced TRIP6 tyrosine phosphorylation in cells; this requires a direct protein-protein interaction and PTPN13 phosphatase activity, resulting in inhibition of TRIP6-Crk association and LPA-induced cell migration.\",\n      \"method\": \"In vitro phosphatase assay (dephosphorylation of pTyr-55 TRIP6), co-immunoprecipitation, TRIP6 focal adhesion dynamics, cell migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro dephosphorylation of identified substrate site plus functional migration phenotype\",\n      \"pmids\": [\"17591779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HPV16 E6 oncoprotein interacts with PTPN13 via its PDZ binding motif and induces loss of PTPN13 protein; PTPN13 loss allows anchorage-independent growth and synergizes with Ras(v12) for invasive growth in vivo; restoring PTPN13 expression reverses anchorage-independent growth.\",\n      \"method\": \"Co-immunoprecipitation, shRNA knockdown, E6 PDZBM mutant, soft-agar assay, in vivo xenograft invasion model, rescue experiment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches, loss-of-function with clear phenotypic rescue, in vivo confirmation\",\n      \"pmids\": [\"18160445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ICSBP/IRF8 represses PTPN13 transcription by binding a cis element in the proximal PTPN13 promoter; this interaction requires phosphorylation of conserved tyrosine residues in the ICSBP IRF domain and increases during myeloid differentiation, thereby reducing Fap-1 (PTPN13) levels and sensitizing cells to Fas-induced apoptosis.\",\n      \"method\": \"CpG island microarray chromatin immunoprecipitation, luciferase reporter, ChIP, ICSBP mutants, Fas apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay identify direct transcriptional repression mechanism; functional apoptosis readout\",\n      \"pmids\": [\"18195016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTPN13 phosphatase activity inhibits Ras/RAF/MEK/ERK (MAP kinase) signaling; wild-type PTPN13 suppresses MAPK signaling in cells overexpressing ErbB2, EGFR, or H-Ras(V12), while a catalytically-inactive PTPN13 does not; MEK inhibitor U0126 blocks anchorage-independent growth in PTPN13-null cells; 20% of HPV-negative HNSCCs harbor PTPN13 phosphatase mutations that fail to inhibit MAPK signaling.\",\n      \"method\": \"Co-transfection of WT vs. catalytically-inactive PTPN13, MAPK phosphorylation assays, MEK inhibitor rescue, soft-agar assay, sequencing of patient tumors\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — catalytic mutant comparison, pharmacological rescue, and clinical mutation validation; multiple orthogonal approaches\",\n      \"pmids\": [\"19734941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTPN13 directly dephosphorylates Src at tyrosine 419 (activating phosphorylation), established by substrate-trapping experiments; PTPN13 silencing increases pY419-Src, activating downstream FAK and p130cas; PTPN13 loss increases tumor growth and invasion in vivo.\",\n      \"method\": \"Substrate-trapping mutant PTPN13, co-immunoprecipitation, siRNA knockdown, Src/FAK/p130cas phosphorylation assays, mouse xenograft tumor model, invasion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — substrate-trapping (classic method for PTP substrate identification) plus in vivo tumor model; replicated in multiple cell lines\",\n      \"pmids\": [\"20501847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 (PTPL1) interacts with TRPM2 calcium channel via PDZ domain binding; PTPN13 co-expression reduces TRPM2 tyrosine phosphorylation and inhibits H2O2/TNFα-induced calcium influx and cell death; PTPN13 knockdown increases TRPM2 phosphorylation and susceptibility to oxidative stress-induced death.\",\n      \"method\": \"PDZ domain array blot, co-immunoprecipitation, GST pulldown, PTPN13 overexpression/siRNA knockdown, intracellular calcium measurement, cell viability assays\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — interaction confirmed by multiple methods; functional consequence demonstrated, but direct dephosphorylation of TRPM2 not reconstituted in vitro\",\n      \"pmids\": [\"17251321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The serologically defined colon cancer antigen-3 (SDCCAG3) forms a complex with PTPN13 at the midbody during cytokinesis; both proteins regulate cytokinesis, as overexpression or downregulation of SDCCAG3 causes multinucleation; SDCCAG3 also interacts with ArfGAP GIT1, linking PTPN13 complex to vesicular trafficking during cell division.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, overexpression/RNAi of SDCCAG3, multinucleation quantification\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP confirmed, localization at midbody shown, but the direct mechanistic role of PTPN13 in this complex not fully dissected\",\n      \"pmids\": [\"23108400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTPN13 regulates a signaling complex involving ErbB2, Src kinase, and EphrinB1 in breast cancer; EphrinB1 (a PTPN13 substrate) interacts with ErbB2; Src mediates EphrinB1 phosphorylation and subsequent MAP kinase signaling; decreased PTPN13 function enhances this signaling.\",\n      \"method\": \"Co-immunoprecipitation, localization studies, EphrinB1 phosphorylation assays, PTPN13 siRNA knockdown, MAP kinase assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and phosphorylation assays demonstrate the complex, but mechanistic dissection is partial\",\n      \"pmids\": [\"22279592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTPN13 (PTPL1) dephosphorylates p85β regulatory subunit of PI3K at Tyr-655 (adjacent to its degron), enabling p85β binding to the F-box protein FBXL2 and subsequent ubiquitylation and proteasomal degradation; this mechanism controls PI3K signaling cascade and, when defective, promotes autophagy.\",\n      \"method\": \"Purification of FBXL2 complex, co-immunoprecipitation, ubiquitylation assay, p85β phosphorylation assays, PTPL1 knockdown, in vitro dephosphorylation, autophagy readout\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical reconstitution of the dephosphorylation-ubiquitylation cascade, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23604317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Valosin-containing protein (VCP/p97) was identified as a direct substrate of PTPN13 by substrate-trapping mass spectrometry; VCP tyrosine phosphorylation may be important for its midbody localization during cytokinesis.\",\n      \"method\": \"Substrate-trapping PTPN13 mutant, mass spectrometry, co-immunoprecipitation, overexpression and localization studies\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — substrate-trapping MS is a validated PTP substrate identification approach; functional link to midbody is suggestive but not fully demonstrated\",\n      \"pmids\": [\"23018179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN13 PDZ2 domain binds the C-terminal PDZ-binding motif of PTEN in a manner dependent on the PDZ1-PDZ2 interdomain arrangement; yeast two-hybrid and GST pull-down with mutational analysis of PTEN PDZ-BM define binding specificity.\",\n      \"method\": \"Yeast two-hybrid, GST pulldown, mutational analysis of PTEN C-terminal PDZ-binding motif\",\n      \"journal\": \"Methods (San Diego, Calif.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — interaction confirmed but functional consequence of PTPN13-PTEN interaction not established\",\n      \"pmids\": [\"25448478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PTPN13 is a PDZ-binding partner of calpain-2 and is cleaved/inactivated by calpain-2, generating stable breakdown products (P13BPs); PTPN13 dephosphorylates and inhibits c-Abl; following TBI, calpain-2 activation cleaves PTPN13, activates c-Abl, and triggers tau tyrosine phosphorylation and tau oligomer accumulation; calpain-2 inhibitor post-TBI blocks this pathway.\",\n      \"method\": \"Co-immunoprecipitation (calpain-2/PTPN13), in vitro calpain cleavage assay, c-Abl phosphorylation assays, calpain-2 selective inhibitor treatment in TBI mouse model, tau oligomer quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical assays, in vivo pharmacological intervention, and defined substrate (c-Abl) for PTPN13\",\n      \"pmids\": [\"28924170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NMR solution structure of PTPN13 PDZ3 domain (apo and in complex with PRK2 C-terminus) reveals that PDZ3 binds the five C-terminal amino acids of PRK2 in the canonical β-groove, with P0 (Cys) and P-2 (Asp) side chains facing the groove and P-1 (Trp) and P-3 (Ala) pointing away — providing a structural basis for class III ligand recognition.\",\n      \"method\": \"Multidimensional NMR spectroscopy (structure determination of apo and ligand-bound PDZ3)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — atomic-resolution NMR structure of a physiologically relevant complex\",\n      \"pmids\": [\"30189200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PTPN13 (PTPL1) functions as an apical membrane anchor for PTEN, requiring a direct protein-protein interaction; this anchoring is necessary for PTEN's role in regulating apical membrane size in polarized intestinal epithelial cells; notably, PTPN13 phosphatase activity is dispensable for this scaffolding function.\",\n      \"method\": \"CRISPR/Cas9 deletion of PTPN13 and PTEN, co-immunoprecipitation, immunofluorescence, brush border phenotype quantification in Ls174T:W4 cells\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic deletion with clear cellular phenotype, direct interaction confirmed, catalytic-independence established\",\n      \"pmids\": [\"29581186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The PTPN13 tandem PDZ2/3 domain allosterically modulates PDZ2 binding to APC; the presence of PDZ3 alters PDZ2's affinity for APC (12 C-terminal APC residues); PRK2 is a weak binding partner of PDZ2; NMR-based HADDOCK model of the PDZ2/3 tandem domain supports allosteric communication from PDZ3 to the PDZ2 ligand-binding site.\",\n      \"method\": \"Heteronuclear multidimensional NMR spectroscopy, NMR titration, HADDOCK molecular modeling\",\n      \"journal\": \"BMC molecular and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — NMR-based structural analysis, but functional consequence of allosteric modulation not directly tested in cells\",\n      \"pmids\": [\"31286859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPN13 inhibits cell motility and invasion via its phosphatase activity; phosphoproteomic analysis of breast cancer cells revealed that PTPN13 regulates intercellular junction-related proteins; in vivo, PTPN13 phosphatase activity deletion in HER2-overexpressing mice strongly increases breast tumor development and invasiveness associated with a loss of mesenchymal-to-epithelial transition phenotype and desmosome disruption.\",\n      \"method\": \"Transgenic mouse model (PTPN13 phosphatase domain deletion × HER2-overexpression), phosphoproteomics, gene ontology analysis, wound healing and invasion assays, immunofluorescence for cell junctions and desmosomes, xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse model with clear in vivo phenotype, phosphoproteomics for mechanism, multiple orthogonal approaches\",\n      \"pmids\": [\"31938048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HBx protein promotes PTPN13 promoter methylation by upregulating and interacting with DNMT3A, which binds the PTPN13 promoter (-343 to -313 bp) to suppress transcription; PTPN13 inhibits tumor growth through competitive binding to IGF2BP1, reducing functional IGF2BP1 levels and promoting c-Myc mRNA degradation independent of PTPN13 phosphatase activity.\",\n      \"method\": \"Co-immunoprecipitation (HBx-DNMT3A, PTPN13-IGF2BP1), ChIP of DNMT3A at PTPN13 promoter, methylation analysis, overexpression/knockdown functional assays, c-Myc mRNA stability assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple mechanisms defined but some aspects (phosphatase-independent IGF2BP1 sequestration) are novel and await independent replication\",\n      \"pmids\": [\"33051595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PTPN13 suppresses TGF-β1-induced epithelial-mesenchymal transition in lung cancer cells by counteracting canonical Smad2/3 and non-canonical p38 MAPK signaling pathways; immunoprecipitation demonstrated direct binding of PTPN13 to p38 MAPK, suggesting p38 MAPK is a direct substrate.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (PTPN13-p38 MAPK), Smad2/3 and p38 phosphorylation assays, cell migration/invasion assays, xenograft lung metastasis model\",\n      \"journal\": \"Acta pharmacologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — interaction demonstrated by co-IP, functional phenotype shown, but direct dephosphorylation of p38 not reconstituted in vitro\",\n      \"pmids\": [\"33536603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPN13 modulates BCR signaling: PTPN13 and β-catenin are stabilized upon B-cell receptor activation; PTPN13 silencing reduces Bruton's tyrosine kinase (BTK) activation and β-catenin levels; pathogenic PTPN13 mutations (found in families with ALL/anemia/IBMF) impair the PTPN13-β-catenin interaction; PTPN13 co-immunoprecipitates with β-catenin.\",\n      \"method\": \"Co-immunoprecipitation (PTPN13-β-catenin), siRNA knockdown, BCR stimulation assays, BTK phosphorylation measurement, flow cytometry for CD25/CD38 markers\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP and functional readouts demonstrated, but mechanism of PTPN13 action on BTK/β-catenin not fully reconstituted\",\n      \"pmids\": [\"41422331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTPN13 directly dephosphorylates STAT1, and loss of APC (common in CRC) leads to PTPN13-mediated STAT1 dephosphorylation, reducing MHC class I antigen presentation and CD8+ T cell infiltration; APC C-terminal 11-aa peptides (APC11) compete for PTPN13 binding, block PTPN13-STAT1 interaction, restore STAT1 phosphorylation and IRF1/MHC-I expression, and enhance anti-PD1 efficacy in vivo.\",\n      \"method\": \"Co-immunoprecipitation (PTPN13-STAT1), STAT1 phosphorylation assays, in vitro dephosphorylation, direct peptide binding assay, mouse CRC models, tumor-infiltrating lymphocyte quantification, combination anti-PD1 therapy\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical dephosphorylation, in vivo rescue with peptide, pharmacological combination; multiple orthogonal methods\",\n      \"pmids\": [\"41486293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDLIM4 recruits PTPN13 (PTP-BL) to dephosphorylate STAT3, STAT4, and STAT6 via PDLIM4's LIM domain interaction with PTPN13; a disease-associated nsSNP in PDLIM4 (Gly→Cys in LIM domain) reduces PDLIM4-PTPN13 binding and impairs STAT3 dephosphorylation; PDLIM4-deficient CD4+ T cells show augmented STAT phosphorylation and enhanced Th1, Th2, and Th17 differentiation.\",\n      \"method\": \"Co-immunoprecipitation, STAT phosphorylation assays, PDLIM4 knockout T cells, mutagenesis of PDLIM4 LIM domain, Th differentiation assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with defined cellular phenotype, direct protein interaction with mutagenesis, mechanistic connection to previous STAT-dephosphorylation findings for PTPN13\",\n      \"pmids\": [\"42028851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPN13 allosteric regulation of PDZ2 binding specificity: PDZ1 directly contacts a surface on PDZ2 opposite the peptide-binding groove, causing long-range allosteric structural changes in the PDZ2 binding groove that alter its preference for class III-type ligands, as demonstrated by phage display library screening and structural NMR studies.\",\n      \"method\": \"Random C-terminal peptide λ phage display library screening, NMR structural studies of PDZ1-PDZ2 interaction\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structural evidence plus functional binding screen demonstrating allosteric inter-domain regulation\",\n      \"pmids\": [\"17979300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTPN13 co-immunoprecipitates with β-catenin, co-localizes with β-catenin in megakaryocytic cell lines, regulates β-catenin phosphorylation and stability, and controls β-catenin transcriptional activity; PTPN13 silencing triggers megakaryocytic differentiation while overexpression inhibits it; PTPN13 is stabilized by Wnt signaling, placing it in the canonical Wnt/β-catenin pathway.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, siRNA knockdown, β-catenin stability assays, differentiation assays in cell lines and murine hematopoietic progenitors\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP and functional knockdown/OE, but direct dephosphorylation of β-catenin not reconstituted in vitro\",\n      \"pmids\": [\"25193362\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN13 is a large multi-domain non-receptor protein tyrosine phosphatase (270 kDa) that is targeted to the apical plasma membrane via FERM domain binding to PtdIns(4,5)P2, where it assembles multiprotein scaffolds through five PDZ domains (with allosteric inter-domain regulation) and directly dephosphorylates a broad set of substrates including ephrinB ligands, IRS-1, Her2/ErbB2, Src (pY419), TRIP6 (pY55), STAT1/4/6, c-Abl, p85β PI3K regulatory subunit, and p38 MAPK, thereby negatively regulating PI3K/Akt, Ras/RAF/MEK/ERK, JAK/STAT, and Src signaling pathways to suppress cancer cell invasion, promote apoptosis, and maintain epithelial cell junction integrity and polarity; it also functions as a phosphatase-independent scaffold anchoring PTEN to the apical membrane and sequestering IGF2BP1 to destabilize c-Myc mRNA.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTPN13 is a large, multi-domain non-receptor protein tyrosine phosphatase that functions as both a catalytic enzyme and a phosphatase-independent scaffold to negatively regulate oncogenic signaling, modulate immune cell differentiation, and maintain epithelial cell polarity. Its FERM domain binds PtdIns(4,5)P2 to anchor the protein at the apical plasma membrane of polarized epithelial cells, while five PDZ domains—subject to allosteric inter-domain regulation—recruit diverse substrates and scaffolding partners including APC, PTEN, ephrinB, TRIP6, and STAT proteins [PMID:10504335, PMID:12766187, PMID:17979300, PMID:29581186]. Catalytically, PTPN13 directly dephosphorylates IRS-1, Her2/ErbB2, Src (pY419), STAT1/4/6, ephrinB ligands, TRIP6 (pY55), p85β, and c-Abl, thereby suppressing PI3K/Akt, Ras/MAPK, JAK/STAT, and Src signaling pathways to inhibit cell invasion, promote apoptosis, sustain intercellular junction integrity, and regulate CD4+ T helper cell differentiation [PMID:17638892, PMID:20501847, PMID:17306571, PMID:23604317, PMID:31938048, PMID:41486293]. Independent of its phosphatase activity, PTPN13 anchors PTEN to the apical membrane to control apical domain size and sequesters IGF2BP1 to destabilize c-Myc mRNA [PMID:29581186, PMID:33051595].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Identification of PTPN13 as a novel multi-domain cytoplasmic PTP established the existence of a uniquely large phosphatase combining FERM, PDZ, and catalytic domains, raising the question of how each domain contributes to function.\",\n      \"evidence\": \"PCR-based cloning and in vitro phosphatase assay on 32P-myelin basic protein\",\n      \"pmids\": [\"7929060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cellular substrates identified\", \"Function of FERM and PDZ domains unknown\", \"No in vivo data\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery that PDZ domains of PTPN13 bind specific C-terminal motifs (Fas, PARG1) established PTPN13 as a scaffolding hub capable of recruiting apoptotic receptors and Rho-regulatory GTPase-activating proteins.\",\n      \"evidence\": \"Peptide affinity chromatography with Fas C-terminus mutagenesis; yeast two-hybrid and in vitro GAP assay for PARG1\",\n      \"pmids\": [\"9261095\", \"9305890\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Fas–PTPN13 interaction on apoptosis not demonstrated\", \"In vivo relevance of PARG1 scaffolding unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that the FERM domain targets PTPN13 to the apical membrane of polarized epithelial cells resolved where PTPN13 operates and implied a role in epithelial polarity.\",\n      \"evidence\": \"Domain constructs in MDCK cells, immuno-EM, and FRAP showing dynamic apical localization\",\n      \"pmids\": [\"10504335\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid-binding mechanism of FERM domain not yet defined\", \"Functional consequence of apical targeting on signaling not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"High-affinity binding of PTPN13 PDZ2 to the tumor suppressor APC and to the focal adhesion protein TRIP6 expanded the interactome to include Wnt-pathway and cytoskeletal components.\",\n      \"evidence\": \"SPR (KD = 8.1 nM for APC), co-IP in COS cells, yeast two-hybrid for TRIP6\",\n      \"pmids\": [\"10951583\", \"10826496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional significance of APC–PTPN13 interaction in Wnt signaling not established\", \"No dephosphorylation of TRIP6 yet shown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"NMR structure of PDZ2 and the discovery that PTPN13 dephosphorylates ephrinB ligands during reverse signaling provided both atomic-level insight into target selectivity and the first defined signaling pathway regulated by PTPN13 catalytic activity.\",\n      \"evidence\": \"NMR structure determination with peptide binding titration; co-IP and phosphorylation assays for ephrinB dephosphorylation\",\n      \"pmids\": [\"11884147\", \"11983165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo significance of ephrinB dephosphorylation in tissue patterning not shown\", \"Structural basis of PDZ–ephrinB interaction not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that PTPN13 triggers apoptosis in breast cancer cells by dephosphorylating IRS-1 and suppressing the PI3K/Akt pathway identified the first direct substrate-to-phenotype link for PTPN13 in cancer.\",\n      \"evidence\": \"Antisense and overexpression in breast cancer cells with PI3K activity, Akt phosphorylation, and apoptosis assays\",\n      \"pmids\": [\"12354757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific IRS-1 phosphosites dephosphorylated not mapped\", \"In vivo tumor suppression not yet demonstrated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of PtdIns(4,5)P2-binding motifs within the FERM domain and PTPN13 localization to centrosomes/midbody during mitosis revealed dual membrane-targeting mechanisms and an unexpected role in cytokinesis.\",\n      \"evidence\": \"PIP2 mutation analysis, protein-lipid overlay for FERM-PIP2 binding; endogenous immunofluorescence at centrosomes/midbody, cytokinesis defect upon overexpression\",\n      \"pmids\": [\"12766187\", \"12529439\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of cytokinesis-relevant substrates unknown\", \"Mechanism linking FERM–actin binding to midbody function unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A burst of substrate identifications—IRS-1, Src pY419, TRIP6 pY55, STAT4/6, Her2/ErbB2—and the discovery of PDZ1-PDZ2 allosteric regulation established PTPN13 as a broad negative regulator of multiple oncogenic and immune signaling pathways with built-in selectivity control.\",\n      \"evidence\": \"In vitro dephosphorylation and substrate-trapping for IRS-1/TRIP6; PTP-BL knockout mice for STAT4/6; siRNA screen and tumor mutant analysis for Her2; NMR/phage display for PDZ allostery\",\n      \"pmids\": [\"17638892\", \"17591779\", \"17306571\", \"17982484\", \"17979300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How allosteric PDZ regulation translates to substrate selectivity in vivo not tested\", \"Whether STAT dephosphorylation is direct or scaffold-mediated not fully resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"HPV16 E6-mediated degradation of PTPN13 provided direct evidence that PTPN13 loss is selected for during viral oncogenesis, enabling anchorage-independent growth.\",\n      \"evidence\": \"Co-IP, shRNA, E6 PDZBM mutant, soft-agar and in vivo xenograft invasion models with rescue\",\n      \"pmids\": [\"18160445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of E6-induced PTPN13 degradation (proteasomal vs. other) not fully defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that PTPN13 phosphatase activity suppresses Ras/RAF/MEK/ERK signaling and that 20% of HPV-negative HNSCCs harbor loss-of-function PTPN13 mutations linked the enzyme to a second major oncogenic pathway.\",\n      \"evidence\": \"Catalytic-mutant comparison, MEK inhibitor rescue, soft-agar assay, patient tumor sequencing\",\n      \"pmids\": [\"19734941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct MAPK pathway substrate of PTPN13 not identified in this study\", \"Comprehensive PTPN13 mutation frequency across cancer types not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Substrate-trapping identified Src pY419 as a direct PTPN13 substrate, and in vivo xenograft experiments showed that PTPN13 loss increases tumor growth and invasion through Src/FAK/p130cas hyperactivation.\",\n      \"evidence\": \"Substrate-trapping mutant co-IP, siRNA, Src/FAK phosphorylation assays, mouse xenograft\",\n      \"pmids\": [\"20501847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PTPN13 dephosphorylates Src at the plasma membrane or in a specific compartment unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that PTPN13 dephosphorylates p85β at Tyr-655 to license its ubiquitylation by FBXL2 revealed a mechanism coupling phosphatase activity to PI3K subunit turnover and autophagy control.\",\n      \"evidence\": \"In vitro dephosphorylation, FBXL2 complex purification, ubiquitylation assay, autophagy readout\",\n      \"pmids\": [\"23604317\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism operates in all PI3K-dependent tissues not tested\", \"Relative contribution of p85β vs. IRS-1 dephosphorylation to PI3K suppression unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"CRISPR deletion established that PTPN13 anchors PTEN to the apical membrane independently of phosphatase activity, separating PTPN13's scaffolding from catalytic tumor suppressor functions.\",\n      \"evidence\": \"CRISPR knockout of PTPN13 and PTEN in polarized Ls174T:W4 cells, co-IP, brush border quantification\",\n      \"pmids\": [\"29581186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which PDZ domain mediates PTEN anchoring in vivo not fully resolved\", \"Whether PTEN anchoring contributes to tumor suppression in mouse models not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Transgenic mouse models with PTPN13 phosphatase domain deletion crossed to HER2-overexpressing mice demonstrated that PTPN13 catalytic activity maintains desmosomes and suppresses breast tumor invasiveness in vivo, with phosphoproteomics implicating junction-related substrates.\",\n      \"evidence\": \"Genetic mouse model, phosphoproteomics, desmosome immunofluorescence, xenograft\",\n      \"pmids\": [\"31938048\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific desmosomal substrates directly dephosphorylated by PTPN13 not identified\", \"Whether junction maintenance is Src-dependent or involves novel substrates unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A phosphatase-independent tumor-suppressive mechanism was uncovered: PTPN13 sequesters IGF2BP1 to promote c-Myc mRNA degradation, and HBx-driven DNMT3A methylation silences the PTPN13 promoter in HBV-related hepatocellular carcinoma.\",\n      \"evidence\": \"Co-IP (PTPN13-IGF2BP1, HBx-DNMT3A), ChIP of DNMT3A at PTPN13 promoter, c-Myc mRNA stability assay\",\n      \"pmids\": [\"33051595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Phosphatase-independent IGF2BP1 sequestration mechanism awaits independent replication\", \"Structural basis of PTPN13-IGF2BP1 interaction unknown\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"APC loss in colorectal cancer frees PTPN13 to dephosphorylate STAT1, suppressing MHC-I expression and CD8+ T cell immunity; a competitive APC-derived peptide restores anti-tumor immunity and enhances anti-PD1 therapy, establishing PTPN13 as a targetable immune evasion mechanism.\",\n      \"evidence\": \"In vitro STAT1 dephosphorylation, co-IP, competitive peptide (APC11) binding, mouse CRC models with anti-PD1 combination\",\n      \"pmids\": [\"41486293\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether APC11 peptide has off-target effects on other PDZ-containing proteins not assessed\", \"Applicability beyond APC-mutant CRC not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"PDLIM4 was identified as a recruiter of PTPN13 to dephosphorylate STAT3/4/6 in T cells, with a disease-associated PDLIM4 SNP impairing PTPN13 binding and causing augmented Th differentiation, demonstrating adaptor-dependent substrate targeting.\",\n      \"evidence\": \"Co-IP, PDLIM4 knockout T cells, STAT phosphorylation assays, LIM domain mutagenesis, Th differentiation assays\",\n      \"pmids\": [\"42028851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDLIM4 recruits PTPN13 to STAT substrates in non-immune cell types unknown\", \"Structural basis of PDLIM4 LIM–PTPN13 interaction not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the identity of direct desmosomal/junction substrates, the structural basis of full-length PTPN13 autoinhibition and inter-domain allosteric regulation, and whether PTPN13's diverse functions can be pharmacologically separated to exploit its tumor-suppressive or immune-potentiating activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure or cryo-EM model exists\", \"Desmosomal substrates not identified\", \"Pharmacological activators or targeted degraders not developed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 3, 9, 11, 15, 16, 17, 18, 19, 23, 27, 30, 38, 39]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [32, 35]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 12, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 5, 13]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 16, 17, 22, 23, 26, 27, 34, 38]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 38, 39]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 16, 21]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 25, 28]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"APC\", \"PTEN\", \"TRIP6\", \"PDLIM4\", \"TAPP1\", \"PRK2\", \"SDCCAG3\", \"IGF2BP1\"],\n    \"other_free_text\": []\n  }\n}\n```"}