{"gene":"PRTG","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2010,"finding":"PRTG protein expression is strong in the neural tube of mouse embryos between E7.75 and E9.5, disappearing after E10.5 when nestin appears; perturbation of PRTG activity by RNAi or dominant-negative mutant in P19 cells and chick embryos increases neuronal differentiation, establishing PRTG as a suppressor of premature neuronal differentiation defining a transition stage between pluripotent epiblasts and committed neural progenitors.","method":"RNAi knockdown, dominant-negative overexpression, in vitro differentiation assay (P19 cells), in ovo chick embryo perturbation","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (RNAi, dominant-negative, in vitro and in vivo assays) in a single study, with defined cellular phenotype","pmids":["20335479"],"is_preprint":false},{"year":2010,"finding":"PRTG binds ERdj3 (a stress-inducible ER DnaJ homolog) as identified by yeast two-hybrid screening and confirmed by in situ binding assay; purified ERdj3 reduces neurogenesis in P19 cells, an effect blocked by neutralizing anti-PRTG antibody or PRTG ectodomain, demonstrating ERdj3 acts as a PRTG ligand to suppress neuronal differentiation.","method":"Yeast two-hybrid screening, in situ binding assay, neutralizing antibody competition, purified protein addition to differentiation assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional validation (ligand addition + antibody/ectodomain blocking) plus yeast two-hybrid identification, single lab with multiple orthogonal methods","pmids":["20335479"],"is_preprint":false},{"year":2010,"finding":"PRTG mediates homophilic cell adhesion as demonstrated by an aggregation assay in L-cells; overexpression of PRTG in presumptive paraxial mesoderm of avian embryos delayed mesodermal cell migration due to augmented adhesiveness, while siRNA knockdown impaired successive ingression of epiblast cells and disorganized somite epithelial structure.","method":"L-cell aggregation assay, in ovo overexpression, siRNA knockdown in chick embryos","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro aggregation assay (Tier 1) plus in vivo gain- and loss-of-function with defined cellular phenotypes, single lab","pmids":["21129372"],"is_preprint":false},{"year":2011,"finding":"PRTG undergoes sequential proteolytic cleavage: first at the extracellular domain, then at the transmembrane/intracellular interface by γ-secretase, releasing the intracellular domain (PRTG-ICD). PRTG-ICD contains a putative nuclear localization signal and translocates to the nucleus in cultured cells and neuroepithelial cells of chick embryos.","method":"Biochemical cleavage analysis, γ-secretase inhibitor experiments, subcellular fractionation/localization in cultured cells and chick embryos","journal":"Development, growth & differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment with functional cleavage mechanism defined, but single lab, single study, abstracts do not detail full mutagenesis controls","pmids":["22150322"],"is_preprint":false},{"year":2013,"finding":"Prtg-deficient mice show increased apoptosis of rostral cephalic neural crest cells (R-CNCCs) leading to palatine and skull malformations; PRTG interacts with Radil (identified by yeast two-hybrid) and overexpression of PRTG induces translocation of Radil from cytoplasm to cell membrane. PRTG and Radil together activate α5β1-integrins to high-affinity conformations, further enhanced by ERdj3 ligand; Radil knockdown abolishes this effect, placing Radil downstream of PRTG in an ERdj3/PRTG/Radil/α5β1-integrin signaling axis that promotes CNCC survival and migration.","method":"Prtg knockout mice, lineage tracing, yeast two-hybrid, overexpression/subcellular localization, integrin activation assay, RNAi knockdown, in vitro transwell migration assay","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockout mouse, yeast two-hybrid, integrin conformational assay, RNAi epistasis) in a single study establishing pathway order","pmids":["23744351"],"is_preprint":false},{"year":2013,"finding":"PRTG is a target of miR-9 in chondroblasts; overexpression of PRTG induces caspase-3 activation and apoptosis in chondroblasts, whereas co-treatment with miR-9 precursor or PRTG-specific siRNA blocks this apoptotic signaling, establishing PRTG as a pro-apoptotic factor regulated by miR-9 during chondrogenesis.","method":"miRNA target validation, PRTG overexpression, caspase-3 activity assay, siRNA knockdown in chondroblasts","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay with siRNA rescue, single lab, single study","pmids":["24007463"],"is_preprint":false},{"year":2013,"finding":"Overexpression of Prtg in Dicer-conditional knockout retinas maintains the early progenitor state and prevents transition to late progenitors, identifying PRTG as a target of let-7/miR-125/miR-9 miRNAs that normally downregulate it to permit temporal progression of retinal neurogenesis.","method":"Microarray identification of targets in Dicer-CKO retinas, overexpression rescue assay in retinal progenitors","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo rescue experiment combined with microarray, single lab, limited mechanistic depth on PRTG specifically","pmids":["23754433"],"is_preprint":false},{"year":2021,"finding":"H. pylori infection promotes ZEB1 stabilization and ZEB1 recruitment to the PRTG promoter to transcriptionally upregulate PRTG; upregulated PRTG then activates cGMP/PKG signaling to promote proliferation, metastasis, and chemoresistance of gastric cancer cells, as confirmed by PKG inhibitor (KT5823) experiments in vitro and in vivo.","method":"Transcription factor binding (ZEB1 ChIP/promoter recruitment), PRTG loss-of-function in cellular and tumor-bearing mouse models, PKG inhibitor treatment","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter recruitment assay plus in vitro and in vivo functional studies, single lab","pmids":["33542225"],"is_preprint":false},{"year":2024,"finding":"PRTG knockout mice exhibit anterior homeotic transformations in vertebral columns with altered Hox gene expression; Prtg-/- embryos show decreased phospho-Smad2 and downstream TGFβ target genes in the developing tail. PRTG physically interacts with GDF11 to enhance GDF11/pSmad2 signaling, and in human iPSC-derived presomitic mesoderm cells PRTG knockout delays posterior HOX gene expression, rescued by GDF11 supplementation.","method":"Prtg knockout mice, transcriptomic profiling, pSmad2 immunodetection, co-immunoprecipitation/interaction assay with GDF11, hiPSC-PSM differentiation model with PRTG KO and GDF11 rescue","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (KO mouse phenotype, pSmad2 biochemistry, protein interaction, iPSC rescue experiment) in a single study establishing GDF11/SMAD2 pathway placement","pmids":["39702818"],"is_preprint":false},{"year":2023,"finding":"WFIKKN2, a secreted protein, was identified as a ligand for the DCC family receptors including Protogenin (Prtg/PRTG); WFIKKN2 acts through divergent DCC family members to guide axons, demonstrating that PRTG participates in axon guidance ligand-receptor interactions.","method":"Ligand-receptor binding identification, axon guidance functional assays in mouse peripheral sensory and motor axons","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, PRTG-specific functional experiments are limited within a broader study; direct Prtg-WFIKKN2 functional interaction not fully validated independently","pmids":["37398498"],"is_preprint":true},{"year":2010,"finding":"Prtg antisense oligonucleotide treatment of cultured mouse mandibles (E10.5) caused significant tooth germ growth inhibition and decreased Bmp-4 expression, placing PRTG upstream of BMP4 in early tooth morphogenesis.","method":"Antisense oligonucleotide (AS-S-ODN) inhibition in mandible explant culture, gene expression analysis","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional perturbation in organ culture with defined molecular readout (Bmp4), single lab, single study","pmids":["21108791"],"is_preprint":false},{"year":2026,"finding":"miR-4458 directly targets PRTG as confirmed by dual-luciferase reporter assay; in ox-LDL-treated VSMCs, miR-4458 overexpression downregulates PRTG and promotes phenotypic transformation, proliferation, and migration, while PRTG knockdown mimics this effect, establishing a miR-4458/PRTG/retinoic acid signaling axis in VSMC dedifferentiation.","method":"Dual-luciferase reporter assay, miRNA overexpression/knockdown, siRNA knockdown, CCK-8 viability assay, Transwell migration assay in ox-LDL-treated VSMCs","journal":"Lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct miRNA-target validation by luciferase assay plus functional gain- and loss-of-function, single lab, single study","pmids":["41631733"],"is_preprint":false}],"current_model":"PRTG (Protogenin) is a transmembrane immunoglobulin superfamily receptor that suppresses premature neuronal differentiation by binding the ligand ERdj3, which activates an ERdj3/PRTG/Radil/α5β1-integrin inside-out signaling axis promoting neural crest cell survival and migration; PRTG undergoes γ-secretase-mediated cleavage releasing a nuclear ICD, mediates homophilic cell adhesion to regulate paraxial mesoderm ingression, interacts with GDF11 to sustain pSmad2 signaling for posterior HOX gene activation and vertebral patterning, promotes chondroblast apoptosis via caspase-3 (negatively regulated by miR-9), and in cancer contexts is transcriptionally induced by ZEB1 downstream of H. pylori to activate cGMP/PKG signaling."},"narrative":{"mechanistic_narrative":"PRTG (Protogenin) is a transmembrane immunoglobulin-superfamily receptor that marks a transitional developmental stage and suppresses premature neuronal differentiation, defining the window between pluripotent epiblasts and committed neural progenitors [PMID:20335479]. It functions as a ligand-activated receptor: ERdj3, a stress-inducible ER DnaJ homolog, binds PRTG and acts as a ligand that suppresses neurogenesis [PMID:20335479], and PRTG signals through Radil to convert α5β1-integrins to high-affinity conformations, forming an ERdj3/PRTG/Radil/α5β1-integrin axis that promotes cephalic neural crest cell survival and migration [PMID:23744351]. In addition to signaling, PRTG mediates homophilic cell adhesion to control the timing of paraxial mesoderm ingression and somite organization [PMID:21129372], and it is processed by sequential proteolysis culminating in γ-secretase cleavage that releases a nuclear-translocating intracellular domain (PRTG-ICD) [PMID:22150322]. PRTG also integrates into TGFβ-family signaling by physically interacting with GDF11 to sustain phospho-Smad2 activity, driving posterior HOX gene expression and vertebral patterning [PMID:39702818]. Its expression is tightly tuned by microRNAs across contexts—let-7/miR-125/miR-9 in retinal progenitors [PMID:23754433] and miR-9 in chondroblasts, where PRTG promotes caspase-3–dependent apoptosis [PMID:24007463]. In disease settings, PRTG is transcriptionally induced by ZEB1 downstream of H. pylori to activate cGMP/PKG signaling and drive gastric cancer progression [PMID:33542225].","teleology":[{"year":2010,"claim":"Established PRTG's core developmental role by showing it defines and maintains an undifferentiated transition stage, answering whether this early embryonic receptor restrains neural commitment.","evidence":"RNAi knockdown, dominant-negative overexpression, and in vitro/in ovo differentiation assays in P19 cells and chick embryos","pmids":["20335479"],"confidence":"High","gaps":["Did not identify the downstream effectors linking PRTG to differentiation control","Mechanism of how PRTG senses the timing signal unresolved"]},{"year":2010,"claim":"Identified ERdj3 as a PRTG ligand, answering what extracellular cue engages the receptor to suppress neurogenesis.","evidence":"Yeast two-hybrid screen, in situ binding assay, neutralizing antibody and ectodomain competition with purified ERdj3 in differentiation assays","pmids":["20335479"],"confidence":"High","gaps":["Did not define the intracellular signaling cascade triggered by ERdj3 binding","Physiological source/availability of secreted ERdj3 in vivo not established"]},{"year":2010,"claim":"Placed PRTG upstream of BMP4 in tooth morphogenesis, extending its role beyond the neural lineage.","evidence":"Antisense oligonucleotide inhibition in cultured mouse mandible explants with Bmp4 expression readout","pmids":["21108791"],"confidence":"Medium","gaps":["Direct versus indirect regulation of Bmp4 not distinguished","No receptor signaling mechanism defined in this context"]},{"year":2010,"claim":"Demonstrated PRTG mediates homophilic adhesion to control mesoderm ingression, distinguishing an adhesion function from its signaling role.","evidence":"L-cell aggregation assay plus in ovo gain- and loss-of-function in chick paraxial mesoderm","pmids":["21129372"],"confidence":"High","gaps":["Structural basis of homophilic binding not defined","Relationship between adhesion and ligand-dependent signaling unresolved"]},{"year":2011,"claim":"Showed PRTG undergoes γ-secretase–dependent cleavage releasing a nuclear ICD, raising the possibility of direct receptor-to-nucleus signaling.","evidence":"Biochemical cleavage analysis, γ-secretase inhibitor experiments, and subcellular localization in cultured cells and chick embryos","pmids":["22150322"],"confidence":"Medium","gaps":["Nuclear targets or transcriptional activity of PRTG-ICD unknown","Single lab without full mutagenesis controls"]},{"year":2013,"claim":"Resolved the intracellular signaling axis by placing Radil downstream of PRTG to activate α5β1-integrins, explaining how ERdj3/PRTG promotes neural crest survival and migration.","evidence":"Prtg knockout mice with lineage tracing, yeast two-hybrid, integrin conformational activation assay, RNAi epistasis, and transwell migration","pmids":["23744351"],"confidence":"High","gaps":["Biochemical link between PRTG cytoplasmic domain and Radil not mapped","How integrin activation feeds back to differentiation control unclear"]},{"year":2013,"claim":"Revealed a context-specific pro-apoptotic role for PRTG in chondroblasts under miR-9 control, contrasting its pro-survival function in neural crest.","evidence":"miR-9 target validation, PRTG overexpression with caspase-3 activity assay, and siRNA rescue in chondroblasts","pmids":["24007463"],"confidence":"Medium","gaps":["Mechanism linking PRTG to caspase-3 activation unknown","Reconciliation with PRTG pro-survival signaling not addressed"]},{"year":2013,"claim":"Showed miRNA-driven downregulation of PRTG is required for temporal progression of retinal neurogenesis, confirming PRTG as a brake on progenitor maturation.","evidence":"Microarray target identification in Dicer-CKO retinas and overexpression rescue in retinal progenitors","pmids":["23754433"],"confidence":"Medium","gaps":["Direct miRNA-PRTG targeting not biochemically confirmed in this study","Downstream effectors maintaining the progenitor state unidentified"]},{"year":2021,"claim":"Connected PRTG to gastric cancer pathogenesis by showing H. pylori–driven ZEB1 induces PRTG to activate cGMP/PKG signaling.","evidence":"ZEB1 promoter recruitment, PRTG loss-of-function in cells and tumor-bearing mice, and PKG inhibitor (KT5823) treatment","pmids":["33542225"],"confidence":"Medium","gaps":["How PRTG mechanistically activates cGMP/PKG signaling not defined","Whether ERdj3/Radil/integrin axis operates in this cancer context untested"]},{"year":2024,"claim":"Integrated PRTG into TGFβ-family signaling by showing it binds GDF11 to sustain pSmad2 and drive posterior HOX activation and vertebral patterning.","evidence":"Prtg knockout mice, transcriptomics, pSmad2 immunodetection, co-IP with GDF11, and hiPSC-PSM differentiation with GDF11 rescue","pmids":["39702818"],"confidence":"High","gaps":["Whether PRTG acts as a co-receptor for GDF11 or stabilizes ligand availability not resolved","Relationship between GDF11/Smad2 role and the ERdj3/Radil axis unknown"]},{"year":2023,"claim":"Proposed WFIKKN2 as a ligand acting through DCC-family receptors including PRTG in axon guidance, expanding the receptor's ligand repertoire.","evidence":"Ligand-receptor binding identification and axon guidance assays in mouse sensory and motor axons (preprint)","pmids":["37398498"],"confidence":"Low","gaps":["PRTG-specific WFIKKN2 functional interaction not independently validated","Preprint, not peer reviewed","Downstream signaling from WFIKKN2-PRTG unmapped"]},{"year":2026,"claim":"Identified a miR-4458/PRTG axis in vascular smooth muscle cell dedifferentiation, extending PRTG regulation to cardiovascular phenotypic transformation.","evidence":"Dual-luciferase reporter assay, miR-4458 and PRTG gain/loss-of-function, viability and migration assays in ox-LDL-treated VSMCs","pmids":["41631733"],"confidence":"Medium","gaps":["Mechanistic link between PRTG and retinoic acid signaling not defined","Single lab, single study"]},{"year":null,"claim":"How PRTG's multiple, context-dependent activities—adhesion, ERdj3/Radil/integrin signaling, GDF11/Smad2 modulation, γ-secretase ICD release, and pro-apoptotic versus pro-survival outputs—are coordinated by a single receptor remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ligand engagement or domain function","Nuclear targets of PRTG-ICD unidentified","Mechanism switching PRTG between pro-survival and pro-apoptotic outputs unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,4,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,7,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5]}],"complexes":[],"partners":["ERDJ3","RADIL","ITGA5","ITGB1","GDF11","WFIKKN2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q2VWP7","full_name":"Protogenin","aliases":["Protein Shen-Dan"],"length_aa":1150,"mass_kda":127.1,"function":"May play a role in anteroposterior axis elongation","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q2VWP7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PRTG","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PRTG","total_profiled":1310},"omim":[{"mim_id":"613261","title":"PROTOGENIN; PRTG","url":"https://www.omim.org/entry/613261"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":9.6},{"tissue":"thyroid gland","ntpm":10.0}],"url":"https://www.proteinatlas.org/search/PRTG"},"hgnc":{"alias_symbol":["FLJ25756","IGDCC5"],"prev_symbol":[]},"alphafold":{"accession":"Q2VWP7","domains":[{"cath_id":"2.60.40.10","chopping":"41-132","consensus_level":"high","plddt":89.3338,"start":41,"end":132},{"cath_id":"2.60.40.10","chopping":"134-230","consensus_level":"medium","plddt":88.1775,"start":134,"end":230},{"cath_id":"2.60.40.10","chopping":"231-325","consensus_level":"medium","plddt":90.6188,"start":231,"end":325},{"cath_id":"2.60.40.10","chopping":"333-407","consensus_level":"high","plddt":89.9883,"start":333,"end":407},{"cath_id":"2.60.40.10","chopping":"423-512","consensus_level":"medium","plddt":83.43,"start":423,"end":512},{"cath_id":"2.60.40.10","chopping":"616-711","consensus_level":"medium","plddt":82.398,"start":616,"end":711},{"cath_id":"2.60.40.10","chopping":"727-814","consensus_level":"high","plddt":75.0935,"start":727,"end":814},{"cath_id":"2.60.40.10","chopping":"828-915","consensus_level":"high","plddt":83.9291,"start":828,"end":915}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2VWP7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q2VWP7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q2VWP7-F1-predicted_aligned_error_v6.png","plddt_mean":73.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PRTG","jax_strain_url":"https://www.jax.org/strain/search?query=PRTG"},"sequence":{"accession":"Q2VWP7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q2VWP7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q2VWP7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q2VWP7"}},"corpus_meta":[{"pmid":"23754433","id":"PMC_23754433","title":"Conserved 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between E7.75 and E9.5, disappearing after E10.5 when nestin appears; perturbation of PRTG activity by RNAi or dominant-negative mutant in P19 cells and chick embryos increases neuronal differentiation, establishing PRTG as a suppressor of premature neuronal differentiation defining a transition stage between pluripotent epiblasts and committed neural progenitors.\",\n      \"method\": \"RNAi knockdown, dominant-negative overexpression, in vitro differentiation assay (P19 cells), in ovo chick embryo perturbation\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (RNAi, dominant-negative, in vitro and in vivo assays) in a single study, with defined cellular phenotype\",\n      \"pmids\": [\"20335479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRTG binds ERdj3 (a stress-inducible ER DnaJ homolog) as identified by yeast two-hybrid screening and confirmed by in situ binding assay; purified ERdj3 reduces neurogenesis in P19 cells, an effect blocked by neutralizing anti-PRTG antibody or PRTG ectodomain, demonstrating ERdj3 acts as a PRTG ligand to suppress neuronal differentiation.\",\n      \"method\": \"Yeast two-hybrid screening, in situ binding assay, neutralizing antibody competition, purified protein addition to differentiation assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional validation (ligand addition + antibody/ectodomain blocking) plus yeast two-hybrid identification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"20335479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PRTG mediates homophilic cell adhesion as demonstrated by an aggregation assay in L-cells; overexpression of PRTG in presumptive paraxial mesoderm of avian embryos delayed mesodermal cell migration due to augmented adhesiveness, while siRNA knockdown impaired successive ingression of epiblast cells and disorganized somite epithelial structure.\",\n      \"method\": \"L-cell aggregation assay, in ovo overexpression, siRNA knockdown in chick embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro aggregation assay (Tier 1) plus in vivo gain- and loss-of-function with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"21129372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PRTG undergoes sequential proteolytic cleavage: first at the extracellular domain, then at the transmembrane/intracellular interface by γ-secretase, releasing the intracellular domain (PRTG-ICD). PRTG-ICD contains a putative nuclear localization signal and translocates to the nucleus in cultured cells and neuroepithelial cells of chick embryos.\",\n      \"method\": \"Biochemical cleavage analysis, γ-secretase inhibitor experiments, subcellular fractionation/localization in cultured cells and chick embryos\",\n      \"journal\": \"Development, growth & differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment with functional cleavage mechanism defined, but single lab, single study, abstracts do not detail full mutagenesis controls\",\n      \"pmids\": [\"22150322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Prtg-deficient mice show increased apoptosis of rostral cephalic neural crest cells (R-CNCCs) leading to palatine and skull malformations; PRTG interacts with Radil (identified by yeast two-hybrid) and overexpression of PRTG induces translocation of Radil from cytoplasm to cell membrane. PRTG and Radil together activate α5β1-integrins to high-affinity conformations, further enhanced by ERdj3 ligand; Radil knockdown abolishes this effect, placing Radil downstream of PRTG in an ERdj3/PRTG/Radil/α5β1-integrin signaling axis that promotes CNCC survival and migration.\",\n      \"method\": \"Prtg knockout mice, lineage tracing, yeast two-hybrid, overexpression/subcellular localization, integrin activation assay, RNAi knockdown, in vitro transwell migration assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockout mouse, yeast two-hybrid, integrin conformational assay, RNAi epistasis) in a single study establishing pathway order\",\n      \"pmids\": [\"23744351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PRTG is a target of miR-9 in chondroblasts; overexpression of PRTG induces caspase-3 activation and apoptosis in chondroblasts, whereas co-treatment with miR-9 precursor or PRTG-specific siRNA blocks this apoptotic signaling, establishing PRTG as a pro-apoptotic factor regulated by miR-9 during chondrogenesis.\",\n      \"method\": \"miRNA target validation, PRTG overexpression, caspase-3 activity assay, siRNA knockdown in chondroblasts\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay with siRNA rescue, single lab, single study\",\n      \"pmids\": [\"24007463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Overexpression of Prtg in Dicer-conditional knockout retinas maintains the early progenitor state and prevents transition to late progenitors, identifying PRTG as a target of let-7/miR-125/miR-9 miRNAs that normally downregulate it to permit temporal progression of retinal neurogenesis.\",\n      \"method\": \"Microarray identification of targets in Dicer-CKO retinas, overexpression rescue assay in retinal progenitors\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo rescue experiment combined with microarray, single lab, limited mechanistic depth on PRTG specifically\",\n      \"pmids\": [\"23754433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"H. pylori infection promotes ZEB1 stabilization and ZEB1 recruitment to the PRTG promoter to transcriptionally upregulate PRTG; upregulated PRTG then activates cGMP/PKG signaling to promote proliferation, metastasis, and chemoresistance of gastric cancer cells, as confirmed by PKG inhibitor (KT5823) experiments in vitro and in vivo.\",\n      \"method\": \"Transcription factor binding (ZEB1 ChIP/promoter recruitment), PRTG loss-of-function in cellular and tumor-bearing mouse models, PKG inhibitor treatment\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter recruitment assay plus in vitro and in vivo functional studies, single lab\",\n      \"pmids\": [\"33542225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRTG knockout mice exhibit anterior homeotic transformations in vertebral columns with altered Hox gene expression; Prtg-/- embryos show decreased phospho-Smad2 and downstream TGFβ target genes in the developing tail. PRTG physically interacts with GDF11 to enhance GDF11/pSmad2 signaling, and in human iPSC-derived presomitic mesoderm cells PRTG knockout delays posterior HOX gene expression, rescued by GDF11 supplementation.\",\n      \"method\": \"Prtg knockout mice, transcriptomic profiling, pSmad2 immunodetection, co-immunoprecipitation/interaction assay with GDF11, hiPSC-PSM differentiation model with PRTG KO and GDF11 rescue\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (KO mouse phenotype, pSmad2 biochemistry, protein interaction, iPSC rescue experiment) in a single study establishing GDF11/SMAD2 pathway placement\",\n      \"pmids\": [\"39702818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"WFIKKN2, a secreted protein, was identified as a ligand for the DCC family receptors including Protogenin (Prtg/PRTG); WFIKKN2 acts through divergent DCC family members to guide axons, demonstrating that PRTG participates in axon guidance ligand-receptor interactions.\",\n      \"method\": \"Ligand-receptor binding identification, axon guidance functional assays in mouse peripheral sensory and motor axons\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, PRTG-specific functional experiments are limited within a broader study; direct Prtg-WFIKKN2 functional interaction not fully validated independently\",\n      \"pmids\": [\"37398498\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Prtg antisense oligonucleotide treatment of cultured mouse mandibles (E10.5) caused significant tooth germ growth inhibition and decreased Bmp-4 expression, placing PRTG upstream of BMP4 in early tooth morphogenesis.\",\n      \"method\": \"Antisense oligonucleotide (AS-S-ODN) inhibition in mandible explant culture, gene expression analysis\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional perturbation in organ culture with defined molecular readout (Bmp4), single lab, single study\",\n      \"pmids\": [\"21108791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"miR-4458 directly targets PRTG as confirmed by dual-luciferase reporter assay; in ox-LDL-treated VSMCs, miR-4458 overexpression downregulates PRTG and promotes phenotypic transformation, proliferation, and migration, while PRTG knockdown mimics this effect, establishing a miR-4458/PRTG/retinoic acid signaling axis in VSMC dedifferentiation.\",\n      \"method\": \"Dual-luciferase reporter assay, miRNA overexpression/knockdown, siRNA knockdown, CCK-8 viability assay, Transwell migration assay in ox-LDL-treated VSMCs\",\n      \"journal\": \"Lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct miRNA-target validation by luciferase assay plus functional gain- and loss-of-function, single lab, single study\",\n      \"pmids\": [\"41631733\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PRTG (Protogenin) is a transmembrane immunoglobulin superfamily receptor that suppresses premature neuronal differentiation by binding the ligand ERdj3, which activates an ERdj3/PRTG/Radil/α5β1-integrin inside-out signaling axis promoting neural crest cell survival and migration; PRTG undergoes γ-secretase-mediated cleavage releasing a nuclear ICD, mediates homophilic cell adhesion to regulate paraxial mesoderm ingression, interacts with GDF11 to sustain pSmad2 signaling for posterior HOX gene activation and vertebral patterning, promotes chondroblast apoptosis via caspase-3 (negatively regulated by miR-9), and in cancer contexts is transcriptionally induced by ZEB1 downstream of H. pylori to activate cGMP/PKG signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PRTG (Protogenin) is a transmembrane immunoglobulin-superfamily receptor that marks a transitional developmental stage and suppresses premature neuronal differentiation, defining the window between pluripotent epiblasts and committed neural progenitors [#0]. It functions as a ligand-activated receptor: ERdj3, a stress-inducible ER DnaJ homolog, binds PRTG and acts as a ligand that suppresses neurogenesis [#1], and PRTG signals through Radil to convert \\u03b15\\u03b21-integrins to high-affinity conformations, forming an ERdj3/PRTG/Radil/\\u03b15\\u03b21-integrin axis that promotes cephalic neural crest cell survival and migration [#4]. In addition to signaling, PRTG mediates homophilic cell adhesion to control the timing of paraxial mesoderm ingression and somite organization [#2], and it is processed by sequential proteolysis culminating in \\u03b3-secretase cleavage that releases a nuclear-translocating intracellular domain (PRTG-ICD) [#3]. PRTG also integrates into TGF\\u03b2-family signaling by physically interacting with GDF11 to sustain phospho-Smad2 activity, driving posterior HOX gene expression and vertebral patterning [#8]. Its expression is tightly tuned by microRNAs across contexts\\u2014let-7/miR-125/miR-9 in retinal progenitors [#6] and miR-9 in chondroblasts, where PRTG promotes caspase-3\\u2013dependent apoptosis [#5]. In disease settings, PRTG is transcriptionally induced by ZEB1 downstream of H. pylori to activate cGMP/PKG signaling and drive gastric cancer progression [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established PRTG's core developmental role by showing it defines and maintains an undifferentiated transition stage, answering whether this early embryonic receptor restrains neural commitment.\",\n      \"evidence\": \"RNAi knockdown, dominant-negative overexpression, and in vitro/in ovo differentiation assays in P19 cells and chick embryos\",\n      \"pmids\": [\"20335479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the downstream effectors linking PRTG to differentiation control\", \"Mechanism of how PRTG senses the timing signal unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified ERdj3 as a PRTG ligand, answering what extracellular cue engages the receptor to suppress neurogenesis.\",\n      \"evidence\": \"Yeast two-hybrid screen, in situ binding assay, neutralizing antibody and ectodomain competition with purified ERdj3 in differentiation assays\",\n      \"pmids\": [\"20335479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the intracellular signaling cascade triggered by ERdj3 binding\", \"Physiological source/availability of secreted ERdj3 in vivo not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Placed PRTG upstream of BMP4 in tooth morphogenesis, extending its role beyond the neural lineage.\",\n      \"evidence\": \"Antisense oligonucleotide inhibition in cultured mouse mandible explants with Bmp4 expression readout\",\n      \"pmids\": [\"21108791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect regulation of Bmp4 not distinguished\", \"No receptor signaling mechanism defined in this context\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated PRTG mediates homophilic adhesion to control mesoderm ingression, distinguishing an adhesion function from its signaling role.\",\n      \"evidence\": \"L-cell aggregation assay plus in ovo gain- and loss-of-function in chick paraxial mesoderm\",\n      \"pmids\": [\"21129372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of homophilic binding not defined\", \"Relationship between adhesion and ligand-dependent signaling unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PRTG undergoes \\u03b3-secretase\\u2013dependent cleavage releasing a nuclear ICD, raising the possibility of direct receptor-to-nucleus signaling.\",\n      \"evidence\": \"Biochemical cleavage analysis, \\u03b3-secretase inhibitor experiments, and subcellular localization in cultured cells and chick embryos\",\n      \"pmids\": [\"22150322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear targets or transcriptional activity of PRTG-ICD unknown\", \"Single lab without full mutagenesis controls\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the intracellular signaling axis by placing Radil downstream of PRTG to activate \\u03b15\\u03b21-integrins, explaining how ERdj3/PRTG promotes neural crest survival and migration.\",\n      \"evidence\": \"Prtg knockout mice with lineage tracing, yeast two-hybrid, integrin conformational activation assay, RNAi epistasis, and transwell migration\",\n      \"pmids\": [\"23744351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical link between PRTG cytoplasmic domain and Radil not mapped\", \"How integrin activation feeds back to differentiation control unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed a context-specific pro-apoptotic role for PRTG in chondroblasts under miR-9 control, contrasting its pro-survival function in neural crest.\",\n      \"evidence\": \"miR-9 target validation, PRTG overexpression with caspase-3 activity assay, and siRNA rescue in chondroblasts\",\n      \"pmids\": [\"24007463\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking PRTG to caspase-3 activation unknown\", \"Reconciliation with PRTG pro-survival signaling not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed miRNA-driven downregulation of PRTG is required for temporal progression of retinal neurogenesis, confirming PRTG as a brake on progenitor maturation.\",\n      \"evidence\": \"Microarray target identification in Dicer-CKO retinas and overexpression rescue in retinal progenitors\",\n      \"pmids\": [\"23754433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miRNA-PRTG targeting not biochemically confirmed in this study\", \"Downstream effectors maintaining the progenitor state unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected PRTG to gastric cancer pathogenesis by showing H. pylori\\u2013driven ZEB1 induces PRTG to activate cGMP/PKG signaling.\",\n      \"evidence\": \"ZEB1 promoter recruitment, PRTG loss-of-function in cells and tumor-bearing mice, and PKG inhibitor (KT5823) treatment\",\n      \"pmids\": [\"33542225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PRTG mechanistically activates cGMP/PKG signaling not defined\", \"Whether ERdj3/Radil/integrin axis operates in this cancer context untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Integrated PRTG into TGF\\u03b2-family signaling by showing it binds GDF11 to sustain pSmad2 and drive posterior HOX activation and vertebral patterning.\",\n      \"evidence\": \"Prtg knockout mice, transcriptomics, pSmad2 immunodetection, co-IP with GDF11, and hiPSC-PSM differentiation with GDF11 rescue\",\n      \"pmids\": [\"39702818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PRTG acts as a co-receptor for GDF11 or stabilizes ligand availability not resolved\", \"Relationship between GDF11/Smad2 role and the ERdj3/Radil axis unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed WFIKKN2 as a ligand acting through DCC-family receptors including PRTG in axon guidance, expanding the receptor's ligand repertoire.\",\n      \"evidence\": \"Ligand-receptor binding identification and axon guidance assays in mouse sensory and motor axons (preprint)\",\n      \"pmids\": [\"37398498\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"PRTG-specific WFIKKN2 functional interaction not independently validated\", \"Preprint, not peer reviewed\", \"Downstream signaling from WFIKKN2-PRTG unmapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a miR-4458/PRTG axis in vascular smooth muscle cell dedifferentiation, extending PRTG regulation to cardiovascular phenotypic transformation.\",\n      \"evidence\": \"Dual-luciferase reporter assay, miR-4458 and PRTG gain/loss-of-function, viability and migration assays in ox-LDL-treated VSMCs\",\n      \"pmids\": [\"41631733\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between PRTG and retinoic acid signaling not defined\", \"Single lab, single study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PRTG's multiple, context-dependent activities\\u2014adhesion, ERdj3/Radil/integrin signaling, GDF11/Smad2 modulation, \\u03b3-secretase ICD release, and pro-apoptotic versus pro-survival outputs\\u2014are coordinated by a single receptor remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ligand engagement or domain function\", \"Nuclear targets of PRTG-ICD unidentified\", \"Mechanism switching PRTG between pro-survival and pro-apoptotic outputs unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 4, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 7, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ERdj3\", \"Radil\", \"ITGA5\", \"ITGB1\", \"GDF11\", \"WFIKKN2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}