{"gene":"PTPRK","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":1994,"finding":"PTPRK mediates homophilic intercellular adhesion via its extracellular domain; this adhesion is calcium-independent, does not require phosphatase activity or proteolytic cleavage, and is mediated by direct interaction of the extracellular domain with PTPRK on opposing cells.","method":"Inducible heterologous expression, purified extracellular domain adhesion assay, bead aggregation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted adhesion with purified domain, multiple orthogonal assays, domain-specific requirements tested","pmids":["8264577"],"is_preprint":false},{"year":1993,"finding":"The PTPRK precursor protein undergoes proteolytic cleavage by the processing endopeptidase furin at a consensus site in the fourth fibronectin type III-like repeat, generating two cleavage products that remain associated; this was established by site-directed mutagenesis of the furin consensus sequence.","method":"Site-directed mutagenesis, antibody-based detection of cleavage products","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis directly identified cleavage site and responsible protease","pmids":["8474452"],"is_preprint":false},{"year":2008,"finding":"PTPRK dephosphorylates beta-catenin, limits its cytosolic tyrosine-phosphorylated pool, impairs nuclear accumulation of wild-type and oncogenic beta-catenin, and promotes relocalization of E-cadherin/beta-catenin complexes to ordered membrane phase at cell-cell contacts, thereby suppressing cyclin D1 and c-myc expression.","method":"PTPRK overexpression and siRNA knockdown in HEK293 and melanoma cell lines, subcellular fractionation, Western blot, immunofluorescence","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional overexpression/knockdown with defined molecular readouts, single lab","pmids":["18276111"],"is_preprint":false},{"year":2007,"finding":"PTPRK is a TGF-beta target gene whose expression is induced by TGF-beta/Smad2 signaling; EBV-encoded EBNA1 decreases Smad2 protein half-life (without directly interacting with Smad2), thereby suppressing PTPRK transcription and promoting Hodgkin lymphoma cell survival and proliferation.","method":"PTPRK overexpression/knockdown in HL cell lines, Smad2 protein stability assays, EBNA1 expression constructs, viability/proliferation assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (gain- and loss-of-function, protein stability, upstream pathway dissection), single lab","pmids":["17720884"],"is_preprint":false},{"year":2007,"finding":"Loss of Ptprk (via ~380 kb deletion) in LEC rats causes a defect in CD4 single-positive T cell maturation in the thymus; reconstitution with Ptprk-expressing bone marrow cells rescues CD4 SP development, establishing Ptprk as required for this differentiation step.","method":"Genetic linkage mapping, bone marrow reconstitution with lentiviral Ptprk expression in LEC rat model","journal":"Mammalian genome","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis via reconstitution rescue experiment clearly assigns Ptprk function","pmids":["17909891"],"is_preprint":false},{"year":2019,"finding":"PTPRK directly and selectively dephosphorylates at least five substrates at cell-cell contacts—Afadin, PARD3, and delta-catenin family members—all cell-cell adhesion regulators; loss of PTPRK phosphatase activity disrupts cell junctions and increases invasive characteristics.","method":"Quantitative tyrosine phosphoproteomics, proximity labeling (BioID), co-immunoprecipitation, in vitro dephosphorylation assays, phosphatase-dead mutant cell lines","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro dephosphorylation assay and phosphoproteomics, replicated across substrates","pmids":["30924770"],"is_preprint":false},{"year":2019,"finding":"PTPRK dephosphorylates CD133 (a stem cell marker); loss of PTPRK activity potentiates the pro-oncogenic CD133-AKT signaling axis in colon cancer cells, increasing phosphorylation of the AKT target Bad and reducing sensitivity to oxaliplatin.","method":"PTPRK knockdown in colon cancer cell lines, Western blot for phospho-CD133 and phospho-Bad, oxaliplatin sensitivity assay","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, knockdown with defined phosphorylation readout but direct dephosphorylation not demonstrated in vitro","pmids":["30947381"],"is_preprint":false},{"year":2020,"finding":"PTPRK dephosphorylates a '4Y' endocytic tyrosine motif in ZNRF3 (a transmembrane E3 ubiquitin ligase targeting Wnt receptors), thereby promoting ZNRF3 internalization and Wnt receptor degradation; PTPRK deficiency increases Wnt signaling and causes head/axial defects in Xenopus embryos.","method":"Xenopus loss-of-function experiments, phosphomutant analysis of ZNRF3 4Y motif, ZNRF3 internalization assays, Wnt signaling reporter assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — direct substrate identification (4Y motif), phosphomutant validation, in vivo epistasis in Xenopus, multiple orthogonal readouts","pmids":["31934854"],"is_preprint":false},{"year":2021,"finding":"The proto-oncogene MET phosphorylates the ZNRF3 '4Y' endocytic motif upon HGF stimulation, counteracting PTPRK dephosphorylation; MET binds ZNRF3 and its phosphorylation blocks ZNRF3-mediated Wnt receptor degradation, establishing a MET-PTPRK kinase-phosphatase rheostat controlling Wnt signaling.","method":"Co-immunoprecipitation, ZNRF3 internalization assays, pharmacological MET inhibition, siRNA depletion, Wnt reporter assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, multiple functional readouts, pharmacological and genetic perturbations converge on same mechanism","pmids":["34590584"],"is_preprint":false},{"year":2022,"finding":"The X-ray crystal structure of the membrane-distal N-terminal domains of PTPRK reveals a head-to-tail homodimer consistent with intermembrane adhesion; SAXS shows the full extracellular domain adopts a rigid extended conformation; mutation of W351 to glycine abolishes PTPRK dimer formation in vitro, identifying W351 as a key determinant of homophilic specificity not shared with PTPRM.","method":"X-ray crystallography, small-angle X-ray scattering (SAXS), site-directed mutagenesis, in vitro dimerization assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis validation of key specificity residue","pmids":["36436563"],"is_preprint":false},{"year":2022,"finding":"Afadin is recruited for dephosphorylation by binding directly to the PTPRK D2 pseudophosphatase domain via a coiled-coil domain in Afadin that is separated by >100 amino acids from the substrate pTyr residue; this interaction is phosphorylation-independent and mediates substrate specificity distinct from PTPRM.","method":"Protein-protein interaction mapping, pulldown assays, mutagenesis defining the D2 pseudophosphatase binding site and Afadin coiled-coil domain","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — direct mapping of interaction interface with mutagenesis, mechanistic explanation for substrate specificity","pmids":["36264065"],"is_preprint":false},{"year":2022,"finding":"PTPRK suppresses E2F transcriptional activity via its cytoplasmic PTP domain; it induces p21Cip1/WAF1 and p27Kip1, suppresses CDK2 activity, and causes G1 cell cycle arrest; this mechanism underlies contact-dependent growth inhibition.","method":"siRNA knockdown, overexpression, luciferase reporter assays, expression profiling, CDK2 activity assay, soft agar and xenograft assays","journal":"Biomedicines","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple functional readouts with domain mapping, single lab","pmids":["36551956"],"is_preprint":false},{"year":2019,"finding":"PTPRK loss-of-function leads to increased STAT3 phosphorylation at Tyr705 in NSCLC cells, suggesting STAT3 is a substrate or downstream target of PTPRK phosphatase activity.","method":"PTPRK siRNA knockdown in NSCLC cell lines, Western blot for phospho-STAT3 Tyr705","journal":"Analytical cellular pathology","confidence":"Low","confidence_rationale":"Tier 3 — single method (Western blot after knockdown), no direct dephosphorylation assay","pmids":["30838170"],"is_preprint":false},{"year":2022,"finding":"PTPRK dephosphorylates EGFR to suppress its activation in intestinal enterocytes; silencing PTPRK in control intestinal organoids increases pEGFR, pERK, and proliferation, while PTPRK overexpression in celiac organoids reduces these.","method":"siRNA silencing and overexpression in intestinal organoids, Western blot for pEGFR and pERK, BrdU incorporation proliferation assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain- and loss-of-function in organoid model with orthogonal readouts, single lab","pmids":["36611909"],"is_preprint":false},{"year":2024,"finding":"PTPRK promotes ZNRF3 internalization and is stabilized at cell-cell contacts in epithelial cells; loss of PTPRK phosphatase activity leads to disrupted cell junctions and increased EMT; however, PTPRK regulation of EGFR is independent of its catalytic function, suggesting additional scaffold/adaptor functions.","method":"Phosphatase-dead PTPRK mutants in colorectal cancer cell lines, invasion assays, mouse colitis model, xenograft tumor suppression assay, signaling pathway analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — catalytic vs. non-catalytic functions distinguished using phosphatase-dead mutants, multiple readouts, in vivo validation","pmids":["38904097"],"is_preprint":false},{"year":2024,"finding":"PTPRK promotes glycolysis via dephosphorylation of fructose-1,6-bisphosphatase 1 (FBP1) in hepatocytes; PTPRK-induced glycolysis enhances PPARγ activity and de novo lipogenesis; PTPRK knockout mice on high-fat diet show lower weight gain and reduced hepatic fat accumulation.","method":"PTPRK knockout mouse model, phosphoproteomic analysis in primary hepatocytes, hepatic metabolomics, high-fat diet experiments, liver cancer xenograft assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — phosphoproteomics identifies substrate, KO mouse with metabolic phenotype, multiple orthogonal methods","pmids":["39496584"],"is_preprint":false},{"year":2025,"finding":"PTPRK promotes postherpetic neuralgia by activating the DUSP1/p38 MAPK signaling pathway in dorsal root ganglia; PTPRK overexpression in DRG cells enhances inflammation via this pathway, while PTPRK knockdown attenuates mechanical allodynia and thermal hypoalgesia in a rat RTX-PHN model.","method":"Rat RTX-induced PHN model, PTPRK overexpression/knockdown in DRG cells/tissue, Western blot for DUSP1 and phospho-p38, ELISA and RT-qPCR for inflammatory cytokines, behavioral pain assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain and loss of function with defined pathway readouts, single lab, no direct dephosphorylation assay of DUSP1","pmids":["41253902"],"is_preprint":false},{"year":2026,"finding":"PTPRK mutant proteins carrying mutations in the D1 phosphatase domain retain binding to integrin beta-4 (ITGB4) but show increased ITGB4 phosphorylation in CRC cells, indicating that these mutations impair PTPRK phosphatase activity toward ITGB4 as a substrate.","method":"Whole exome sequencing of colorectal tumors, co-immunoprecipitation (PTPRK-ITGB4 binding), phosphorylation analysis of ITGB4 in CRC cells expressing mutant PTPRK, in vivo xenograft proliferation assay","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding and phosphorylation assays identify ITGB4 as substrate, single lab, in vitro dephosphorylation not directly shown","pmids":["41820225"],"is_preprint":false}],"current_model":"PTPRK is a transmembrane receptor tyrosine phosphatase that mediates homophilic cell-cell adhesion via its extracellular MAM-Ig-fibronectin III domain (processed by furin and ADAM10), and whose intracellular D1 catalytic domain directly dephosphorylates multiple junctional regulators (Afadin recruited via D2 pseudophosphatase domain, PARD3, delta-catenin family members, CD133, ITGB4, and the ZNRF3 '4Y' endocytic motif), thereby promoting cell-cell adhesion, suppressing Wnt/beta-catenin and EGFR/ERK signaling, inhibiting E2F-driven proliferation, and functioning as a tumor suppressor whose activity is antagonized by MET-mediated phosphorylation of the ZNRF3 4Y motif."},"narrative":{"teleology":[{"year":1993,"claim":"Establishing that PTPRK is processed by furin into two associated subunits resolved how the mature receptor is generated at the cell surface and set the stage for understanding ectodomain regulation.","evidence":"Site-directed mutagenesis of the furin consensus site in the fourth FNIII repeat, antibody-based detection of cleavage products","pmids":["8474452"],"confidence":"High","gaps":["Whether furin cleavage is required for adhesion or phosphatase activity was not addressed","Additional ectodomain shedding events (e.g., by ADAM10) were not examined"]},{"year":1994,"claim":"Demonstrating that PTPRK mediates calcium-independent homophilic adhesion via its extracellular domain—independent of phosphatase activity—established a dual functionality as both an adhesion molecule and a phosphatase.","evidence":"Heterologous expression, purified extracellular domain bead aggregation assay","pmids":["8264577"],"confidence":"High","gaps":["The specific extracellular domain regions sufficient for adhesion were not mapped","In vivo contribution of homophilic adhesion versus phosphatase activity to cell-cell contact was unknown"]},{"year":2007,"claim":"Identifying PTPRK as a TGF-beta/Smad2 target gene linked its transcriptional regulation to a major growth-inhibitory pathway and revealed how EBV-encoded EBNA1 suppresses PTPRK to promote lymphoma cell survival.","evidence":"PTPRK gain- and loss-of-function in Hodgkin lymphoma cell lines, Smad2 protein stability assays, EBNA1 expression constructs","pmids":["17720884"],"confidence":"Medium","gaps":["Whether Smad2 binds the PTPRK promoter directly was not shown","Generalizability beyond Hodgkin lymphoma was untested"]},{"year":2007,"claim":"Genetic deletion and reconstitution in the LEC rat demonstrated that Ptprk is required for CD4 single-positive T cell maturation in the thymus, establishing an in vivo immune function.","evidence":"Linkage mapping of ~380 kb Ptprk deletion in LEC rats, bone marrow reconstitution with lentiviral Ptprk expression","pmids":["17909891"],"confidence":"High","gaps":["The substrate(s) mediating T cell maturation are unknown","Whether this reflects a T-cell-intrinsic or stromal function was not resolved"]},{"year":2008,"claim":"Showing that PTPRK dephosphorylates beta-catenin and suppresses its nuclear accumulation, thereby reducing cyclin D1 and c-myc, provided the first mechanistic link between PTPRK and Wnt/beta-catenin target gene suppression.","evidence":"Overexpression and siRNA knockdown in HEK293 and melanoma cells, subcellular fractionation, Western blot","pmids":["18276111"],"confidence":"Medium","gaps":["Direct in vitro dephosphorylation of beta-catenin was not demonstrated","The specific tyrosine residue(s) targeted on beta-catenin were not identified"]},{"year":2019,"claim":"Unbiased phosphoproteomics and in vitro dephosphorylation assays identified Afadin, PARD3, and delta-catenin family members as direct PTPRK substrates at cell-cell contacts, redefining PTPRK as a junction-focused phosphatase whose loss disrupts epithelial integrity.","evidence":"Quantitative tyrosine phosphoproteomics, BioID proximity labeling, co-immunoprecipitation, in vitro dephosphorylation, phosphatase-dead mutant cell lines","pmids":["30924770"],"confidence":"High","gaps":["Structural basis for substrate recognition at the active site was not determined","Relative contribution of each substrate to junction maintenance was not dissected"]},{"year":2020,"claim":"Identifying the ZNRF3 '4Y' endocytic motif as a direct PTPRK substrate revealed how PTPRK controls Wnt receptor turnover: dephosphorylation of this motif promotes ZNRF3 internalization and Wnt receptor degradation, with PTPRK loss causing Wnt-dependent axial defects in Xenopus.","evidence":"Phosphomutant analysis of ZNRF3 4Y motif, ZNRF3 internalization assays, Wnt reporter assays, Xenopus loss-of-function embryos","pmids":["31934854"],"confidence":"High","gaps":["Whether the PTPRK-ZNRF3 axis operates in mammalian intestinal stem cells in vivo was not shown","How PTPRK is recruited to ZNRF3 was not defined"]},{"year":2021,"claim":"The discovery that MET phosphorylates the same ZNRF3 4Y motif that PTPRK dephosphorylates established a kinase-phosphatase rheostat controlling Wnt receptor degradation downstream of HGF signaling.","evidence":"Reciprocal co-immunoprecipitation of MET-ZNRF3, pharmacological MET inhibition, siRNA, ZNRF3 internalization and Wnt reporter assays","pmids":["34590584"],"confidence":"High","gaps":["In vivo validation of the MET-PTPRK rheostat in tumor models was lacking","Other kinases that may phosphorylate the 4Y motif were not surveyed"]},{"year":2022,"claim":"The crystal structure of the PTPRK N-terminal domains revealed a head-to-tail homodimer, and mutagenesis of W351 abolished dimerization, defining the molecular determinant of homophilic specificity distinguishing PTPRK from PTPRM.","evidence":"X-ray crystallography, SAXS, site-directed mutagenesis of W351, in vitro dimerization assay","pmids":["36436563"],"confidence":"High","gaps":["Full-length ectodomain structure in the context of a membrane is unavailable","Whether W351-dependent dimerization regulates phosphatase activity in trans was not tested"]},{"year":2022,"claim":"Mapping the Afadin-PTPRK interaction to the D2 pseudophosphatase domain (binding Afadin's coiled-coil distal from the substrate pTyr) resolved how PTPRK achieves substrate specificity through a two-site recognition mechanism distinct from PTPRM.","evidence":"Pulldown assays, mutagenesis of D2 domain and Afadin coiled-coil, interaction mapping","pmids":["36264065"],"confidence":"High","gaps":["Whether D2-mediated recruitment applies to substrates beyond Afadin was not determined","No co-crystal structure of the D2-Afadin interface exists"]},{"year":2022,"claim":"Demonstrating that PTPRK suppresses E2F transcriptional activity by inducing p21/p27 and inhibiting CDK2 established a cell-cycle arrest mechanism underlying contact-dependent growth inhibition.","evidence":"siRNA knockdown, overexpression, E2F luciferase reporter, CDK2 activity assay, soft agar and xenograft assays","pmids":["36551956"],"confidence":"Medium","gaps":["The direct PTPRK substrate linking dephosphorylation to CDK inhibitor induction is unidentified","Whether this pathway is independent of beta-catenin dephosphorylation was not addressed"]},{"year":2022,"claim":"Showing that PTPRK dephosphorylates EGFR in intestinal organoids and that its loss increases pEGFR/pERK and proliferation connected PTPRK to epithelial homeostasis and suggested relevance to celiac disease pathology.","evidence":"siRNA silencing and overexpression in intestinal organoids, pEGFR/pERK Western blot, BrdU proliferation assay","pmids":["36611909"],"confidence":"Medium","gaps":["Direct in vitro dephosphorylation of EGFR by PTPRK was not shown","EGFR regulation was later shown to be partly catalytic-activity-independent (PMID:38904097)"]},{"year":2024,"claim":"Separation-of-function analysis using phosphatase-dead mutants revealed that PTPRK regulation of EGFR is independent of catalytic activity, establishing additional scaffold/adaptor functions beyond its enzymatic role.","evidence":"Phosphatase-dead PTPRK mutants in CRC cell lines, invasion assays, mouse colitis model, xenograft assays","pmids":["38904097"],"confidence":"Medium","gaps":["The non-catalytic mechanism by which PTPRK regulates EGFR is undefined","Whether other reported substrates are similarly regulated by scaffolding remains untested"]},{"year":2024,"claim":"Identifying FBP1 as a PTPRK substrate in hepatocytes expanded its functional repertoire to metabolic regulation: PTPRK dephosphorylation of FBP1 promotes glycolysis, PPARγ-driven lipogenesis, and hepatic fat accumulation.","evidence":"Phosphoproteomics in primary hepatocytes, PTPRK knockout mouse on high-fat diet, hepatic metabolomics, xenograft assays","pmids":["39496584"],"confidence":"High","gaps":["The specific FBP1 phosphosite(s) targeted by PTPRK were not structurally characterized","How PTPRK accesses the cytosolic enzyme FBP1 given its membrane localization was not explained"]},{"year":2025,"claim":"PTPRK was implicated in postherpetic neuralgia through activation of DUSP1/p38 MAPK signaling in dorsal root ganglia, extending its roles to neuroinflammation and pain.","evidence":"Rat RTX-induced PHN model, PTPRK overexpression/knockdown in DRG, Western blot for DUSP1/phospho-p38, behavioral pain assays","pmids":["41253902"],"confidence":"Medium","gaps":["Direct dephosphorylation of DUSP1 by PTPRK was not demonstrated","The mechanism by which a phosphatase 'activates' a MAPK pathway is counterintuitive and unresolved"]},{"year":2026,"claim":"Identification of ITGB4 as a PTPRK-binding partner and substrate in CRC, with tumor-derived D1 domain mutations impairing ITGB4 dephosphorylation, provided genetic evidence linking PTPRK catalytic loss to integrin-driven tumor progression.","evidence":"Whole exome sequencing of CRC tumors, co-immunoprecipitation, ITGB4 phosphorylation in cells expressing mutant PTPRK, xenograft assays","pmids":["41820225"],"confidence":"Medium","gaps":["In vitro dephosphorylation of ITGB4 by wild-type vs. mutant PTPRK was not directly shown","Which ITGB4 tyrosine site(s) are targeted was not mapped"]},{"year":null,"claim":"Key open questions include: (1) a structural model of the full intracellular tandem phosphatase domain with bound substrate, (2) the identity of the direct substrate(s) mediating CD4 T cell maturation, (3) the non-catalytic mechanism by which PTPRK regulates EGFR, and (4) how PTPRK substrate selection is regulated by cell-contact-dependent trans-dimerization.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length intracellular domain structure exists","In vivo substrate identification in T cells has not been performed","The catalytic-independent EGFR regulatory mechanism is molecularly undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,5,6,7,10,13,15,17]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,7,9,14]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,8,13]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,5,9]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4]}],"complexes":[],"partners":["AFDN","PARD3","ZNRF3","CTNNB1","ITGB4","FBP1","EGFR","PROM1"],"other_free_text":[]},"mechanistic_narrative":"PTPRK is a transmembrane receptor-type protein tyrosine phosphatase that functions as a key regulator of cell-cell adhesion, contact-dependent growth inhibition, and Wnt/EGFR signaling through both catalytic dephosphorylation and homophilic intercellular adhesion. Its extracellular MAM-Ig-fibronectin III domain mediates calcium-independent trans-homophilic binding via a head-to-tail dimer interface dependent on residue W351, while its intracellular D1 catalytic domain dephosphorylates junctional substrates (Afadin, PARD3, delta-catenin family members, ITGB4), the Wnt-receptor-degrading E3 ligase ZNRF3 at a '4Y' endocytic motif to promote Wnt receptor turnover, EGFR, beta-catenin, CD133, and the metabolic enzyme FBP1 [PMID:30924770, PMID:31934854, PMID:18276111, PMID:39496584, PMID:41820225]. Substrate recruitment is achieved in part through the D2 pseudophosphatase domain, which binds the Afadin coiled-coil region independently of phosphorylation, conferring specificity distinct from the paralog PTPRM [PMID:36264065]. PTPRK suppresses proliferative signaling by inhibiting E2F transcriptional activity through induction of CDK inhibitors p21 and p27, by limiting Wnt/beta-catenin nuclear accumulation and target gene expression—opposed by MET-mediated phosphorylation of ZNRF3—and by restraining EGFR/ERK signaling in intestinal epithelium [PMID:36551956, PMID:34590584, PMID:36611909]."},"prefetch_data":{"uniprot":{"accession":"Q15262","full_name":"Receptor-type tyrosine-protein phosphatase kappa","aliases":[],"length_aa":1439,"mass_kda":162.1,"function":"Regulation of processes involving cell contact and adhesion such as growth control, tumor invasion, and metastasis. Negative regulator of EGFR signaling pathway. Forms complexes with beta-catenin and gamma-catenin/plakoglobin. Beta-catenin may be a substrate for the catalytic activity of PTPRK/PTP-kappa","subcellular_location":"Cell junction, adherens junction; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q15262/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPRK","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPRK","total_profiled":1310},"omim":[{"mim_id":"615977","title":"MICRO RNA 339; MIR339","url":"https://www.omim.org/entry/615977"},{"mim_id":"602545","title":"PROTEIN-TYROSINE PHOSPHATASE, RECEPTOR-TYPE, KAPPA; PTPRK","url":"https://www.omim.org/entry/602545"},{"mim_id":"114500","title":"COLORECTAL CANCER; CRC","url":"https://www.omim.org/entry/114500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cell Junctions","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PTPRK"},"hgnc":{"alias_symbol":["R-PTP-kappa"],"prev_symbol":[]},"alphafold":{"accession":"Q15262","domains":[{"cath_id":"2.60.120.200","chopping":"32-194","consensus_level":"medium","plddt":87.8756,"start":32,"end":194},{"cath_id":"2.60.40.10","chopping":"203-290","consensus_level":"medium","plddt":88.8115,"start":203,"end":290},{"cath_id":"2.60.40.10","chopping":"292-384","consensus_level":"high","plddt":88.1213,"start":292,"end":384},{"cath_id":"2.60.40.10","chopping":"397-485","consensus_level":"high","plddt":85.1555,"start":397,"end":485},{"cath_id":"2.60.40.10","chopping":"496-590","consensus_level":"high","plddt":88.0695,"start":496,"end":590},{"cath_id":"2.60.40,2.60.40","chopping":"606-639_655-732","consensus_level":"high","plddt":84.9532,"start":606,"end":732},{"cath_id":"3.90.190.10","chopping":"903-1147","consensus_level":"high","plddt":93.6746,"start":903,"end":1147},{"cath_id":"3.90.190.10","chopping":"1174-1438","consensus_level":"medium","plddt":91.3115,"start":1174,"end":1438}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15262","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15262-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15262-F1-predicted_aligned_error_v6.png","plddt_mean":82.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPRK","jax_strain_url":"https://www.jax.org/strain/search?query=PTPRK"},"sequence":{"accession":"Q15262","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15262.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15262/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15262"}},"corpus_meta":[{"pmid":"8264577","id":"PMC_8264577","title":"Receptor tyrosine phosphatase R-PTP-kappa mediates homophilic binding.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8264577","citation_count":204,"is_preprint":false},{"pmid":"26700806","id":"PMC_26700806","title":"Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26700806","citation_count":202,"is_preprint":false},{"pmid":"8474452","id":"PMC_8474452","title":"Cloning and characterization of R-PTP-kappa, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region.","date":"1993","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8474452","citation_count":141,"is_preprint":false},{"pmid":"26924569","id":"PMC_26924569","title":"Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma.","date":"2016","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/26924569","citation_count":107,"is_preprint":false},{"pmid":"17720884","id":"PMC_17720884","title":"Down-regulation of the TGF-beta target gene, PTPRK, by the Epstein-Barr virus encoded EBNA1 contributes to the growth and survival of Hodgkin lymphoma cells.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17720884","citation_count":85,"is_preprint":false},{"pmid":"18276111","id":"PMC_18276111","title":"PTPRK negatively regulates transcriptional activity of wild type and mutated oncogenic beta-catenin and affects membrane distribution of beta-catenin/E-cadherin complexes in cancer cells.","date":"2008","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/18276111","citation_count":39,"is_preprint":false},{"pmid":"30924770","id":"PMC_30924770","title":"The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell-cell adhesion.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/30924770","citation_count":34,"is_preprint":false},{"pmid":"31934854","id":"PMC_31934854","title":"The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31934854","citation_count":33,"is_preprint":false},{"pmid":"29628123","id":"PMC_29628123","title":"MiR-1260b promotes the migration and invasion in non-small cell lung cancer via targeting PTPRK.","date":"2018","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/29628123","citation_count":30,"is_preprint":false},{"pmid":"23820479","id":"PMC_23820479","title":"THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge.","date":"2013","source":"European journal of human genetics : 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SRA1.","date":"2018","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/31938108","citation_count":14,"is_preprint":false},{"pmid":"30947381","id":"PMC_30947381","title":"PTPRK suppresses progression and chemo-resistance of colon cancer cells via direct inhibition of pro-oncogenic CD133.","date":"2019","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/30947381","citation_count":12,"is_preprint":false},{"pmid":"37461624","id":"PMC_37461624","title":"Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies LRRC4C, LHX5-AS1 and nominates ancestry-specific loci PTPRK , GRB14 , and KIAA0825 as novel risk loci for Alzheimer's disease: the Alzheimer's Disease Genetics Consortium.","date":"2023","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37461624","citation_count":11,"is_preprint":false},{"pmid":"34590584","id":"PMC_34590584","title":"A MET-PTPRK 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aggregation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted adhesion with purified domain, multiple orthogonal assays, domain-specific requirements tested\",\n      \"pmids\": [\"8264577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"The PTPRK precursor protein undergoes proteolytic cleavage by the processing endopeptidase furin at a consensus site in the fourth fibronectin type III-like repeat, generating two cleavage products that remain associated; this was established by site-directed mutagenesis of the furin consensus sequence.\",\n      \"method\": \"Site-directed mutagenesis, antibody-based detection of cleavage products\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis directly identified cleavage site and responsible protease\",\n      \"pmids\": [\"8474452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTPRK dephosphorylates beta-catenin, limits its cytosolic tyrosine-phosphorylated pool, impairs nuclear accumulation of wild-type and oncogenic beta-catenin, and promotes relocalization of E-cadherin/beta-catenin complexes to ordered membrane phase at cell-cell contacts, thereby suppressing cyclin D1 and c-myc expression.\",\n      \"method\": \"PTPRK overexpression and siRNA knockdown in HEK293 and melanoma cell lines, subcellular fractionation, Western blot, immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional overexpression/knockdown with defined molecular readouts, single lab\",\n      \"pmids\": [\"18276111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTPRK is a TGF-beta target gene whose expression is induced by TGF-beta/Smad2 signaling; EBV-encoded EBNA1 decreases Smad2 protein half-life (without directly interacting with Smad2), thereby suppressing PTPRK transcription and promoting Hodgkin lymphoma cell survival and proliferation.\",\n      \"method\": \"PTPRK overexpression/knockdown in HL cell lines, Smad2 protein stability assays, EBNA1 expression constructs, viability/proliferation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (gain- and loss-of-function, protein stability, upstream pathway dissection), single lab\",\n      \"pmids\": [\"17720884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Loss of Ptprk (via ~380 kb deletion) in LEC rats causes a defect in CD4 single-positive T cell maturation in the thymus; reconstitution with Ptprk-expressing bone marrow cells rescues CD4 SP development, establishing Ptprk as required for this differentiation step.\",\n      \"method\": \"Genetic linkage mapping, bone marrow reconstitution with lentiviral Ptprk expression in LEC rat model\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via reconstitution rescue experiment clearly assigns Ptprk function\",\n      \"pmids\": [\"17909891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRK directly and selectively dephosphorylates at least five substrates at cell-cell contacts—Afadin, PARD3, and delta-catenin family members—all cell-cell adhesion regulators; loss of PTPRK phosphatase activity disrupts cell junctions and increases invasive characteristics.\",\n      \"method\": \"Quantitative tyrosine phosphoproteomics, proximity labeling (BioID), co-immunoprecipitation, in vitro dephosphorylation assays, phosphatase-dead mutant cell lines\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro dephosphorylation assay and phosphoproteomics, replicated across substrates\",\n      \"pmids\": [\"30924770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRK dephosphorylates CD133 (a stem cell marker); loss of PTPRK activity potentiates the pro-oncogenic CD133-AKT signaling axis in colon cancer cells, increasing phosphorylation of the AKT target Bad and reducing sensitivity to oxaliplatin.\",\n      \"method\": \"PTPRK knockdown in colon cancer cell lines, Western blot for phospho-CD133 and phospho-Bad, oxaliplatin sensitivity assay\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, knockdown with defined phosphorylation readout but direct dephosphorylation not demonstrated in vitro\",\n      \"pmids\": [\"30947381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PTPRK dephosphorylates a '4Y' endocytic tyrosine motif in ZNRF3 (a transmembrane E3 ubiquitin ligase targeting Wnt receptors), thereby promoting ZNRF3 internalization and Wnt receptor degradation; PTPRK deficiency increases Wnt signaling and causes head/axial defects in Xenopus embryos.\",\n      \"method\": \"Xenopus loss-of-function experiments, phosphomutant analysis of ZNRF3 4Y motif, ZNRF3 internalization assays, Wnt signaling reporter assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct substrate identification (4Y motif), phosphomutant validation, in vivo epistasis in Xenopus, multiple orthogonal readouts\",\n      \"pmids\": [\"31934854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The proto-oncogene MET phosphorylates the ZNRF3 '4Y' endocytic motif upon HGF stimulation, counteracting PTPRK dephosphorylation; MET binds ZNRF3 and its phosphorylation blocks ZNRF3-mediated Wnt receptor degradation, establishing a MET-PTPRK kinase-phosphatase rheostat controlling Wnt signaling.\",\n      \"method\": \"Co-immunoprecipitation, ZNRF3 internalization assays, pharmacological MET inhibition, siRNA depletion, Wnt reporter assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, multiple functional readouts, pharmacological and genetic perturbations converge on same mechanism\",\n      \"pmids\": [\"34590584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The X-ray crystal structure of the membrane-distal N-terminal domains of PTPRK reveals a head-to-tail homodimer consistent with intermembrane adhesion; SAXS shows the full extracellular domain adopts a rigid extended conformation; mutation of W351 to glycine abolishes PTPRK dimer formation in vitro, identifying W351 as a key determinant of homophilic specificity not shared with PTPRM.\",\n      \"method\": \"X-ray crystallography, small-angle X-ray scattering (SAXS), site-directed mutagenesis, in vitro dimerization assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis validation of key specificity residue\",\n      \"pmids\": [\"36436563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Afadin is recruited for dephosphorylation by binding directly to the PTPRK D2 pseudophosphatase domain via a coiled-coil domain in Afadin that is separated by >100 amino acids from the substrate pTyr residue; this interaction is phosphorylation-independent and mediates substrate specificity distinct from PTPRM.\",\n      \"method\": \"Protein-protein interaction mapping, pulldown assays, mutagenesis defining the D2 pseudophosphatase binding site and Afadin coiled-coil domain\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct mapping of interaction interface with mutagenesis, mechanistic explanation for substrate specificity\",\n      \"pmids\": [\"36264065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRK suppresses E2F transcriptional activity via its cytoplasmic PTP domain; it induces p21Cip1/WAF1 and p27Kip1, suppresses CDK2 activity, and causes G1 cell cycle arrest; this mechanism underlies contact-dependent growth inhibition.\",\n      \"method\": \"siRNA knockdown, overexpression, luciferase reporter assays, expression profiling, CDK2 activity assay, soft agar and xenograft assays\",\n      \"journal\": \"Biomedicines\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple functional readouts with domain mapping, single lab\",\n      \"pmids\": [\"36551956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTPRK loss-of-function leads to increased STAT3 phosphorylation at Tyr705 in NSCLC cells, suggesting STAT3 is a substrate or downstream target of PTPRK phosphatase activity.\",\n      \"method\": \"PTPRK siRNA knockdown in NSCLC cell lines, Western blot for phospho-STAT3 Tyr705\",\n      \"journal\": \"Analytical cellular pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (Western blot after knockdown), no direct dephosphorylation assay\",\n      \"pmids\": [\"30838170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTPRK dephosphorylates EGFR to suppress its activation in intestinal enterocytes; silencing PTPRK in control intestinal organoids increases pEGFR, pERK, and proliferation, while PTPRK overexpression in celiac organoids reduces these.\",\n      \"method\": \"siRNA silencing and overexpression in intestinal organoids, Western blot for pEGFR and pERK, BrdU incorporation proliferation assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain- and loss-of-function in organoid model with orthogonal readouts, single lab\",\n      \"pmids\": [\"36611909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRK promotes ZNRF3 internalization and is stabilized at cell-cell contacts in epithelial cells; loss of PTPRK phosphatase activity leads to disrupted cell junctions and increased EMT; however, PTPRK regulation of EGFR is independent of its catalytic function, suggesting additional scaffold/adaptor functions.\",\n      \"method\": \"Phosphatase-dead PTPRK mutants in colorectal cancer cell lines, invasion assays, mouse colitis model, xenograft tumor suppression assay, signaling pathway analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — catalytic vs. non-catalytic functions distinguished using phosphatase-dead mutants, multiple readouts, in vivo validation\",\n      \"pmids\": [\"38904097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTPRK promotes glycolysis via dephosphorylation of fructose-1,6-bisphosphatase 1 (FBP1) in hepatocytes; PTPRK-induced glycolysis enhances PPARγ activity and de novo lipogenesis; PTPRK knockout mice on high-fat diet show lower weight gain and reduced hepatic fat accumulation.\",\n      \"method\": \"PTPRK knockout mouse model, phosphoproteomic analysis in primary hepatocytes, hepatic metabolomics, high-fat diet experiments, liver cancer xenograft assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphoproteomics identifies substrate, KO mouse with metabolic phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"39496584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PTPRK promotes postherpetic neuralgia by activating the DUSP1/p38 MAPK signaling pathway in dorsal root ganglia; PTPRK overexpression in DRG cells enhances inflammation via this pathway, while PTPRK knockdown attenuates mechanical allodynia and thermal hypoalgesia in a rat RTX-PHN model.\",\n      \"method\": \"Rat RTX-induced PHN model, PTPRK overexpression/knockdown in DRG cells/tissue, Western blot for DUSP1 and phospho-p38, ELISA and RT-qPCR for inflammatory cytokines, behavioral pain assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain and loss of function with defined pathway readouts, single lab, no direct dephosphorylation assay of DUSP1\",\n      \"pmids\": [\"41253902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PTPRK mutant proteins carrying mutations in the D1 phosphatase domain retain binding to integrin beta-4 (ITGB4) but show increased ITGB4 phosphorylation in CRC cells, indicating that these mutations impair PTPRK phosphatase activity toward ITGB4 as a substrate.\",\n      \"method\": \"Whole exome sequencing of colorectal tumors, co-immunoprecipitation (PTPRK-ITGB4 binding), phosphorylation analysis of ITGB4 in CRC cells expressing mutant PTPRK, in vivo xenograft proliferation assay\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding and phosphorylation assays identify ITGB4 as substrate, single lab, in vitro dephosphorylation not directly shown\",\n      \"pmids\": [\"41820225\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPRK is a transmembrane receptor tyrosine phosphatase that mediates homophilic cell-cell adhesion via its extracellular MAM-Ig-fibronectin III domain (processed by furin and ADAM10), and whose intracellular D1 catalytic domain directly dephosphorylates multiple junctional regulators (Afadin recruited via D2 pseudophosphatase domain, PARD3, delta-catenin family members, CD133, ITGB4, and the ZNRF3 '4Y' endocytic motif), thereby promoting cell-cell adhesion, suppressing Wnt/beta-catenin and EGFR/ERK signaling, inhibiting E2F-driven proliferation, and functioning as a tumor suppressor whose activity is antagonized by MET-mediated phosphorylation of the ZNRF3 4Y motif.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PTPRK is a transmembrane receptor-type protein tyrosine phosphatase that functions as a key regulator of cell-cell adhesion, contact-dependent growth inhibition, and Wnt/EGFR signaling through both catalytic dephosphorylation and homophilic intercellular adhesion. Its extracellular MAM-Ig-fibronectin III domain mediates calcium-independent trans-homophilic binding via a head-to-tail dimer interface dependent on residue W351, while its intracellular D1 catalytic domain dephosphorylates junctional substrates (Afadin, PARD3, delta-catenin family members, ITGB4), the Wnt-receptor-degrading E3 ligase ZNRF3 at a '4Y' endocytic motif to promote Wnt receptor turnover, EGFR, beta-catenin, CD133, and the metabolic enzyme FBP1 [PMID:30924770, PMID:31934854, PMID:18276111, PMID:39496584, PMID:41820225]. Substrate recruitment is achieved in part through the D2 pseudophosphatase domain, which binds the Afadin coiled-coil region independently of phosphorylation, conferring specificity distinct from the paralog PTPRM [PMID:36264065]. PTPRK suppresses proliferative signaling by inhibiting E2F transcriptional activity through induction of CDK inhibitors p21 and p27, by limiting Wnt/beta-catenin nuclear accumulation and target gene expression—opposed by MET-mediated phosphorylation of ZNRF3—and by restraining EGFR/ERK signaling in intestinal epithelium [PMID:36551956, PMID:34590584, PMID:36611909].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that PTPRK is processed by furin into two associated subunits resolved how the mature receptor is generated at the cell surface and set the stage for understanding ectodomain regulation.\",\n      \"evidence\": \"Site-directed mutagenesis of the furin consensus site in the fourth FNIII repeat, antibody-based detection of cleavage products\",\n      \"pmids\": [\"8474452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether furin cleavage is required for adhesion or phosphatase activity was not addressed\", \"Additional ectodomain shedding events (e.g., by ADAM10) were not examined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that PTPRK mediates calcium-independent homophilic adhesion via its extracellular domain—independent of phosphatase activity—established a dual functionality as both an adhesion molecule and a phosphatase.\",\n      \"evidence\": \"Heterologous expression, purified extracellular domain bead aggregation assay\",\n      \"pmids\": [\"8264577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific extracellular domain regions sufficient for adhesion were not mapped\", \"In vivo contribution of homophilic adhesion versus phosphatase activity to cell-cell contact was unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identifying PTPRK as a TGF-beta/Smad2 target gene linked its transcriptional regulation to a major growth-inhibitory pathway and revealed how EBV-encoded EBNA1 suppresses PTPRK to promote lymphoma cell survival.\",\n      \"evidence\": \"PTPRK gain- and loss-of-function in Hodgkin lymphoma cell lines, Smad2 protein stability assays, EBNA1 expression constructs\",\n      \"pmids\": [\"17720884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Smad2 binds the PTPRK promoter directly was not shown\", \"Generalizability beyond Hodgkin lymphoma was untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Genetic deletion and reconstitution in the LEC rat demonstrated that Ptprk is required for CD4 single-positive T cell maturation in the thymus, establishing an in vivo immune function.\",\n      \"evidence\": \"Linkage mapping of ~380 kb Ptprk deletion in LEC rats, bone marrow reconstitution with lentiviral Ptprk expression\",\n      \"pmids\": [\"17909891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The substrate(s) mediating T cell maturation are unknown\", \"Whether this reflects a T-cell-intrinsic or stromal function was not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that PTPRK dephosphorylates beta-catenin and suppresses its nuclear accumulation, thereby reducing cyclin D1 and c-myc, provided the first mechanistic link between PTPRK and Wnt/beta-catenin target gene suppression.\",\n      \"evidence\": \"Overexpression and siRNA knockdown in HEK293 and melanoma cells, subcellular fractionation, Western blot\",\n      \"pmids\": [\"18276111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro dephosphorylation of beta-catenin was not demonstrated\", \"The specific tyrosine residue(s) targeted on beta-catenin were not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Unbiased phosphoproteomics and in vitro dephosphorylation assays identified Afadin, PARD3, and delta-catenin family members as direct PTPRK substrates at cell-cell contacts, redefining PTPRK as a junction-focused phosphatase whose loss disrupts epithelial integrity.\",\n      \"evidence\": \"Quantitative tyrosine phosphoproteomics, BioID proximity labeling, co-immunoprecipitation, in vitro dephosphorylation, phosphatase-dead mutant cell lines\",\n      \"pmids\": [\"30924770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for substrate recognition at the active site was not determined\", \"Relative contribution of each substrate to junction maintenance was not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying the ZNRF3 '4Y' endocytic motif as a direct PTPRK substrate revealed how PTPRK controls Wnt receptor turnover: dephosphorylation of this motif promotes ZNRF3 internalization and Wnt receptor degradation, with PTPRK loss causing Wnt-dependent axial defects in Xenopus.\",\n      \"evidence\": \"Phosphomutant analysis of ZNRF3 4Y motif, ZNRF3 internalization assays, Wnt reporter assays, Xenopus loss-of-function embryos\",\n      \"pmids\": [\"31934854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the PTPRK-ZNRF3 axis operates in mammalian intestinal stem cells in vivo was not shown\", \"How PTPRK is recruited to ZNRF3 was not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The discovery that MET phosphorylates the same ZNRF3 4Y motif that PTPRK dephosphorylates established a kinase-phosphatase rheostat controlling Wnt receptor degradation downstream of HGF signaling.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of MET-ZNRF3, pharmacological MET inhibition, siRNA, ZNRF3 internalization and Wnt reporter assays\",\n      \"pmids\": [\"34590584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo validation of the MET-PTPRK rheostat in tumor models was lacking\", \"Other kinases that may phosphorylate the 4Y motif were not surveyed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The crystal structure of the PTPRK N-terminal domains revealed a head-to-tail homodimer, and mutagenesis of W351 abolished dimerization, defining the molecular determinant of homophilic specificity distinguishing PTPRK from PTPRM.\",\n      \"evidence\": \"X-ray crystallography, SAXS, site-directed mutagenesis of W351, in vitro dimerization assay\",\n      \"pmids\": [\"36436563\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length ectodomain structure in the context of a membrane is unavailable\", \"Whether W351-dependent dimerization regulates phosphatase activity in trans was not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapping the Afadin-PTPRK interaction to the D2 pseudophosphatase domain (binding Afadin's coiled-coil distal from the substrate pTyr) resolved how PTPRK achieves substrate specificity through a two-site recognition mechanism distinct from PTPRM.\",\n      \"evidence\": \"Pulldown assays, mutagenesis of D2 domain and Afadin coiled-coil, interaction mapping\",\n      \"pmids\": [\"36264065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether D2-mediated recruitment applies to substrates beyond Afadin was not determined\", \"No co-crystal structure of the D2-Afadin interface exists\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that PTPRK suppresses E2F transcriptional activity by inducing p21/p27 and inhibiting CDK2 established a cell-cycle arrest mechanism underlying contact-dependent growth inhibition.\",\n      \"evidence\": \"siRNA knockdown, overexpression, E2F luciferase reporter, CDK2 activity assay, soft agar and xenograft assays\",\n      \"pmids\": [\"36551956\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The direct PTPRK substrate linking dephosphorylation to CDK inhibitor induction is unidentified\", \"Whether this pathway is independent of beta-catenin dephosphorylation was not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that PTPRK dephosphorylates EGFR in intestinal organoids and that its loss increases pEGFR/pERK and proliferation connected PTPRK to epithelial homeostasis and suggested relevance to celiac disease pathology.\",\n      \"evidence\": \"siRNA silencing and overexpression in intestinal organoids, pEGFR/pERK Western blot, BrdU proliferation assay\",\n      \"pmids\": [\"36611909\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct in vitro dephosphorylation of EGFR by PTPRK was not shown\", \"EGFR regulation was later shown to be partly catalytic-activity-independent (PMID:38904097)\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Separation-of-function analysis using phosphatase-dead mutants revealed that PTPRK regulation of EGFR is independent of catalytic activity, establishing additional scaffold/adaptor functions beyond its enzymatic role.\",\n      \"evidence\": \"Phosphatase-dead PTPRK mutants in CRC cell lines, invasion assays, mouse colitis model, xenograft assays\",\n      \"pmids\": [\"38904097\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The non-catalytic mechanism by which PTPRK regulates EGFR is undefined\", \"Whether other reported substrates are similarly regulated by scaffolding remains untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying FBP1 as a PTPRK substrate in hepatocytes expanded its functional repertoire to metabolic regulation: PTPRK dephosphorylation of FBP1 promotes glycolysis, PPARγ-driven lipogenesis, and hepatic fat accumulation.\",\n      \"evidence\": \"Phosphoproteomics in primary hepatocytes, PTPRK knockout mouse on high-fat diet, hepatic metabolomics, xenograft assays\",\n      \"pmids\": [\"39496584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The specific FBP1 phosphosite(s) targeted by PTPRK were not structurally characterized\", \"How PTPRK accesses the cytosolic enzyme FBP1 given its membrane localization was not explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PTPRK was implicated in postherpetic neuralgia through activation of DUSP1/p38 MAPK signaling in dorsal root ganglia, extending its roles to neuroinflammation and pain.\",\n      \"evidence\": \"Rat RTX-induced PHN model, PTPRK overexpression/knockdown in DRG, Western blot for DUSP1/phospho-p38, behavioral pain assays\",\n      \"pmids\": [\"41253902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct dephosphorylation of DUSP1 by PTPRK was not demonstrated\", \"The mechanism by which a phosphatase 'activates' a MAPK pathway is counterintuitive and unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identification of ITGB4 as a PTPRK-binding partner and substrate in CRC, with tumor-derived D1 domain mutations impairing ITGB4 dephosphorylation, provided genetic evidence linking PTPRK catalytic loss to integrin-driven tumor progression.\",\n      \"evidence\": \"Whole exome sequencing of CRC tumors, co-immunoprecipitation, ITGB4 phosphorylation in cells expressing mutant PTPRK, xenograft assays\",\n      \"pmids\": [\"41820225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro dephosphorylation of ITGB4 by wild-type vs. mutant PTPRK was not directly shown\", \"Which ITGB4 tyrosine site(s) are targeted was not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) a structural model of the full intracellular tandem phosphatase domain with bound substrate, (2) the identity of the direct substrate(s) mediating CD4 T cell maturation, (3) the non-catalytic mechanism by which PTPRK regulates EGFR, and (4) how PTPRK substrate selection is regulated by cell-contact-dependent trans-dimerization.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length intracellular domain structure exists\", \"In vivo substrate identification in T cells has not been performed\", \"The catalytic-independent EGFR regulatory mechanism is molecularly undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 5, 6, 7, 10, 13, 15, 17]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 7, 9, 14]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 8, 13]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 5, 9]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AFDN\",\n      \"PARD3\",\n      \"ZNRF3\",\n      \"CTNNB1\",\n      \"ITGB4\",\n      \"FBP1\",\n      \"EGFR\",\n      \"PROM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}