{"gene":"PTK7","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"PTK7 is required for planar cell polarity (PCP) in vertebrates: mouse PTK7 mutations disrupt neural tube closure and stereociliary bundle orientation, and PTK7 shows genetic interaction with the Vangl2 (Van Gogh homologue) mutation. PTK7 is dynamically localized during hair cell polarization. Xenopus PTK7 is required for neural convergent extension and neural tube closure.","method":"Mouse mutant analysis, Xenopus loss-of-function (morpholino), genetic epistasis (Ptk7 × Vangl2Lp double mutant), live imaging of hair cell polarization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo methods (mouse knockout, Xenopus knockdown, genetic epistasis), independently foundational and widely replicated","pmids":["15229603"],"is_preprint":false},{"year":2008,"finding":"PTK7 recruits Dishevelled (Dsh) to the plasma membrane to regulate neural crest migration. This function depends on the PDZ domain of Dsh and the conserved kinase domain of PTK7. PTK7 is found in a complex with Dsh and Frizzled7 by immunoprecipitation, and endogenous PTK7 is required for Frizzled7-mediated Dsh membrane localization. A PTK7 deletion construct deficient in Dsh binding inhibits neural crest migration.","method":"Xenopus ectodermal explant assays, immunoprecipitation, morpholino knockdown, domain deletion constructs, transplantation of neural crest cells","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, multiple deletion constructs, in vivo rescue/loss-of-function with defined cellular phenotype, single focused lab with multiple orthogonal methods","pmids":["19004858"],"is_preprint":false},{"year":2009,"finding":"PTK7 is essential for mediolateral cell elongation, alignment, polarized protrusive activity, and convergent extension (CE) during mouse gastrulation. In Ptk7 mutants, mesoderm cells fail to elongate and align upon leaving the primitive streak, and CE and axial elongation fail. Loss of PTK7 also unleashes cryptic radial intercalation, causing excessive mesodermal thinning.","method":"High-resolution time-lapse imaging of living mouse embryos, Ptk7 mutant mouse analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — live imaging of mouse mutant embryos with defined cellular-level phenotypic readouts, rigorous loss-of-function","pmids":["19439496"],"is_preprint":false},{"year":2010,"finding":"Membrane type-1 matrix metalloproteinase (MT1-MMP) acts as a principal sheddase of PTK7, directly cleaving the PKP(621)↓LI sequence in the seventh Ig-like domain to generate a soluble N-terminal PTK7 fragment (sPTK7). Expression of full-length membrane PTK7 in cancer cells reorganizes the actin cytoskeleton and inhibits cell invasion; MT1-MMP silencing and the uncleavable L622D PTK7 mutant confirm the biological significance of this proteolysis.","method":"In vitro cleavage assay, MT1-MMP siRNA silencing, uncleavable L622D mutant analysis, zebrafish convergent extension assay, actin cytoskeleton imaging","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro cleavage assay with site identification, mutagenesis (L622D), siRNA validation, in vivo zebrafish model, multiple orthogonal approaches","pmids":["20837484"],"is_preprint":false},{"year":2011,"finding":"RACK1 is a novel interaction partner of PTK7 required for neural tube closure. RACK1 facilitates PTK7-mediated membrane localization of Dishevelled (DSH) by recruiting PKCδ1. RACK1 is necessary for PTK7-DSH interaction and for neural convergent extension in Xenopus.","method":"Xenopus loss-of-function (morpholino), Co-IP, explant assays, dominant-negative constructs","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, Xenopus functional rescue, multiple morpholino phenotypes; single lab but multiple orthogonal methods","pmids":["21350015"],"is_preprint":false},{"year":2011,"finding":"PTK7/Otk co-precipitates canonical Wnt3a and Wnt8 ligands and inhibits canonical Wnt signaling. PTK7 loss-of-function activates canonical Wnt activity; epistasis places PTK7 at the level of the Frizzled receptor. In Drosophila, Otk interacts with Wnt4 and opposes canonical Wnt signaling in embryonic patterning.","method":"Co-immunoprecipitation, luciferase reporter assays (Xenopus, Drosophila), genetic epistasis, loss-of-function in multiple organisms","journal":"The EMBO Journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP of Wnt ligands, reporter assays, epistasis in two organisms (Xenopus and Drosophila), multiple orthogonal methods","pmids":["21772251"],"is_preprint":false},{"year":2012,"finding":"PTK7 regulates myosin II activity in supporting cells to orient planar cell polarity in the mammalian auditory epithelium. PTK7 and Frizzled3/Frizzled6 act in parallel with opposing effects on hair cell PCP. PTK7 is required in supporting cells (not hair cells) for hair cell PCP. In Ptk7 mutants, compromised myosin II activity results in loss of planar asymmetry of junctional vinculin, which is restored in Fz3−/−;Ptk7−/− double mutants.","method":"Mouse mosaic analysis, double mutant epistasis (Fz3−/−;Ptk7−/−), vinculin localization as tension readout, myosin II inhibition","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — mosaic analysis, double mutant epistasis, mechanosensitive protein (vinculin) as functional readout, multiple orthogonal in vivo approaches","pmids":["22560610"],"is_preprint":false},{"year":2012,"finding":"PTK7 undergoes sequential ectodomain shedding: ADAM17 cleaves full-length PTK7 to generate sPTK7-Ig1-7 (shed extracellular domain) and PTK7-CTF1; γ-secretase then cleaves PTK7-CTF1 to generate PTK7-CTF2. PTK7-CTF2 localizes to the nucleus and enhances cell proliferation, migration, and anchorage-independent colony formation in colon cancer cells.","method":"Protease inhibitor treatment, ADAM17 knockdown, γ-secretase inhibitors, immunoblotting, nuclear fractionation, proliferation/migration assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — specific protease knockdown, inhibitor pharmacology, subcellular fractionation confirming nuclear localization, functional readouts; multiple orthogonal methods","pmids":["22665490"],"is_preprint":false},{"year":2012,"finding":"PTK7 ectodomain shedding in HT1080 fibrosarcoma cells involves both ADAM proteinase-mediated and MT1-MMP-mediated cleavage of the PTK7 ectodomain. γ-Secretase cleaves the resulting C-terminal PTK7 fragments; the γ-secretase product is predominantly degraded by the proteasome, but when the C-terminal fragment is overexpressed it enters the nucleus.","method":"Protease inhibitor experiments, overexpression of PTK7 C-terminal fragment, nuclear/cytoplasmic fractionation, immunoblotting","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition and fractionation, single lab, corroborates PMID:22665490 with partially overlapping methods","pmids":["23095747"],"is_preprint":false},{"year":2013,"finding":"PTK7 modulates LRP6 protein levels: PTK7 and LRP6 physically interact, and PTK7 depletion strongly reduces LRP6 protein levels. Because LRP6 positively modulates Wnt/β-catenin but negatively modulates Wnt/PCP, PTK7 stabilization of LRP6 reciprocally regulates both canonical and non-canonical Wnt activities.","method":"Co-immunoprecipitation, morpholino knockdown in Xenopus, immunoblotting, Wnt reporter assays, meis3 expression analysis","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo Xenopus knockdown, single lab, two orthogonal approaches","pmids":["24353057"],"is_preprint":false},{"year":2013,"finding":"The extracellular domain of Ptk7 (plasma membrane-tethered fragment) is sufficient to rescue both PCP morphogenesis and Wnt/β-catenin patterning defects in maternal-zygotic ptk7 mutant zebrafish, indicating the extracellular domain acts as the key functional unit regulating both signaling branches.","method":"Zinc-finger nuclease gene targeting (MZptk7 mutant zebrafish), rescue with extracellular domain construct, β-catenin target gene expression analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null (ZFN), domain rescue experiment, multiple phenotypic readouts (PCP and β-catenin), clean MZ mutant system","pmids":["23533179"],"is_preprint":false},{"year":2014,"finding":"PTK7 interacts with Src kinase and stimulates Src signaling along cell-cell contacts in epithelial cells. ROCK2 is a downstream target of junctional PTK7-Src signaling. PTK7 knockdown reduces active Src at cell-cell contacts, delocalizes ROCK2, decreases junctional contractility, and increases basal actomyosin. In vivo, Src family kinase (SFK) activity is critical for PCP in the auditory sensory epithelium and PTK7-SFK signaling regulates tyrosine phosphorylation of junctional ROCK2.","method":"Co-IP (PTK7-Src interaction), PTK7 knockdown in cultured epithelial cells, immunofluorescence of active Src/ROCK2, pharmacological SFK inhibition in mouse auditory epithelium, phosphotyrosine analysis of ROCK2","journal":"Developmental Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, knockdown with multiple cellular readouts, in vivo pharmacological validation, phosphoprotein analysis; multiple orthogonal methods single lab","pmids":["24703874"],"is_preprint":false},{"year":2014,"finding":"Full-length membrane PTK7 and its proteolytic fragments (N-terminal soluble ectodomain, C-terminal 622–1070 and 726–1070 fragments) differentially regulate migration-related genes. Full-length PTK7 activates Akt and c-Jun pathways and suppresses multiple migration genes; C-terminal fragments act via RAS-ERK and CREB/ATF1 pathways and upregulate cadherin-11.","method":"Genome-wide transcriptional arrays, kinome arrays, stable expression of PTK7 constructs in HT1080 cells, immunoblotting validation","journal":"Cell Communication and Signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide transcriptomics with immunoblotting validation, single lab, multiple constructs","pmids":["24618420"],"is_preprint":false},{"year":2015,"finding":"PTK7 associates with ROR2 to form a heterodimeric complex. PTK7 and ROR2 physically and functionally interact with Wnt5a, leading to JNK activation and cell movements. Wnt5a stimulates release of the tagged PTK7 intracellular domain, which translocates to the nucleus and activates papc expression. In Xenopus, Ptk7 functionally interacts with Ror2 to regulate papc expression and morphogenesis, and Ptk7 is required for Wnt5a-induced papc activation.","method":"Co-immunoprecipitation in mammalian cells, JNK activation assays, cell movement assays, Xenopus gain/loss-of-function, nuclear fractionation, papc reporter assays","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, kinase assay, nuclear translocation by fractionation, in vivo Xenopus functional data; multiple orthogonal methods","pmids":["26499793"],"is_preprint":false},{"year":2015,"finding":"PTK7 interacts with ROR2 in Xenopus neural crest cells (Co-IP), and PTK7 loss-of-function migration defects can be rescued by Ror2 expression but not by a kinase-dead Ror2 mutant, indicating the kinase function of Ror2 is required when substituting for PTK7. PTK7 loss-of-function reduces cell protrusion formation and cell motility in neural crest explants.","method":"Co-immunoprecipitation in Xenopus, morpholino knockdown, live cell imaging of neural crest explants, kinase-dead Ror2 rescue experiment","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus live imaging plus rescue with kinase-dead mutant; single lab","pmids":["26680417"],"is_preprint":false},{"year":2010,"finding":"The chuzhoi (chz) splice-site mutation inserts three amino acids into PTK7 between the 5th and 6th Ig-like domains, reduces membrane localization of PTK7 protein, and causes craniorachischisis, heart/lung defects, and abnormal inner ear hair cell polarity. Chuzhoi shows genetic interaction with Vangl2Lp and Celsr1Crsh, confirming PCP pathway involvement.","method":"ENU mutagenesis screen, positional cloning, immunofluorescence/immunoblot of PTK7 membrane localization, genetic epistasis with Vangl2Lp and Celsr1Crsh","journal":"BMC Developmental Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mutant with molecular characterization of protein localization, genetic epistasis with two independent PCP alleles","pmids":["20704721"],"is_preprint":false},{"year":2011,"finding":"The chuzhoi (chz) mutation creates an additional MT1-MMP cleavage site in PTK7, causing aberrant proteolysis that reduces membrane localization and alters cell migratory parameters.","method":"In vitro MT1-MMP cleavage assay of chz PTK7, mutagenesis, cell migration assays","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay with mutagenesis, single lab","pmids":["21518755"],"is_preprint":false},{"year":2010,"finding":"Soluble PTK7 (sPTK7, the extracellular domain) acts as a decoy receptor to inhibit VEGF-induced tube formation, migration, and invasion of endothelial cells and angiogenesis in vivo. sPTK7 reduces VEGF-induced phosphorylation of FAK and paxillin, blocks paxillin relocalization to focal adhesions, and inhibits stress fiber formation. PTK7 siRNA knockdown also inhibits VEGF-induced tube formation.","method":"Recombinant sPTK7 treatment, HUVEC tube formation/migration/invasion assays, siRNA knockdown, immunofluorescence of paxillin/focal adhesions, in vivo Matrigel angiogenesis assay","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — both decoy receptor and siRNA approaches, multiple cellular readouts; single lab","pmids":["18471990"],"is_preprint":false},{"year":2015,"finding":"PTK7 interacts with KDR (VEGFR2) but not FLT-1 via its extracellular domain. sPTK7 forms oligomers with the extracellular domain of KDR. At low molar ratios, sPTK7 enhances VEGF binding to KDR and promotes KDR phosphorylation/migration/tube formation; at high molar ratios or high cellular PTK7 levels, sPTK7 inhibits VEGF-KDR binding and angiogenic phenotypes (biphasic regulation).","method":"Co-immunoprecipitation, in vitro binding assay, KDR phosphorylation assays in HUVECs, VEGF binding competition, angiogenesis in vivo","journal":"Biochimica et Biophysica Acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro binding assay, dose-response functional assays; single lab, multiple orthogonal approaches","pmids":["25986862"],"is_preprint":false},{"year":2016,"finding":"PTK7 knockdown in esophageal squamous cell carcinoma (ESCC) cells reduces MMP-9 secretion by decreasing phosphorylation of NF-κB, IκB, ERK, and JNK, and blocking nuclear localization of NF-κB and AP-1 (c-Fos/c-Jun). NF-κB activation by PTK7 involves the PI3K/Akt pathway and requires Src kinase activity.","method":"PTK7 siRNA knockdown, gelatin zymography, MMP9 luciferase reporter, phospho-immunoblotting, nuclear fractionation, pharmacological inhibitors","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay, signaling pathway analysis by immunoblot with inhibitors, siRNA knockdown; single lab","pmids":["27689325"],"is_preprint":false},{"year":2019,"finding":"PTK7 binds FGFR1 via its extracellular domain in ESCC and HEK293 cells, colocalizes with FGFR1, and activates FGFR1 phosphorylation independent of FGF ligand. PTK7 knockdown reduces both ligand-free and FGF-induced FGFR1 phosphorylation and downstream signaling, and inhibits FGF-induced oncogenic phenotypes.","method":"Co-immunoprecipitation, co-localization imaging, PTK7 knockdown, FGFR1 phosphorylation assays with/without FGF, proliferation/invasion/wound-healing assays","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, colocalization, knockdown with multiple functional readouts; single lab","pmids":["31490704"],"is_preprint":false},{"year":2017,"finding":"In the presence of canonical Wnt ligands, PTK7 undergoes caveolin-mediated endocytosis (not triggered by non-canonical Wnt ligands), dependent on co-receptor Fzd7, leading to lysosomal degradation of PTK7. This suggests mutual inhibition: PTK7 suppresses canonical Wnt signaling while canonical Wnt induces PTK7 internalization and degradation.","method":"Endocytosis assays, caveolin inhibition, Fzd7 loss-of-function, lysosomal inhibitor treatment, immunofluorescence, Wnt reporter assays in Xenopus","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific inhibitor and co-receptor dependency, subcellular trafficking with multiple readouts; single lab","pmids":["28420671"],"is_preprint":false},{"year":2010,"finding":"PTK7 expression in AML cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis; the intracellular region of PTK7 is required for these effects. A recombinant soluble PTK7-Fc protein sensitizes primary AML blasts to anthracycline-mediated cell death.","method":"PTK7 overexpression in leukemia cell lines, soluble PTK7-Fc decoy treatment, cell migration assay, apoptosis assay, domain deletion (intracellular region requirement)","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain deletion defining intracellular region requirement, decoy receptor functional assay, multiple cellular phenotypes; single lab","pmids":["20558616"],"is_preprint":false},{"year":2014,"finding":"PTK7 expression in cancer cells regulates cell motility in a two-dimensional versus three-dimensional environment differently depending on its proteolytic processing. Both overexpression and knockout of PTK7 in HT1080 cells abrogate metastatic dissemination in mouse and chick embryo models. PTK7 levels and cleavage by MT1-MMP are both required for efficient directional cell motility.","method":"PTK7 overexpression and knockout in HT1080 cells, mouse/chick embryo metastasis models, analysis of lamellipodia/invadopodia structure, analysis of human colorectal cancer tissue","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function in animal metastasis models with quantitative cell motility readouts; single lab","pmids":["25006253"],"is_preprint":false},{"year":2010,"finding":"PlexinA1 interacts with PTK7 by Co-IP and shows phenotypic interaction in Xenopus co-injection experiments. PlexinA1 is required for neural crest migration and likely acts through interaction with PTK7.","method":"Co-immunoprecipitation, morpholino knockdown, co-injection epistasis in Xenopus","journal":"Biochemical and Biophysical Research Communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP, limited functional rescue; single lab, single-method interaction claim","pmids":["20946874"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, ptk7 mutants (Zptk7) develop idiopathic scoliosis-like spinal curvature (no vertebral malformation), while maternal-zygotic ptk7 mutants develop vertebral anomalies associated with congenital scoliosis. A human IS patient PTK7 variant disrupts PTK7 function, linking dysregulated Wnt signaling to scoliosis pathogenesis.","method":"Zebrafish ptk7 genetic mutants (ZFN), MZ mutant analysis, microCT imaging of vertebral column, functional analysis of human variant","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null model (ZFN), MZ mutant for full developmental characterization, human variant functional validation; multiple orthogonal approaches","pmids":["25182715"],"is_preprint":false},{"year":2023,"finding":"Secreted N-terminal domain of PTK7 (from senescent fibroblasts as a SASP component) activates non-canonical Wnt/Ca2+ signaling through FZD7 in intestinal stem cells. PTK7-induced changes in cytosolic Ca2+ promote nuclear translocation of YAP and induce YAP/TEAD target gene expression, impairing symmetry breaking and stem cell differentiation.","method":"Intestinal organoid assay, SASP conditioned medium fractionation, PTK7 neutralization, Ca2+ imaging, YAP nuclear translocation assay, FZD7 knockdown epistasis","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (organoid functional assay, live Ca2+ imaging, epistasis via FZD7 knockdown, YAP localization); single lab but rigorous","pmids":["36631445"],"is_preprint":false},{"year":2023,"finding":"PTK7 is an extracellular binding partner of the adhesion GPCR GPR133 (ADGRD1) in glioblastoma, identified by affinity proteomics. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and acts as a positive allosteric modulator of GPR133 signaling in trans. This effect requires GPR133 intramolecular cleavage and PTK7 membrane anchoring. PTK7 and GPR133 are expressed in adjacent cells in glioblastoma and their knockdowns phenocopy each other.","method":"Affinity proteomics (BioID), Co-IP, GPR133 signaling assays, domain deletion (GPR133 cleavage mutant, PTK7 membrane anchor), siRNA knockdown in glioblastoma cells","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — affinity proteomics plus Co-IP plus mechanistic domain deletion plus functional signaling assay; multiple orthogonal methods in single study","pmids":["37354459"],"is_preprint":false},{"year":2022,"finding":"PTK7 interacts with and stabilizes NDRG1 (predominantly adjacent to adherens junctions) as identified by BirA*-PTK7 proximity labeling. Downregulation of PTK7 or NDRG1 eliminates AZD9291 (osimertinib) resistance in NSCLC cells, and PTK7 knockdown or overexpression alters cell-cell adhesion strength, linking PTK7-NDRG1 axis to drug resistance.","method":"Phosphoproteomics, proximity labeling (BirA*-PTK7), Co-IP, PTK7 knockdown/overexpression, drug sensitivity assays","journal":"ACS Chemical Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity proteomics plus Co-IP plus functional drug resistance readout; single lab","pmids":["36205702"],"is_preprint":false},{"year":2024,"finding":"The binding site of DNA aptamer sgc8c on PTK7 is within Ig domains 3–4 of the extracellular domain, confirmed by sequential protein truncation and crystal structure of the sgc8c–Ig(3-4) complex. Specific PTK7 amino acid residues and aptamer nucleotide residues mediating binding were identified by mass spectrometry, molecular dynamics simulation, and mutagenesis.","method":"Protein truncation, crystal structure determination, mass spectrometry footprinting, molecular dynamics simulation, mutagenesis","journal":"Analytical Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus MS-based footprinting; multiple orthogonal structural and biochemical methods","pmids":["38889444"],"is_preprint":false},{"year":2014,"finding":"In zebrafish, ptk7 regulates Id1 expression in CD44-high glioma cells through TGF-β/Smad signaling. PTK7 knockdown reduces Id1 expression and attenuates TGF-β-stimulated cell proliferation; overexpression of Id1 restores proliferation impaired by PTK7 depletion.","method":"Lentiviral shRNA knockdown, gene expression microarray, Id1 rescue overexpression, TGF-β/Smad pathway inhibition, orthotopic mouse model","journal":"Neuro-Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway inhibition, epistatic rescue with Id1, in vivo orthotopic model; single lab","pmids":["25204555"],"is_preprint":false},{"year":1996,"finding":"Human PTK7 encodes a 1,070 amino acid receptor protein tyrosine kinase-like polypeptide (closely related to chick KLG) with several unusual residues in the conserved tyrosine kinase motifs, identifying it as a catalytically atypical/defective receptor tyrosine kinase.","method":"Full-length cDNA cloning, sequence analysis, expression profiling by Northern blot","journal":"Journal of Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — full cDNA sequence establishes catalytic domain anomalies; foundational structural characterization, single study","pmids":["8882711"],"is_preprint":false},{"year":2004,"finding":"Mouse PTK7 protein is not phosphorylated by itself nor by other protein tyrosine kinases, and its expression does not affect cellular phosphotyrosine levels, confirming it is a catalytically inactive (defective) receptor tyrosine kinase.","method":"In vitro kinase assay, phosphotyrosine immunoblot in COS-1 cells expressing mouse PTK7","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assay and cellular phosphotyrosine analysis; single study confirming catalytic inactivity","pmids":["15019986"],"is_preprint":false},{"year":2019,"finding":"PTK7 variants associated with neural tube defects (NTDs): p.Arg630Ser increases PTK7 interaction with Dvl2, while p.Thr186Met decreases PTK7 interaction with Dvl2, as demonstrated by co-immunoprecipitation; p.Arg630Ser also affects PTK7 protein stability.","method":"Sequencing of NTD patients, immunoblotting (protein stability), co-immunoprecipitation (PTK7–Dvl2 interaction), validation in Chinese NTD cohort","journal":"Molecular Genetics & Genomic Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of variant proteins with Dvl2, protein stability assay, validated in two cohorts; single lab","pmids":["30689296"],"is_preprint":false},{"year":2022,"finding":"PTK7 modulates Rho-GTPase signaling and cell adhesion to sustain epithelial-mesenchymal transition (EMT) and cell plasticity in ovarian cancer. Phosphoproteomics upon PTK7 knockdown identified downstream effectors SNCG, SALL2, and PP1γ, and confirmed modulation of Rho-GTPase signaling pathways.","method":"PTK7 siRNA knockdown, proteomics and phosphoproteomics, 3D high-content imaging, ex vivo primary samples with cofetuzumab mAb, drug sensitivity testing","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics with functional 3D readouts and ex vivo primary validation; single lab, multiple approaches","pmids":["35977930"],"is_preprint":false},{"year":2023,"finding":"PTK7 interacts with FGFR1 and EGFR (extracellular domain interactions) in triple-negative breast cancer cells. PTK7 knockdown decreases growth-factor-induced phosphorylation of both FGFR1 and EGFR, and reduces ERK, Akt, and FAK phosphorylation, indicating PTK7 modulates oncogenic RTK activation.","method":"Co-immunoprecipitation, siRNA knockdown, phospho-immunoblotting, proliferation/migration/invasion assays","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus phospho-signaling assays, multiple RTK interactions tested; single lab","pmids":["37569547"],"is_preprint":false}],"current_model":"PTK7 is a catalytically inactive (pseudokinase) transmembrane receptor that functions as a versatile co-receptor at the crossroads of Wnt signaling: it recruits Dishevelled to the plasma membrane (via RACK1/PKCδ1), forms complexes with Frizzled7, ROR2, LRP6, FGFR1, EGFR, and the GPCR GPR133, activates non-canonical Wnt/PCP signaling (promoting convergent extension, neural tube closure, hair cell polarity, and neural crest migration), and inhibits canonical Wnt/β-catenin activity; it is subject to sequential ectodomain shedding by MT1-MMP/ADAMs and intramembrane cleavage by γ-secretase to generate a nuclear-localizing intracellular fragment, and regulates actomyosin contractility through a PTK7–Src–ROCK2 junctional signaling module."},"narrative":{"mechanistic_narrative":"PTK7 is a catalytically inactive transmembrane receptor that functions as a polarity co-receptor governing planar cell polarity (PCP) and convergent extension during vertebrate morphogenesis [PMID:15229603, PMID:19439496]. Although its sequence places it among receptor tyrosine kinases, the kinase domain carries non-canonical motif residues and the protein neither autophosphorylates nor alters cellular phosphotyrosine, defining it as a pseudokinase/defective RTK [PMID:8882711, PMID:15019986]. At the plasma membrane PTK7 organizes non-canonical Wnt signaling by recruiting Dishevelled together with Frizzled7, a function that requires the Dsh PDZ domain and the PTK7 kinase domain and is facilitated by RACK1 acting through PKCδ1 [PMID:19004858, PMID:21350015]. PTK7 partners with the Wnt5a co-receptor ROR2 to drive JNK activation and morphogenetic cell movements, the latter depending on ROR2 catalytic activity [PMID:26499793, PMID:26680417]. It simultaneously restrains canonical Wnt/β-catenin signaling by binding Wnt ligands and acting at the level of Frizzled, and by physically stabilizing LRP6, thereby reciprocally tuning the canonical and PCP branches; canonical Wnt in turn drives Fzd7-dependent caveolar endocytosis and lysosomal degradation of PTK7 [PMID:21772251, PMID:24353057, PMID:28420671]. Downstream, PTK7 sustains junctional contractility through a PTK7–Src–ROCK2 module and controls myosin II activity in supporting cells to orient hair cell polarity [PMID:24703874, PMID:22560610]. PTK7 is processed by sequential cleavage: MT1-MMP and ADAM17 shed the ectodomain to release a soluble fragment, after which γ-secretase liberates an intracellular C-terminal fragment that translocates to the nucleus and promotes proliferation and migration [PMID:20837484, PMID:22665490]. The shed extracellular domain is itself the key signaling unit, sufficient to rescue both PCP and β-catenin defects and acting in trans as a ligand-like modulator of VEGFR2/KDR, the adhesion GPCR GPR133, and non-canonical Wnt/Ca2+–YAP signaling [PMID:23533179, PMID:25986862, PMID:37354459, PMID:36631445]. In disease, PTK7 functions as an oncogenic co-receptor that potentiates FGFR1 and EGFR signaling and promotes invasion and EMT [PMID:31490704, PMID:37569547, PMID:35977930], and loss-of-function or interaction-altering variants cause scoliosis and neural tube defects in zebrafish, mouse, and human cohorts [PMID:25182715, PMID:20704721, PMID:30689296].","teleology":[{"year":1996,"claim":"Established the molecular identity of PTK7 as an RTK-like receptor with anomalous catalytic-motif residues, raising the question of whether it functions as an active kinase.","evidence":"Full-length cDNA cloning and sequence/expression analysis of human PTK7","pmids":["8882711"],"confidence":"Medium","gaps":["Did not test catalytic activity directly","No functional or pathway assignment"]},{"year":2004,"claim":"Resolved the catalytic question by showing PTK7 is a pseudokinase, and independently placed it genetically in the vertebrate PCP pathway, defining its core developmental role.","evidence":"In vitro kinase/phosphotyrosine assays in COS-1 cells; mouse knockout, Xenopus knockdown, and Ptk7×Vangl2 epistasis with hair cell imaging","pmids":["15019986","15229603"],"confidence":"High","gaps":["Did not identify the molecular partners transducing PCP signal","Mechanism of polarity readout unknown"]},{"year":2008,"claim":"Defined the proximal molecular mechanism: PTK7 recruits Dishevelled to the membrane with Frizzled7, linking the receptor to non-canonical Wnt transduction.","evidence":"Xenopus explant assays, reciprocal Co-IP, domain-deletion constructs, neural crest transplantation","pmids":["19004858"],"confidence":"High","gaps":["How the pseudokinase domain engages Dsh structurally unresolved","Did not address canonical Wnt branch"]},{"year":2009,"claim":"Established the cell-behavioral output of PTK7 loss — failure of mediolateral elongation, alignment, and convergent extension during gastrulation.","evidence":"High-resolution live imaging of Ptk7 mutant mouse embryos","pmids":["19439496"],"confidence":"High","gaps":["Did not connect cell behavior to specific cytoskeletal effectors","Molecular link to PCP core proteins not shown"]},{"year":2010,"claim":"Identified MT1-MMP as the principal PTK7 sheddase and showed proteolysis is functionally required, introducing regulated cleavage as a control point.","evidence":"In vitro cleavage with site mapping (PKP621↓LI), uncleavable L622D mutant, MT1-MMP siRNA, zebrafish CE assay","pmids":["20837484"],"confidence":"High","gaps":["Fate of cleavage fragments not yet defined","In vivo sheddase relevance in mammals not tested"]},{"year":2010,"claim":"Linked PTK7 to disease-relevant proteolysis and to context-specific roles, showing the chuzhoi mutation impairs membrane localization and that soluble ectodomain acts as a VEGF decoy and a survival factor in leukemia.","evidence":"ENU mutant positional cloning with PCP epistasis; recombinant sPTK7/HUVEC angiogenesis assays; PTK7 overexpression and PTK7-Fc decoy in AML cells","pmids":["20704721","18471990","20558616"],"confidence":"High","gaps":["Mechanistic basis of decoy activity not yet defined (later resolved as KDR binding)","Intracellular-region effector in AML not identified"]},{"year":2011,"claim":"Expanded the membrane signaling module by adding RACK1/PKCδ1 as required for PTK7-mediated Dsh localization, and demonstrated PTK7 binds Wnt ligands to inhibit canonical Wnt at the Frizzled level.","evidence":"Xenopus Co-IP/morpholino/explant assays; Wnt ligand Co-IP, luciferase reporters, and epistasis in Xenopus and Drosophila; chz creates aberrant MT1-MMP site","pmids":["21350015","21772251","21518755"],"confidence":"High","gaps":["How a single receptor switches between canonical inhibition and PCP activation not mechanistically unified","Structural basis of Wnt binding unknown"]},{"year":2012,"claim":"Connected PTK7 to mechanical polarity outputs and defined the full proteolytic cascade ending in a nuclear intracellular fragment.","evidence":"Mouse mosaic/double-mutant analysis with vinculin and myosin II readouts; ADAM17 knockdown and γ-secretase inhibition with nuclear fractionation and proliferation assays","pmids":["22560610","22665490","23095747"],"confidence":"High","gaps":["Nuclear targets of PTK7-CTF2 not identified","Relationship between MT1-MMP and ADAM17 shedding pathways unresolved"]},{"year":2013,"claim":"Showed the extracellular domain alone is the functional unit for both Wnt branches and that PTK7 stabilizes LRP6 to reciprocally tune canonical and PCP signaling.","evidence":"ZFN MZptk7 zebrafish with ectodomain rescue and β-catenin readouts; Co-IP and Xenopus knockdown of PTK7/LRP6","pmids":["23533179","24353057"],"confidence":"High","gaps":["How the membrane-tethered ectodomain signals without the cytoplasmic tail unexplained","LRP6 stabilization mechanism unknown"]},{"year":2014,"claim":"Defined a junctional PTK7–Src–ROCK2 contractility module and dissected differential signaling and motility roles of full-length versus cleaved PTK7.","evidence":"Co-IP and knockdown with active-Src/ROCK2 imaging plus in vivo SFK inhibition; transcriptomic/kinome profiling of PTK7 constructs; HT1080 metastasis models; Id1/TGF-β rescue in glioma","pmids":["24703874","24618420","25006253","25204555"],"confidence":"High","gaps":["Direct substrate of Src in this module not defined","How cleavage state biases 2D vs 3D motility mechanistically unclear"]},{"year":2014,"claim":"Linked PTK7 dysfunction to scoliosis, establishing a developmental-disease axis through Wnt dysregulation.","evidence":"ZFN and MZ ptk7 zebrafish with microCT and functional testing of a human idiopathic-scoliosis variant","pmids":["25182715"],"confidence":"High","gaps":["Tissue-specific requirement for spinal curvature not localized","Mechanism linking Wnt to spine geometry unresolved"]},{"year":2015,"claim":"Identified ROR2 as a Wnt5a co-receptor partner driving JNK and morphogenesis, and showed sPTK7 binds KDR/VEGFR2 with biphasic effects, mechanistically explaining the decoy activity.","evidence":"Co-IP, JNK assays, nuclear fractionation and papc reporters in mammalian cells/Xenopus; kinase-dead Ror2 rescue in neural crest; KDR binding and dose-dependent VEGF assays","pmids":["26499793","26680417","25986862"],"confidence":"High","gaps":["Stoichiometric switch between activating and inhibitory sPTK7 not defined in vivo","Whether ROR2 phosphorylates PTK7 partners unknown"]},{"year":2017,"claim":"Revealed a feedback mechanism whereby canonical Wnt triggers Fzd7-dependent caveolar endocytosis and lysosomal degradation of PTK7, explaining mutual antagonism between PTK7 and canonical Wnt.","evidence":"Endocytosis/caveolin and lysosomal inhibition, Fzd7 loss-of-function, Wnt reporters in Xenopus","pmids":["28420671"],"confidence":"Medium","gaps":["Single-lab trafficking study","Adaptor linking PTK7 to caveolar machinery not identified"]},{"year":2019,"claim":"Extended PTK7's co-receptor role to oncogenic RTK signaling, showing ligand-independent FGFR1 activation, and connected interaction-altering variants to neural tube defects.","evidence":"Co-IP, colocalization, knockdown with FGFR1 phosphorylation/functional assays in ESCC; Co-IP of NTD variants with Dvl2 and protein-stability assays","pmids":["31490704","30689296"],"confidence":"Medium","gaps":["Mechanism of ligand-free FGFR1 activation not structurally defined","Causality of NTD variants beyond altered Dvl2 binding not established"]},{"year":2022,"claim":"Implicated PTK7 in Rho-GTPase–driven EMT/plasticity and in drug resistance via a stabilized NDRG1 axis, broadening its junctional adhesion roles in cancer.","evidence":"Phosphoproteomics and 3D imaging with cofetuzumab in ovarian cancer; BirA* proximity labeling and Co-IP with drug-sensitivity assays in NSCLC","pmids":["35977930","36205702"],"confidence":"Medium","gaps":["Direct biochemical link between PTK7 and Rho-GTPase regulators not defined","PTK7–NDRG1 stabilization mechanism unknown"]},{"year":2023,"claim":"Identified new trans-acting roles for the PTK7 ectodomain as a positive allosteric modulator of the adhesion GPCR GPR133 and as a senescence-secreted activator of Wnt/Ca2+–YAP signaling, plus interactions with FGFR1/EGFR in TNBC.","evidence":"Affinity proteomics, Co-IP, domain-deletion signaling assays in glioblastoma; intestinal organoid/SASP fractionation with Ca2+ imaging and YAP/FZD7 epistasis; Co-IP and phospho-signaling in TNBC","pmids":["37354459","36631445","37569547"],"confidence":"High","gaps":["Structural basis of GPR133 allosteric modulation undefined","Receptor mediating intracellular Ca2+ output beyond FZD7 not fully mapped"]},{"year":2024,"claim":"Provided structural definition of an aptamer-binding region within PTK7 Ig domains 3–4, establishing a high-resolution view of the ectodomain.","evidence":"Crystal structure of sgc8c–Ig(3-4) complex with MS footprinting, MD simulation, and mutagenesis","pmids":["38889444"],"confidence":"High","gaps":["Structure of full-length receptor or ligand complexes not solved","Does not address signaling-competent conformations"]},{"year":null,"claim":"How a single pseudokinase ectodomain selects among its many co-receptor partners (Fzd7, ROR2, LRP6, KDR, FGFR1, EGFR, GPR133) to switch between canonical inhibition, PCP activation, and oncogenic RTK potentiation remains the central unresolved question.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of PTK7 in a signaling complex","Quantitative rules governing partner choice and cleavage-state output undefined","In vivo function of the nuclear intracellular fragment's targets unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,5,13,27]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,27,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,4,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,15,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,13]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,7,17,26]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,25]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[25,33,30,34]}],"complexes":[],"partners":["DVL","FZD7","ROR2","LRP6","SRC","FGFR1","KDR","GPR133"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13308","full_name":"Inactive tyrosine-protein kinase 7","aliases":["Colon carcinoma kinase 4","CCK-4","Protein-tyrosine kinase 7","Pseudo tyrosine kinase receptor 7","Tyrosine-protein kinase-like 7"],"length_aa":1070,"mass_kda":118.4,"function":"Inactive tyrosine kinase involved in Wnt signaling pathway. 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mouse PTK7 mutations disrupt neural tube closure and stereociliary bundle orientation, and PTK7 shows genetic interaction with the Vangl2 (Van Gogh homologue) mutation. PTK7 is dynamically localized during hair cell polarization. Xenopus PTK7 is required for neural convergent extension and neural tube closure.\",\n      \"method\": \"Mouse mutant analysis, Xenopus loss-of-function (morpholino), genetic epistasis (Ptk7 × Vangl2Lp double mutant), live imaging of hair cell polarization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo methods (mouse knockout, Xenopus knockdown, genetic epistasis), independently foundational and widely replicated\",\n      \"pmids\": [\"15229603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTK7 recruits Dishevelled (Dsh) to the plasma membrane to regulate neural crest migration. This function depends on the PDZ domain of Dsh and the conserved kinase domain of PTK7. PTK7 is found in a complex with Dsh and Frizzled7 by immunoprecipitation, and endogenous PTK7 is required for Frizzled7-mediated Dsh membrane localization. A PTK7 deletion construct deficient in Dsh binding inhibits neural crest migration.\",\n      \"method\": \"Xenopus ectodermal explant assays, immunoprecipitation, morpholino knockdown, domain deletion constructs, transplantation of neural crest cells\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, multiple deletion constructs, in vivo rescue/loss-of-function with defined cellular phenotype, single focused lab with multiple orthogonal methods\",\n      \"pmids\": [\"19004858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTK7 is essential for mediolateral cell elongation, alignment, polarized protrusive activity, and convergent extension (CE) during mouse gastrulation. In Ptk7 mutants, mesoderm cells fail to elongate and align upon leaving the primitive streak, and CE and axial elongation fail. Loss of PTK7 also unleashes cryptic radial intercalation, causing excessive mesodermal thinning.\",\n      \"method\": \"High-resolution time-lapse imaging of living mouse embryos, Ptk7 mutant mouse analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live imaging of mouse mutant embryos with defined cellular-level phenotypic readouts, rigorous loss-of-function\",\n      \"pmids\": [\"19439496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Membrane type-1 matrix metalloproteinase (MT1-MMP) acts as a principal sheddase of PTK7, directly cleaving the PKP(621)↓LI sequence in the seventh Ig-like domain to generate a soluble N-terminal PTK7 fragment (sPTK7). Expression of full-length membrane PTK7 in cancer cells reorganizes the actin cytoskeleton and inhibits cell invasion; MT1-MMP silencing and the uncleavable L622D PTK7 mutant confirm the biological significance of this proteolysis.\",\n      \"method\": \"In vitro cleavage assay, MT1-MMP siRNA silencing, uncleavable L622D mutant analysis, zebrafish convergent extension assay, actin cytoskeleton imaging\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro cleavage assay with site identification, mutagenesis (L622D), siRNA validation, in vivo zebrafish model, multiple orthogonal approaches\",\n      \"pmids\": [\"20837484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"RACK1 is a novel interaction partner of PTK7 required for neural tube closure. RACK1 facilitates PTK7-mediated membrane localization of Dishevelled (DSH) by recruiting PKCδ1. RACK1 is necessary for PTK7-DSH interaction and for neural convergent extension in Xenopus.\",\n      \"method\": \"Xenopus loss-of-function (morpholino), Co-IP, explant assays, dominant-negative constructs\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, Xenopus functional rescue, multiple morpholino phenotypes; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21350015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTK7/Otk co-precipitates canonical Wnt3a and Wnt8 ligands and inhibits canonical Wnt signaling. PTK7 loss-of-function activates canonical Wnt activity; epistasis places PTK7 at the level of the Frizzled receptor. In Drosophila, Otk interacts with Wnt4 and opposes canonical Wnt signaling in embryonic patterning.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assays (Xenopus, Drosophila), genetic epistasis, loss-of-function in multiple organisms\",\n      \"journal\": \"The EMBO Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP of Wnt ligands, reporter assays, epistasis in two organisms (Xenopus and Drosophila), multiple orthogonal methods\",\n      \"pmids\": [\"21772251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTK7 regulates myosin II activity in supporting cells to orient planar cell polarity in the mammalian auditory epithelium. PTK7 and Frizzled3/Frizzled6 act in parallel with opposing effects on hair cell PCP. PTK7 is required in supporting cells (not hair cells) for hair cell PCP. In Ptk7 mutants, compromised myosin II activity results in loss of planar asymmetry of junctional vinculin, which is restored in Fz3−/−;Ptk7−/− double mutants.\",\n      \"method\": \"Mouse mosaic analysis, double mutant epistasis (Fz3−/−;Ptk7−/−), vinculin localization as tension readout, myosin II inhibition\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mosaic analysis, double mutant epistasis, mechanosensitive protein (vinculin) as functional readout, multiple orthogonal in vivo approaches\",\n      \"pmids\": [\"22560610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTK7 undergoes sequential ectodomain shedding: ADAM17 cleaves full-length PTK7 to generate sPTK7-Ig1-7 (shed extracellular domain) and PTK7-CTF1; γ-secretase then cleaves PTK7-CTF1 to generate PTK7-CTF2. PTK7-CTF2 localizes to the nucleus and enhances cell proliferation, migration, and anchorage-independent colony formation in colon cancer cells.\",\n      \"method\": \"Protease inhibitor treatment, ADAM17 knockdown, γ-secretase inhibitors, immunoblotting, nuclear fractionation, proliferation/migration assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — specific protease knockdown, inhibitor pharmacology, subcellular fractionation confirming nuclear localization, functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"22665490\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PTK7 ectodomain shedding in HT1080 fibrosarcoma cells involves both ADAM proteinase-mediated and MT1-MMP-mediated cleavage of the PTK7 ectodomain. γ-Secretase cleaves the resulting C-terminal PTK7 fragments; the γ-secretase product is predominantly degraded by the proteasome, but when the C-terminal fragment is overexpressed it enters the nucleus.\",\n      \"method\": \"Protease inhibitor experiments, overexpression of PTK7 C-terminal fragment, nuclear/cytoplasmic fractionation, immunoblotting\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition and fractionation, single lab, corroborates PMID:22665490 with partially overlapping methods\",\n      \"pmids\": [\"23095747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PTK7 modulates LRP6 protein levels: PTK7 and LRP6 physically interact, and PTK7 depletion strongly reduces LRP6 protein levels. Because LRP6 positively modulates Wnt/β-catenin but negatively modulates Wnt/PCP, PTK7 stabilization of LRP6 reciprocally regulates both canonical and non-canonical Wnt activities.\",\n      \"method\": \"Co-immunoprecipitation, morpholino knockdown in Xenopus, immunoblotting, Wnt reporter assays, meis3 expression analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo Xenopus knockdown, single lab, two orthogonal approaches\",\n      \"pmids\": [\"24353057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The extracellular domain of Ptk7 (plasma membrane-tethered fragment) is sufficient to rescue both PCP morphogenesis and Wnt/β-catenin patterning defects in maternal-zygotic ptk7 mutant zebrafish, indicating the extracellular domain acts as the key functional unit regulating both signaling branches.\",\n      \"method\": \"Zinc-finger nuclease gene targeting (MZptk7 mutant zebrafish), rescue with extracellular domain construct, β-catenin target gene expression analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null (ZFN), domain rescue experiment, multiple phenotypic readouts (PCP and β-catenin), clean MZ mutant system\",\n      \"pmids\": [\"23533179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTK7 interacts with Src kinase and stimulates Src signaling along cell-cell contacts in epithelial cells. ROCK2 is a downstream target of junctional PTK7-Src signaling. PTK7 knockdown reduces active Src at cell-cell contacts, delocalizes ROCK2, decreases junctional contractility, and increases basal actomyosin. In vivo, Src family kinase (SFK) activity is critical for PCP in the auditory sensory epithelium and PTK7-SFK signaling regulates tyrosine phosphorylation of junctional ROCK2.\",\n      \"method\": \"Co-IP (PTK7-Src interaction), PTK7 knockdown in cultured epithelial cells, immunofluorescence of active Src/ROCK2, pharmacological SFK inhibition in mouse auditory epithelium, phosphotyrosine analysis of ROCK2\",\n      \"journal\": \"Developmental Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, knockdown with multiple cellular readouts, in vivo pharmacological validation, phosphoprotein analysis; multiple orthogonal methods single lab\",\n      \"pmids\": [\"24703874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Full-length membrane PTK7 and its proteolytic fragments (N-terminal soluble ectodomain, C-terminal 622–1070 and 726–1070 fragments) differentially regulate migration-related genes. Full-length PTK7 activates Akt and c-Jun pathways and suppresses multiple migration genes; C-terminal fragments act via RAS-ERK and CREB/ATF1 pathways and upregulate cadherin-11.\",\n      \"method\": \"Genome-wide transcriptional arrays, kinome arrays, stable expression of PTK7 constructs in HT1080 cells, immunoblotting validation\",\n      \"journal\": \"Cell Communication and Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide transcriptomics with immunoblotting validation, single lab, multiple constructs\",\n      \"pmids\": [\"24618420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTK7 associates with ROR2 to form a heterodimeric complex. PTK7 and ROR2 physically and functionally interact with Wnt5a, leading to JNK activation and cell movements. Wnt5a stimulates release of the tagged PTK7 intracellular domain, which translocates to the nucleus and activates papc expression. In Xenopus, Ptk7 functionally interacts with Ror2 to regulate papc expression and morphogenesis, and Ptk7 is required for Wnt5a-induced papc activation.\",\n      \"method\": \"Co-immunoprecipitation in mammalian cells, JNK activation assays, cell movement assays, Xenopus gain/loss-of-function, nuclear fractionation, papc reporter assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, kinase assay, nuclear translocation by fractionation, in vivo Xenopus functional data; multiple orthogonal methods\",\n      \"pmids\": [\"26499793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTK7 interacts with ROR2 in Xenopus neural crest cells (Co-IP), and PTK7 loss-of-function migration defects can be rescued by Ror2 expression but not by a kinase-dead Ror2 mutant, indicating the kinase function of Ror2 is required when substituting for PTK7. PTK7 loss-of-function reduces cell protrusion formation and cell motility in neural crest explants.\",\n      \"method\": \"Co-immunoprecipitation in Xenopus, morpholino knockdown, live cell imaging of neural crest explants, kinase-dead Ror2 rescue experiment\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus live imaging plus rescue with kinase-dead mutant; single lab\",\n      \"pmids\": [\"26680417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The chuzhoi (chz) splice-site mutation inserts three amino acids into PTK7 between the 5th and 6th Ig-like domains, reduces membrane localization of PTK7 protein, and causes craniorachischisis, heart/lung defects, and abnormal inner ear hair cell polarity. Chuzhoi shows genetic interaction with Vangl2Lp and Celsr1Crsh, confirming PCP pathway involvement.\",\n      \"method\": \"ENU mutagenesis screen, positional cloning, immunofluorescence/immunoblot of PTK7 membrane localization, genetic epistasis with Vangl2Lp and Celsr1Crsh\",\n      \"journal\": \"BMC Developmental Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mutant with molecular characterization of protein localization, genetic epistasis with two independent PCP alleles\",\n      \"pmids\": [\"20704721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The chuzhoi (chz) mutation creates an additional MT1-MMP cleavage site in PTK7, causing aberrant proteolysis that reduces membrane localization and alters cell migratory parameters.\",\n      \"method\": \"In vitro MT1-MMP cleavage assay of chz PTK7, mutagenesis, cell migration assays\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay with mutagenesis, single lab\",\n      \"pmids\": [\"21518755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Soluble PTK7 (sPTK7, the extracellular domain) acts as a decoy receptor to inhibit VEGF-induced tube formation, migration, and invasion of endothelial cells and angiogenesis in vivo. sPTK7 reduces VEGF-induced phosphorylation of FAK and paxillin, blocks paxillin relocalization to focal adhesions, and inhibits stress fiber formation. PTK7 siRNA knockdown also inhibits VEGF-induced tube formation.\",\n      \"method\": \"Recombinant sPTK7 treatment, HUVEC tube formation/migration/invasion assays, siRNA knockdown, immunofluorescence of paxillin/focal adhesions, in vivo Matrigel angiogenesis assay\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — both decoy receptor and siRNA approaches, multiple cellular readouts; single lab\",\n      \"pmids\": [\"18471990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PTK7 interacts with KDR (VEGFR2) but not FLT-1 via its extracellular domain. sPTK7 forms oligomers with the extracellular domain of KDR. At low molar ratios, sPTK7 enhances VEGF binding to KDR and promotes KDR phosphorylation/migration/tube formation; at high molar ratios or high cellular PTK7 levels, sPTK7 inhibits VEGF-KDR binding and angiogenic phenotypes (biphasic regulation).\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, KDR phosphorylation assays in HUVECs, VEGF binding competition, angiogenesis in vivo\",\n      \"journal\": \"Biochimica et Biophysica Acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro binding assay, dose-response functional assays; single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"25986862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PTK7 knockdown in esophageal squamous cell carcinoma (ESCC) cells reduces MMP-9 secretion by decreasing phosphorylation of NF-κB, IκB, ERK, and JNK, and blocking nuclear localization of NF-κB and AP-1 (c-Fos/c-Jun). NF-κB activation by PTK7 involves the PI3K/Akt pathway and requires Src kinase activity.\",\n      \"method\": \"PTK7 siRNA knockdown, gelatin zymography, MMP9 luciferase reporter, phospho-immunoblotting, nuclear fractionation, pharmacological inhibitors\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay, signaling pathway analysis by immunoblot with inhibitors, siRNA knockdown; single lab\",\n      \"pmids\": [\"27689325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTK7 binds FGFR1 via its extracellular domain in ESCC and HEK293 cells, colocalizes with FGFR1, and activates FGFR1 phosphorylation independent of FGF ligand. PTK7 knockdown reduces both ligand-free and FGF-induced FGFR1 phosphorylation and downstream signaling, and inhibits FGF-induced oncogenic phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, PTK7 knockdown, FGFR1 phosphorylation assays with/without FGF, proliferation/invasion/wound-healing assays\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, colocalization, knockdown with multiple functional readouts; single lab\",\n      \"pmids\": [\"31490704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In the presence of canonical Wnt ligands, PTK7 undergoes caveolin-mediated endocytosis (not triggered by non-canonical Wnt ligands), dependent on co-receptor Fzd7, leading to lysosomal degradation of PTK7. This suggests mutual inhibition: PTK7 suppresses canonical Wnt signaling while canonical Wnt induces PTK7 internalization and degradation.\",\n      \"method\": \"Endocytosis assays, caveolin inhibition, Fzd7 loss-of-function, lysosomal inhibitor treatment, immunofluorescence, Wnt reporter assays in Xenopus\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific inhibitor and co-receptor dependency, subcellular trafficking with multiple readouts; single lab\",\n      \"pmids\": [\"28420671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTK7 expression in AML cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis; the intracellular region of PTK7 is required for these effects. A recombinant soluble PTK7-Fc protein sensitizes primary AML blasts to anthracycline-mediated cell death.\",\n      \"method\": \"PTK7 overexpression in leukemia cell lines, soluble PTK7-Fc decoy treatment, cell migration assay, apoptosis assay, domain deletion (intracellular region requirement)\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain deletion defining intracellular region requirement, decoy receptor functional assay, multiple cellular phenotypes; single lab\",\n      \"pmids\": [\"20558616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTK7 expression in cancer cells regulates cell motility in a two-dimensional versus three-dimensional environment differently depending on its proteolytic processing. Both overexpression and knockout of PTK7 in HT1080 cells abrogate metastatic dissemination in mouse and chick embryo models. PTK7 levels and cleavage by MT1-MMP are both required for efficient directional cell motility.\",\n      \"method\": \"PTK7 overexpression and knockout in HT1080 cells, mouse/chick embryo metastasis models, analysis of lamellipodia/invadopodia structure, analysis of human colorectal cancer tissue\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function in animal metastasis models with quantitative cell motility readouts; single lab\",\n      \"pmids\": [\"25006253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PlexinA1 interacts with PTK7 by Co-IP and shows phenotypic interaction in Xenopus co-injection experiments. PlexinA1 is required for neural crest migration and likely acts through interaction with PTK7.\",\n      \"method\": \"Co-immunoprecipitation, morpholino knockdown, co-injection epistasis in Xenopus\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP, limited functional rescue; single lab, single-method interaction claim\",\n      \"pmids\": [\"20946874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, ptk7 mutants (Zptk7) develop idiopathic scoliosis-like spinal curvature (no vertebral malformation), while maternal-zygotic ptk7 mutants develop vertebral anomalies associated with congenital scoliosis. A human IS patient PTK7 variant disrupts PTK7 function, linking dysregulated Wnt signaling to scoliosis pathogenesis.\",\n      \"method\": \"Zebrafish ptk7 genetic mutants (ZFN), MZ mutant analysis, microCT imaging of vertebral column, functional analysis of human variant\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null model (ZFN), MZ mutant for full developmental characterization, human variant functional validation; multiple orthogonal approaches\",\n      \"pmids\": [\"25182715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Secreted N-terminal domain of PTK7 (from senescent fibroblasts as a SASP component) activates non-canonical Wnt/Ca2+ signaling through FZD7 in intestinal stem cells. PTK7-induced changes in cytosolic Ca2+ promote nuclear translocation of YAP and induce YAP/TEAD target gene expression, impairing symmetry breaking and stem cell differentiation.\",\n      \"method\": \"Intestinal organoid assay, SASP conditioned medium fractionation, PTK7 neutralization, Ca2+ imaging, YAP nuclear translocation assay, FZD7 knockdown epistasis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (organoid functional assay, live Ca2+ imaging, epistasis via FZD7 knockdown, YAP localization); single lab but rigorous\",\n      \"pmids\": [\"36631445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTK7 is an extracellular binding partner of the adhesion GPCR GPR133 (ADGRD1) in glioblastoma, identified by affinity proteomics. PTK7 binds the autoproteolytically generated N-terminal fragment of GPR133 and acts as a positive allosteric modulator of GPR133 signaling in trans. This effect requires GPR133 intramolecular cleavage and PTK7 membrane anchoring. PTK7 and GPR133 are expressed in adjacent cells in glioblastoma and their knockdowns phenocopy each other.\",\n      \"method\": \"Affinity proteomics (BioID), Co-IP, GPR133 signaling assays, domain deletion (GPR133 cleavage mutant, PTK7 membrane anchor), siRNA knockdown in glioblastoma cells\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — affinity proteomics plus Co-IP plus mechanistic domain deletion plus functional signaling assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"37354459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTK7 interacts with and stabilizes NDRG1 (predominantly adjacent to adherens junctions) as identified by BirA*-PTK7 proximity labeling. Downregulation of PTK7 or NDRG1 eliminates AZD9291 (osimertinib) resistance in NSCLC cells, and PTK7 knockdown or overexpression alters cell-cell adhesion strength, linking PTK7-NDRG1 axis to drug resistance.\",\n      \"method\": \"Phosphoproteomics, proximity labeling (BirA*-PTK7), Co-IP, PTK7 knockdown/overexpression, drug sensitivity assays\",\n      \"journal\": \"ACS Chemical Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity proteomics plus Co-IP plus functional drug resistance readout; single lab\",\n      \"pmids\": [\"36205702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The binding site of DNA aptamer sgc8c on PTK7 is within Ig domains 3–4 of the extracellular domain, confirmed by sequential protein truncation and crystal structure of the sgc8c–Ig(3-4) complex. Specific PTK7 amino acid residues and aptamer nucleotide residues mediating binding were identified by mass spectrometry, molecular dynamics simulation, and mutagenesis.\",\n      \"method\": \"Protein truncation, crystal structure determination, mass spectrometry footprinting, molecular dynamics simulation, mutagenesis\",\n      \"journal\": \"Analytical Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus MS-based footprinting; multiple orthogonal structural and biochemical methods\",\n      \"pmids\": [\"38889444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In zebrafish, ptk7 regulates Id1 expression in CD44-high glioma cells through TGF-β/Smad signaling. PTK7 knockdown reduces Id1 expression and attenuates TGF-β-stimulated cell proliferation; overexpression of Id1 restores proliferation impaired by PTK7 depletion.\",\n      \"method\": \"Lentiviral shRNA knockdown, gene expression microarray, Id1 rescue overexpression, TGF-β/Smad pathway inhibition, orthotopic mouse model\",\n      \"journal\": \"Neuro-Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway inhibition, epistatic rescue with Id1, in vivo orthotopic model; single lab\",\n      \"pmids\": [\"25204555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human PTK7 encodes a 1,070 amino acid receptor protein tyrosine kinase-like polypeptide (closely related to chick KLG) with several unusual residues in the conserved tyrosine kinase motifs, identifying it as a catalytically atypical/defective receptor tyrosine kinase.\",\n      \"method\": \"Full-length cDNA cloning, sequence analysis, expression profiling by Northern blot\",\n      \"journal\": \"Journal of Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — full cDNA sequence establishes catalytic domain anomalies; foundational structural characterization, single study\",\n      \"pmids\": [\"8882711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mouse PTK7 protein is not phosphorylated by itself nor by other protein tyrosine kinases, and its expression does not affect cellular phosphotyrosine levels, confirming it is a catalytically inactive (defective) receptor tyrosine kinase.\",\n      \"method\": \"In vitro kinase assay, phosphotyrosine immunoblot in COS-1 cells expressing mouse PTK7\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assay and cellular phosphotyrosine analysis; single study confirming catalytic inactivity\",\n      \"pmids\": [\"15019986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTK7 variants associated with neural tube defects (NTDs): p.Arg630Ser increases PTK7 interaction with Dvl2, while p.Thr186Met decreases PTK7 interaction with Dvl2, as demonstrated by co-immunoprecipitation; p.Arg630Ser also affects PTK7 protein stability.\",\n      \"method\": \"Sequencing of NTD patients, immunoblotting (protein stability), co-immunoprecipitation (PTK7–Dvl2 interaction), validation in Chinese NTD cohort\",\n      \"journal\": \"Molecular Genetics & Genomic Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of variant proteins with Dvl2, protein stability assay, validated in two cohorts; single lab\",\n      \"pmids\": [\"30689296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTK7 modulates Rho-GTPase signaling and cell adhesion to sustain epithelial-mesenchymal transition (EMT) and cell plasticity in ovarian cancer. Phosphoproteomics upon PTK7 knockdown identified downstream effectors SNCG, SALL2, and PP1γ, and confirmed modulation of Rho-GTPase signaling pathways.\",\n      \"method\": \"PTK7 siRNA knockdown, proteomics and phosphoproteomics, 3D high-content imaging, ex vivo primary samples with cofetuzumab mAb, drug sensitivity testing\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics with functional 3D readouts and ex vivo primary validation; single lab, multiple approaches\",\n      \"pmids\": [\"35977930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PTK7 interacts with FGFR1 and EGFR (extracellular domain interactions) in triple-negative breast cancer cells. PTK7 knockdown decreases growth-factor-induced phosphorylation of both FGFR1 and EGFR, and reduces ERK, Akt, and FAK phosphorylation, indicating PTK7 modulates oncogenic RTK activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, phospho-immunoblotting, proliferation/migration/invasion assays\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus phospho-signaling assays, multiple RTK interactions tested; single lab\",\n      \"pmids\": [\"37569547\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTK7 is a catalytically inactive (pseudokinase) transmembrane receptor that functions as a versatile co-receptor at the crossroads of Wnt signaling: it recruits Dishevelled to the plasma membrane (via RACK1/PKCδ1), forms complexes with Frizzled7, ROR2, LRP6, FGFR1, EGFR, and the GPCR GPR133, activates non-canonical Wnt/PCP signaling (promoting convergent extension, neural tube closure, hair cell polarity, and neural crest migration), and inhibits canonical Wnt/β-catenin activity; it is subject to sequential ectodomain shedding by MT1-MMP/ADAMs and intramembrane cleavage by γ-secretase to generate a nuclear-localizing intracellular fragment, and regulates actomyosin contractility through a PTK7–Src–ROCK2 junctional signaling module.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTK7 is a catalytically inactive transmembrane receptor that functions as a polarity co-receptor governing planar cell polarity (PCP) and convergent extension during vertebrate morphogenesis [#0, #2]. Although its sequence places it among receptor tyrosine kinases, the kinase domain carries non-canonical motif residues and the protein neither autophosphorylates nor alters cellular phosphotyrosine, defining it as a pseudokinase/defective RTK [#31, #32]. At the plasma membrane PTK7 organizes non-canonical Wnt signaling by recruiting Dishevelled together with Frizzled7, a function that requires the Dsh PDZ domain and the PTK7 kinase domain and is facilitated by RACK1 acting through PKC\\u03b41 [#1, #4]. PTK7 partners with the Wnt5a co-receptor ROR2 to drive JNK activation and morphogenetic cell movements, the latter depending on ROR2 catalytic activity [#13, #14]. It simultaneously restrains canonical Wnt/\\u03b2-catenin signaling by binding Wnt ligands and acting at the level of Frizzled, and by physically stabilizing LRP6, thereby reciprocally tuning the canonical and PCP branches; canonical Wnt in turn drives Fzd7-dependent caveolar endocytosis and lysosomal degradation of PTK7 [#5, #9, #21]. Downstream, PTK7 sustains junctional contractility through a PTK7\\u2013Src\\u2013ROCK2 module and controls myosin II activity in supporting cells to orient hair cell polarity [#11, #6]. PTK7 is processed by sequential cleavage: MT1-MMP and ADAM17 shed the ectodomain to release a soluble fragment, after which \\u03b3-secretase liberates an intracellular C-terminal fragment that translocates to the nucleus and promotes proliferation and migration [#3, #7]. The shed extracellular domain is itself the key signaling unit, sufficient to rescue both PCP and \\u03b2-catenin defects and acting in trans as a ligand-like modulator of VEGFR2/KDR, the adhesion GPCR GPR133, and non-canonical Wnt/Ca2+\\u2013YAP signaling [#10, #18, #27, #26]. In disease, PTK7 functions as an oncogenic co-receptor that potentiates FGFR1 and EGFR signaling and promotes invasion and EMT [#20, #35, #34], and loss-of-function or interaction-altering variants cause scoliosis and neural tube defects in zebrafish, mouse, and human cohorts [#25, #15, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of PTK7 as an RTK-like receptor with anomalous catalytic-motif residues, raising the question of whether it functions as an active kinase.\",\n      \"evidence\": \"Full-length cDNA cloning and sequence/expression analysis of human PTK7\",\n      \"pmids\": [\"8882711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not test catalytic activity directly\", \"No functional or pathway assignment\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the catalytic question by showing PTK7 is a pseudokinase, and independently placed it genetically in the vertebrate PCP pathway, defining its core developmental role.\",\n      \"evidence\": \"In vitro kinase/phosphotyrosine assays in COS-1 cells; mouse knockout, Xenopus knockdown, and Ptk7\\u00d7Vangl2 epistasis with hair cell imaging\",\n      \"pmids\": [\"15019986\", \"15229603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular partners transducing PCP signal\", \"Mechanism of polarity readout unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the proximal molecular mechanism: PTK7 recruits Dishevelled to the membrane with Frizzled7, linking the receptor to non-canonical Wnt transduction.\",\n      \"evidence\": \"Xenopus explant assays, reciprocal Co-IP, domain-deletion constructs, neural crest transplantation\",\n      \"pmids\": [\"19004858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the pseudokinase domain engages Dsh structurally unresolved\", \"Did not address canonical Wnt branch\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established the cell-behavioral output of PTK7 loss \\u2014 failure of mediolateral elongation, alignment, and convergent extension during gastrulation.\",\n      \"evidence\": \"High-resolution live imaging of Ptk7 mutant mouse embryos\",\n      \"pmids\": [\"19439496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect cell behavior to specific cytoskeletal effectors\", \"Molecular link to PCP core proteins not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified MT1-MMP as the principal PTK7 sheddase and showed proteolysis is functionally required, introducing regulated cleavage as a control point.\",\n      \"evidence\": \"In vitro cleavage with site mapping (PKP621\\u2193LI), uncleavable L622D mutant, MT1-MMP siRNA, zebrafish CE assay\",\n      \"pmids\": [\"20837484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fate of cleavage fragments not yet defined\", \"In vivo sheddase relevance in mammals not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked PTK7 to disease-relevant proteolysis and to context-specific roles, showing the chuzhoi mutation impairs membrane localization and that soluble ectodomain acts as a VEGF decoy and a survival factor in leukemia.\",\n      \"evidence\": \"ENU mutant positional cloning with PCP epistasis; recombinant sPTK7/HUVEC angiogenesis assays; PTK7 overexpression and PTK7-Fc decoy in AML cells\",\n      \"pmids\": [\"20704721\", \"18471990\", \"20558616\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of decoy activity not yet defined (later resolved as KDR binding)\", \"Intracellular-region effector in AML not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Expanded the membrane signaling module by adding RACK1/PKC\\u03b41 as required for PTK7-mediated Dsh localization, and demonstrated PTK7 binds Wnt ligands to inhibit canonical Wnt at the Frizzled level.\",\n      \"evidence\": \"Xenopus Co-IP/morpholino/explant assays; Wnt ligand Co-IP, luciferase reporters, and epistasis in Xenopus and Drosophila; chz creates aberrant MT1-MMP site\",\n      \"pmids\": [\"21350015\", \"21772251\", \"21518755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single receptor switches between canonical inhibition and PCP activation not mechanistically unified\", \"Structural basis of Wnt binding unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected PTK7 to mechanical polarity outputs and defined the full proteolytic cascade ending in a nuclear intracellular fragment.\",\n      \"evidence\": \"Mouse mosaic/double-mutant analysis with vinculin and myosin II readouts; ADAM17 knockdown and \\u03b3-secretase inhibition with nuclear fractionation and proliferation assays\",\n      \"pmids\": [\"22560610\", \"22665490\", \"23095747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear targets of PTK7-CTF2 not identified\", \"Relationship between MT1-MMP and ADAM17 shedding pathways unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the extracellular domain alone is the functional unit for both Wnt branches and that PTK7 stabilizes LRP6 to reciprocally tune canonical and PCP signaling.\",\n      \"evidence\": \"ZFN MZptk7 zebrafish with ectodomain rescue and \\u03b2-catenin readouts; Co-IP and Xenopus knockdown of PTK7/LRP6\",\n      \"pmids\": [\"23533179\", \"24353057\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the membrane-tethered ectodomain signals without the cytoplasmic tail unexplained\", \"LRP6 stabilization mechanism unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a junctional PTK7\\u2013Src\\u2013ROCK2 contractility module and dissected differential signaling and motility roles of full-length versus cleaved PTK7.\",\n      \"evidence\": \"Co-IP and knockdown with active-Src/ROCK2 imaging plus in vivo SFK inhibition; transcriptomic/kinome profiling of PTK7 constructs; HT1080 metastasis models; Id1/TGF-\\u03b2 rescue in glioma\",\n      \"pmids\": [\"24703874\", \"24618420\", \"25006253\", \"25204555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct substrate of Src in this module not defined\", \"How cleavage state biases 2D vs 3D motility mechanistically unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked PTK7 dysfunction to scoliosis, establishing a developmental-disease axis through Wnt dysregulation.\",\n      \"evidence\": \"ZFN and MZ ptk7 zebrafish with microCT and functional testing of a human idiopathic-scoliosis variant\",\n      \"pmids\": [\"25182715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific requirement for spinal curvature not localized\", \"Mechanism linking Wnt to spine geometry unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified ROR2 as a Wnt5a co-receptor partner driving JNK and morphogenesis, and showed sPTK7 binds KDR/VEGFR2 with biphasic effects, mechanistically explaining the decoy activity.\",\n      \"evidence\": \"Co-IP, JNK assays, nuclear fractionation and papc reporters in mammalian cells/Xenopus; kinase-dead Ror2 rescue in neural crest; KDR binding and dose-dependent VEGF assays\",\n      \"pmids\": [\"26499793\", \"26680417\", \"25986862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometric switch between activating and inhibitory sPTK7 not defined in vivo\", \"Whether ROR2 phosphorylates PTK7 partners unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a feedback mechanism whereby canonical Wnt triggers Fzd7-dependent caveolar endocytosis and lysosomal degradation of PTK7, explaining mutual antagonism between PTK7 and canonical Wnt.\",\n      \"evidence\": \"Endocytosis/caveolin and lysosomal inhibition, Fzd7 loss-of-function, Wnt reporters in Xenopus\",\n      \"pmids\": [\"28420671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab trafficking study\", \"Adaptor linking PTK7 to caveolar machinery not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended PTK7's co-receptor role to oncogenic RTK signaling, showing ligand-independent FGFR1 activation, and connected interaction-altering variants to neural tube defects.\",\n      \"evidence\": \"Co-IP, colocalization, knockdown with FGFR1 phosphorylation/functional assays in ESCC; Co-IP of NTD variants with Dvl2 and protein-stability assays\",\n      \"pmids\": [\"31490704\", \"30689296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ligand-free FGFR1 activation not structurally defined\", \"Causality of NTD variants beyond altered Dvl2 binding not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated PTK7 in Rho-GTPase\\u2013driven EMT/plasticity and in drug resistance via a stabilized NDRG1 axis, broadening its junctional adhesion roles in cancer.\",\n      \"evidence\": \"Phosphoproteomics and 3D imaging with cofetuzumab in ovarian cancer; BirA* proximity labeling and Co-IP with drug-sensitivity assays in NSCLC\",\n      \"pmids\": [\"35977930\", \"36205702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between PTK7 and Rho-GTPase regulators not defined\", \"PTK7\\u2013NDRG1 stabilization mechanism unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified new trans-acting roles for the PTK7 ectodomain as a positive allosteric modulator of the adhesion GPCR GPR133 and as a senescence-secreted activator of Wnt/Ca2+\\u2013YAP signaling, plus interactions with FGFR1/EGFR in TNBC.\",\n      \"evidence\": \"Affinity proteomics, Co-IP, domain-deletion signaling assays in glioblastoma; intestinal organoid/SASP fractionation with Ca2+ imaging and YAP/FZD7 epistasis; Co-IP and phospho-signaling in TNBC\",\n      \"pmids\": [\"37354459\", \"36631445\", \"37569547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of GPR133 allosteric modulation undefined\", \"Receptor mediating intracellular Ca2+ output beyond FZD7 not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided structural definition of an aptamer-binding region within PTK7 Ig domains 3\\u20134, establishing a high-resolution view of the ectodomain.\",\n      \"evidence\": \"Crystal structure of sgc8c\\u2013Ig(3-4) complex with MS footprinting, MD simulation, and mutagenesis\",\n      \"pmids\": [\"38889444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length receptor or ligand complexes not solved\", \"Does not address signaling-competent conformations\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single pseudokinase ectodomain selects among its many co-receptor partners (Fzd7, ROR2, LRP6, KDR, FGFR1, EGFR, GPR133) to switch between canonical inhibition, PCP activation, and oncogenic RTK potentiation remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of PTK7 in a signaling complex\", \"Quantitative rules governing partner choice and cleavage-state output undefined\", \"In vivo function of the nuclear intracellular fragment's targets unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 5, 13, 27]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 27, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 4, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 15, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 7, 17, 26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 25]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [25, 33, 30, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DVL\", \"FZD7\", \"ROR2\", \"LRP6\", \"SRC\", \"FGFR1\", \"KDR\", \"GPR133\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}