{"gene":"PODXL","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2001,"finding":"Podocalyxin (PC) is linked to the actin cytoskeleton via a tripartite complex with NHERF2 (a PDZ-domain scaffold protein) and ezrin (an ERM-family linker). The cytoplasmic tail of PC contains a C-terminal PDZ-binding motif (DTHL) that binds specifically to the second PDZ domain of NHERF2, as demonstrated by yeast two-hybrid and in vitro pull-down assays. PC, NHERF2, and ezrin co-immunoprecipitate, forming a multimeric complex. This PC/NHERF2/ezrin/actin interaction is disrupted in glomerular epithelial cells from puromycin aminonucleoside-, protamine sulfate-, or sialidase-treated rats that show loss of foot processes, establishing that this complex is required for maintaining podocyte architecture.","method":"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunocytochemistry, disease model (puromycin aminonucleoside nephrosis)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (Y2H, pulldown, Co-IP, localization) in one study with functional disease-model validation","pmids":["11457882"],"is_preprint":false},{"year":1998,"finding":"Podocalyxin-like protein (PCLP) expressed on high endothelial venules (HEV) functions as a ligand for L-selectin, supporting lymphocyte tethering and rolling under physiological flow conditions in vitro. Purified HEV-derived PCLP bound recombinant L-selectin and the HEV-specific monoclonal antibody MECA-79, demonstrating its role as a sialomucin-type adhesion molecule for leukocyte homing.","method":"Protein purification from HEV, recombinant L-selectin binding assay, flow-based lymphocyte rolling assay, MECA-79 immunoreactivity","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted binding assay plus physiological flow assay with purified native protein","pmids":["9625756"],"is_preprint":false},{"year":2003,"finding":"The human embryonal carcinoma tumor antigen gp200 (also known as GCTM-2) was identified as podocalyxin by peptide mass spectrometry and confirmed by reactivity of two distinct anti-podocalyxin monoclonal antibodies, establishing that podocalyxin is expressed on malignant testicular germ cell tumors and is the molecular identity of these previously characterized cancer antigens.","method":"Protein sequence analysis of gp200 peptides by mass spectrometry, immunoreactivity with two distinct anti-podocalyxin monoclonal antibodies","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — MS-based protein identification confirmed by two independent antibodies","pmids":["12504081"],"is_preprint":false},{"year":2005,"finding":"In MDCK epithelial cells, podocalyxin (gp135) marks a preapical domain that is established before tight junction formation. The C-terminal PDZ-binding motif of podocalyxin is required for targeting it to the free surface of single cells and to a subdomain of the terminally polarized apical membrane. Podocalyxin co-localizes with NHERF-2 at this preapical domain, and RNAi depletion of podocalyxin causes defects in epithelial polarization, demonstrating a functional role in establishing apical polarity.","method":"Domain-deletion mutagenesis, RNAi knockdown, immunofluorescence, identification of gp135 as dog podocalyxin orthologue","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis plus RNAi loss-of-function with defined polarization phenotype","pmids":["15642748"],"is_preprint":false},{"year":2004,"finding":"Forced overexpression of podocalyxin in MCF-7 breast carcinoma cells perturbed cell-cell junctions and caused cell shedding from confluent monolayers, demonstrating a direct anti-adhesive function of podocalyxin that can promote tumor cell detachment.","method":"Forced expression (overexpression) in MCF-7 cells, cell junction analysis, confluent monolayer shedding assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain-of-function with defined cellular phenotype, single study single method","pmids":["15289306"],"is_preprint":false},{"year":2008,"finding":"PODXL (podocalyxin-like protein) is selectively expressed on early progenitor mesenchymal stem cells (MSCs). RNAi-mediated inhibition of PODXL expression caused cell aggregation in culture, indicating that PODXL normally functions to prevent cell-cell aggregation in MSCs. PODXL-high/CD49f-high MSCs showed greater clonogenicity, more efficient differentiation, and preferential homing to infarcted heart after intravenous infusion in mice.","method":"FACS isolation, RNA interference (RNAi) knockdown with aggregation phenotype, in vivo intravenous infusion homing assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2-3 — RNAi loss-of-function with defined cellular phenotype plus in vivo homing data, single study","pmids":["18818395"],"is_preprint":false},{"year":2008,"finding":"A monoclonal antibody (mAb 84) targeting podocalyxin-like protein-1 (PODXL) on undifferentiated human embryonic stem cells (hESCs) induces rapid, complement-independent cell death within 30 minutes, selectively killing undifferentiated hESCs but not differentiated derivatives. Immunoprecipitation identified PODXL as the target antigen of mAb 84, and pre-treatment prevented teratoma formation in SCID mice.","method":"Immunoprecipitation antigen identification, cytotoxicity assay, complement inhibition, in vivo teratoma suppression assay","journal":"Stem cells (Dayton, Ohio)","confidence":"High","confidence_rationale":"Tier 2 — antigen identified by IP, cytotoxicity mechanism characterized, in vivo functional validation","pmids":["18356574"],"is_preprint":false},{"year":2016,"finding":"miR-5100 directly binds the 3′ UTR of PODXL mRNA and post-transcriptionally represses PODXL expression in pancreatic cancer cells. Silencing PODXL phenocopied miR-5100 overexpression, inhibiting cell migration and invasion, establishing PODXL as a pro-metastatic effector downstream of miR-5100 in pancreatic cancer.","method":"3′UTR luciferase reporter assay, miRNA overexpression, siRNA knockdown, migration and invasion assays","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — 3′UTR reporter plus siRNA knockdown with functional migration/invasion phenotype, single study","pmids":["26892887"],"is_preprint":false},{"year":2016,"finding":"Conditional endothelial-specific deletion of Podxl in mice disrupts endothelial barrier integrity: Podxl-deficient lung endothelial cells show increased permeability to dextran and enhanced macrophage transmigration. After thrombin stimulation, ECs lacking Podxl exhibit delayed recovery of VE-cadherin contacts, persistence of F-actin stress fibers, sustained phosphorylation of the ERM complex, and sustained RhoA activation, indicating that Podxl normally promotes endothelial barrier re-sealing by restraining RhoA activity and facilitating VE-cadherin junction restoration.","method":"Conditional knockout mouse, dextran permeability assay, macrophage transmigration assay, VE-cadherin immunofluorescence, F-actin staining, ERM phosphorylation western blot, RhoA activation assay","journal":"European journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple orthogonal cellular readouts establishing mechanism","pmids":["27289182"],"is_preprint":false},{"year":2016,"finding":"PODXL carries the major post-translational epitopes responsible for pluripotent surface markers TRA-1-60, TRA-1-81, GCTM2, GP200, and mAb84 in human pluripotent stem cells. PODXL expression is activated by KLF4 during early reprogramming, and a residual PODXL-positive population persists after extended differentiation. A universal anti-PODXL antibody (3D3) causes massive necrosis and apoptosis of human pluripotent stem cells.","method":"mRNA and protein expression analysis during reprogramming, KLF4 overexpression, antibody-mediated cytotoxicity, flow cytometry","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 3 — expression studies plus functional antibody cytotoxicity, limited mechanistic depth","pmids":["26886504"],"is_preprint":false},{"year":2016,"finding":"A frameshift mutation (c.89_90insGTCGCCCC) in exon 1 of PODXL resulting in loss of protein was identified as causal for autosomal-recessive juvenile Parkinsonism. Functional validation in differentiated PC12 cells showed significant differences in neurite branching and length (p<0.0001) between cells expressing wild-type versus mutant PODXL constructs, establishing a role for PODXL in neural process morphology.","method":"Whole exome sequencing, Sanger sequencing for segregation, functional assay in differentiated PC12 cells (neurite branching and length measurement)","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — human genetics plus cellular functional validation in neuronal model, single study","pmids":["26864383"],"is_preprint":false},{"year":2020,"finding":"Long non-coding RNA BBOX1-AS1 acts as a competing endogenous RNA (ceRNA) that sequesters miR-361-3p, thereby relieving miR-361-3p-mediated repression of PODXL and increasing PODXL expression in ovarian cancer cells. PODXL depletion reversed the pro-tumorigenic effects of BBOX1-AS1 silencing rescue, placing PODXL as a downstream effector in the BBOX1-AS1/miR-361-3p/PODXL regulatory axis promoting ovarian cancer cell proliferation and survival.","method":"lncRNA and miRNA overexpression/knockdown, luciferase reporter assays, siRNA-mediated PODXL silencing, proliferation and apoptosis assays","journal":"Reproductive sciences","confidence":"Medium","confidence_rationale":"Tier 3 — reporter assays and epistasis rescue experiment, single study","pmids":["33159291"],"is_preprint":false},{"year":2021,"finding":"Transcription factor TCF3 directly regulates PODXL transcription in human spermatogonial stem cells (SSCs). ChIP assay demonstrated TCF3 binding to the PODXL promoter. TCF3 overexpression promoted SSC proliferation and suppressed apoptosis, while PODXL silencing compromised SSC stem cell activity (proliferation and survival), placing PODXL as a direct TCF3 target gene required for SSC self-renewal.","method":"RNA sequencing, chromatin immunoprecipitation (ChIP), PODXL siRNA knockdown, proliferation and apoptosis assays, TCF3 overexpression","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP confirms direct promoter binding; functional knockdown with defined phenotype, single study","pmids":["34422820"],"is_preprint":false}],"current_model":"PODXL is a transmembrane sialomucin that links to the actin cytoskeleton via a NHERF2/ezrin scaffold (through its C-terminal PDZ-binding motif), functions as an anti-adhesive molecule that maintains podocyte foot process architecture, promotes epithelial apical polarity, serves as an L-selectin ligand on high endothelial venules, restrains RhoA-mediated endothelial contraction to maintain vascular barrier integrity, and is required for neurite outgrowth and spermatogonial stem cell self-renewal, with its expression regulated by KLF4, TCF3, and miR-5100/miR-361-3p post-transcriptional mechanisms."},"narrative":{"teleology":[{"year":1998,"claim":"Identifying PODXL as an L-selectin ligand on HEV established it as a functional sialomucin mediating leukocyte tethering and rolling, resolving the molecular identity of a key lymphocyte-homing receptor.","evidence":"Purified HEV-derived PODXL bound recombinant L-selectin and supported lymphocyte rolling under physiological flow in vitro","pmids":["9625756"],"confidence":"High","gaps":["Contribution relative to other HEV sialomucins (GlyCAM-1, CD34) not dissected","In vivo lymphocyte homing dependence on PODXL not tested"]},{"year":2001,"claim":"Demonstration that PODXL links to actin via an NHERF2/ezrin scaffold through its C-terminal PDZ-binding motif provided the first mechanistic explanation for how the extracellular mucin domain is transduced to cytoskeletal architecture in podocytes.","evidence":"Yeast two-hybrid, pull-down, co-IP, and immunocytochemistry in normal and puromycin aminonucleoside-treated rat podocytes","pmids":["11457882"],"confidence":"High","gaps":["Stoichiometry and direct vs. indirect binding within the trimeric complex not resolved","Whether other ERM proteins substitute for ezrin not tested"]},{"year":2004,"claim":"Gain-of-function in MCF-7 cells revealed that PODXL overexpression directly disrupts cell–cell junctions and promotes cell detachment, establishing an intrinsic anti-adhesive activity relevant to tumor cell shedding.","evidence":"Forced overexpression in MCF-7 breast carcinoma monolayers with junction analysis and shedding quantification","pmids":["15289306"],"confidence":"Medium","gaps":["Anti-adhesive mechanism (charge repulsion vs. signaling) not distinguished","Relevance to endogenous expression levels in primary tumors uncertain"]},{"year":2005,"claim":"RNAi depletion and domain-deletion studies in MDCK cells demonstrated that PODXL and its PDZ-binding motif are required for apical membrane identity before tight-junction formation, extending its role from podocyte architecture to general epithelial polarity.","evidence":"RNAi knockdown and C-terminal deletion mutagenesis in polarizing MDCK cells with immunofluorescence","pmids":["15642748"],"confidence":"High","gaps":["Whether PODXL instructs or merely marks the preapical domain not fully resolved","Downstream effectors beyond NHERF2 not identified"]},{"year":2008,"claim":"PODXL was shown to prevent cell–cell aggregation in mesenchymal stem cells and to mark high-clonogenicity progenitors with enhanced in vivo homing capacity, broadening its anti-adhesive role beyond epithelia.","evidence":"RNAi knockdown aggregation phenotype in MSCs; FACS-sorted PODXL-high cells showed improved clonogenicity and homing to infarcted heart in mice","pmids":["18818395"],"confidence":"Medium","gaps":["Homing mechanism (selectin-based vs. charge-based) not dissected","Single study without independent replication"]},{"year":2016,"claim":"Conditional endothelial knockout revealed that PODXL maintains vascular barrier integrity by restraining RhoA activation, facilitating VE-cadherin junction recovery, and limiting stress-fiber persistence after inflammatory challenge.","evidence":"Endothelial-specific Podxl conditional KO mice with dextran permeability, macrophage transmigration, RhoA pull-down, and VE-cadherin imaging","pmids":["27289182"],"confidence":"High","gaps":["Direct molecular link between PODXL and RhoA inhibition not identified","Whether the NHERF2/ezrin complex mediates this endothelial function not tested"]},{"year":2016,"claim":"A homozygous frameshift loss-of-function mutation in PODXL was identified as causal for autosomal-recessive juvenile parkinsonism, and mutant constructs impaired neurite branching in PC12 cells, establishing a neuronal requirement.","evidence":"Whole-exome sequencing with Sanger-confirmed segregation; functional rescue in differentiated PC12 cells","pmids":["26864383"],"confidence":"Medium","gaps":["Mechanism by which PODXL regulates neurite morphology unknown","Single family — genetic finding awaits replication in independent cohorts"]},{"year":2016,"claim":"PODXL was identified as the carrier of major pluripotency surface epitopes (TRA-1-60, TRA-1-81, GCTM2) and shown to be transcriptionally activated by KLF4 during reprogramming, connecting its expression to the pluripotency network.","evidence":"Expression analysis during reprogramming, KLF4 overexpression, antibody-mediated cytotoxicity in hPSCs","pmids":["26886504"],"confidence":"Medium","gaps":["Whether KLF4 directly binds the PODXL promoter not determined","Functional role of PODXL in pluripotency maintenance versus as a passive marker not resolved"]},{"year":2016,"claim":"Post-transcriptional regulation of PODXL by miR-5100 was established, linking PODXL expression levels to pancreatic cancer cell migration and invasion.","evidence":"3′UTR luciferase reporter, miR-5100 overexpression, siRNA knockdown with Transwell migration/invasion assays","pmids":["26892887"],"confidence":"Medium","gaps":["In vivo metastasis dependence on PODXL not tested","Signal transduction downstream of PODXL in migration not delineated"]},{"year":2021,"claim":"ChIP-confirmed direct transcriptional regulation of PODXL by TCF3 in spermatogonial stem cells, with PODXL knockdown compromising SSC proliferation and survival, placed PODXL in the SSC self-renewal program.","evidence":"ChIP of TCF3 at PODXL promoter, siRNA knockdown of PODXL, proliferation and apoptosis assays in human SSCs","pmids":["34422820"],"confidence":"Medium","gaps":["Whether PODXL acts via anti-adhesion or distinct signaling in SSCs is unknown","Single study without in vivo validation"]},{"year":null,"claim":"The direct molecular mechanism by which PODXL restrains RhoA activity in endothelial cells and the structural basis of its cytoplasmic interactions remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of the PODXL cytoplasmic domain or its NHERF2 complex","Mechanism linking PODXL to RhoA inhibition not identified","Whether PODXL neuronal and endothelial functions share a common NHERF2/ezrin-dependent mechanism is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[1,4,5,8]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,8]}],"pathway":[{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,3,4,8]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]}],"complexes":[],"partners":["NHERF2","EZR","L-SELECTIN","VE-CADHERIN","KLF4","TCF3"],"other_free_text":[]},"mechanistic_narrative":"Podocalyxin (PODXL) is a transmembrane sialomucin that functions as a multivalent regulator of cell adhesion, polarity, and cytoskeletal organization across diverse cell types. Its cytoplasmic C-terminal PDZ-binding motif (DTHL) nucleates a tripartite complex with the scaffold NHERF2 and the ERM-family linker ezrin, coupling PODXL to the cortical actin cytoskeleton; disruption of this complex accompanies podocyte foot-process effacement in nephrotic disease models, and conditional endothelial deletion shows that PODXL restrains RhoA activity to maintain vascular barrier integrity and VE-cadherin junction recovery after thrombin challenge [PMID:11457882, PMID:27289182]. PODXL acts as an anti-adhesive charge-barrier that prevents cell–cell aggregation, establishes the preapical membrane domain in polarizing epithelia through its PDZ-binding motif and NHERF2 interaction, and serves as an L-selectin ligand on high endothelial venules to support lymphocyte rolling [PMID:15642748, PMID:9625756, PMID:18818395]. A homozygous frameshift mutation in PODXL causes autosomal-recessive juvenile parkinsonism, and loss of PODXL impairs neurite branching in differentiated PC12 cells, establishing a requirement for neural process morphogenesis [PMID:26864383]."},"prefetch_data":{"uniprot":{"accession":"O00592","full_name":"Podocalyxin","aliases":["GCTM-2 antigen","Gp200","Podocalyxin-like protein 1","PC","PCLP-1"],"length_aa":558,"mass_kda":58.6,"function":"Involved in the regulation of both adhesion and cell morphology and cancer progression. Functions as an anti-adhesive molecule that maintains an open filtration pathway between neighboring foot processes in the podocyte by charge repulsion. Acts as a pro-adhesive molecule, enhancing the adherence of cells to immobilized ligands, increasing the rate of migration and cell-cell contacts in an integrin-dependent manner. Induces the formation of apical actin-dependent microvilli. Involved in the formation of a preapical plasma membrane subdomain to set up initial epithelial polarization and the apical lumen formation during renal tubulogenesis. Plays a role in cancer development and aggressiveness by inducing cell migration and invasion through its interaction with the actin-binding protein EZR. Affects EZR-dependent signaling events, leading to increased activities of the MAPK and PI3K pathways in cancer cells","subcellular_location":"Apical cell membrane; Cell projection, lamellipodium; Cell projection, filopodium; Cell projection, ruffle; Cell projection, microvillus; Membrane raft; Membrane","url":"https://www.uniprot.org/uniprotkb/O00592/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PODXL","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SLC9A3R2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PODXL","total_profiled":1310},"omim":[{"mim_id":"616627","title":"PODOCALYXIN-LIKE 2; PODXL2","url":"https://www.omim.org/entry/616627"},{"mim_id":"606553","title":"SOLUTE CARRIER FAMILY 9, MEMBER 3, REGULATOR 2; SLC9A3R2","url":"https://www.omim.org/entry/606553"},{"mim_id":"602632","title":"PODOCALYXIN-LIKE; PODXL","url":"https://www.omim.org/entry/602632"},{"mim_id":"600116","title":"PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2","url":"https://www.omim.org/entry/600116"},{"mim_id":"123900","title":"EZRIN; EZR","url":"https://www.omim.org/entry/123900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Vesicles","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":130.6}],"url":"https://www.proteinatlas.org/search/PODXL"},"hgnc":{"alias_symbol":["PCLP","Gp200","PC","PODXL1","PDX","gp135"],"prev_symbol":[]},"alphafold":{"accession":"O00592","domains":[{"cath_id":"-","chopping":"341-348_356-419","consensus_level":"high","plddt":80.0483,"start":341,"end":419},{"cath_id":"-","chopping":"420-451","consensus_level":"medium","plddt":81.9425,"start":420,"end":451},{"cath_id":"1.20.5","chopping":"460-498","consensus_level":"medium","plddt":83.2136,"start":460,"end":498}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00592","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00592-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00592-F1-predicted_aligned_error_v6.png","plddt_mean":52.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PODXL","jax_strain_url":"https://www.jax.org/strain/search?query=PODXL"},"sequence":{"accession":"O00592","fasta_url":"https://rest.uniprot.org/uniprotkb/O00592.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00592/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00592"}},"corpus_meta":[{"pmid":"8631275","id":"PMC_8631275","title":"PDX-1 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cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15146197","id":"PMC_15146197","title":"Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation.","date":"2004","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/15146197","citation_count":266,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12874460","id":"PMC_12874460","title":"Expression of podocyte-associated molecules in acquired human kidney diseases.","date":"2003","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/12874460","citation_count":250,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11457882","id":"PMC_11457882","title":"Loss of glomerular foot processes is associated with uncoupling of podocalyxin from the actin cytoskeleton.","date":"2001","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11457882","citation_count":218,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9625756","id":"PMC_9625756","title":"Identification of podocalyxin-like protein as a high endothelial venule ligand for L-selectin: parallels to CD34.","date":"1998","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9625756","citation_count":208,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18356574","id":"PMC_18356574","title":"Selection against undifferentiated human embryonic stem cells by a cytotoxic antibody recognizing podocalyxin-like protein-1.","date":"2008","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/18356574","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15642748","id":"PMC_15642748","title":"Gp135/podocalyxin and NHERF-2 participate in the formation of a preapical domain during polarization of MDCK cells.","date":"2005","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15642748","citation_count":165,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12690205","id":"PMC_12690205","title":"Human chromosome 7: DNA sequence and biology.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12690205","citation_count":154,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18818395","id":"PMC_18818395","title":"The CD34-like protein PODXL and alpha6-integrin (CD49f) identify early progenitor MSCs with increased clonogenicity and migration to infarcted heart in mice.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18818395","citation_count":148,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15289306","id":"PMC_15289306","title":"Overexpression of the anti-adhesin podocalyxin is an independent predictor of breast cancer progression.","date":"2004","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15289306","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23533145","id":"PMC_23533145","title":"In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.","date":"2013","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/23533145","citation_count":138,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31871319","id":"PMC_31871319","title":"Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms.","date":"2019","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31871319","citation_count":137,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10737800","id":"PMC_10737800","title":"Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of 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cell","url":"https://pubmed.ncbi.nlm.nih.gov/30639242","citation_count":124,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48745,"output_tokens":1908,"usd":0.087428},"stage2":{"model":"claude-opus-4-6","input_tokens":5176,"output_tokens":1968,"usd":0.11262},"total_usd":0.479874,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60616,"output_tokens":4816,"usd":0.127044},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":7221,"output_tokens":2630,"usd":0.152782}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Podocalyxin (PODXL) was identified as the molecular identity of the tumor antigen gp200/GCTM-2 expressed on human embryonal carcinoma cells, establishing it as a surface membrane glycoprotein on malignant stem cells of testicular tumors with a putative cell adhesion function.\",\n      \"method\": \"Protein sequencing of gp200 peptides matched to podocalyxin sequence; confirmed by two distinct monoclonal antibodies specific for podocalyxin reacting positively with gp200\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal antibody confirmation and peptide sequencing; single study\",\n      \"pmids\": [\"12504081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional knockout of Podxl specifically in vascular endothelial cells causes loss of endothelial barrier integrity: Podxl-deficient ECs show increased permeability, delayed recovery of VE-cadherin contacts after thrombin stimulation, persistence of F-actin stress fibers, and sustained phosphorylation of the ERM complex with prolonged RhoA activation, indicating a role for PODXL in restoring endothelial barrier integrity after injury.\",\n      \"method\": \"Conditional endothelial-specific Podxl knockout mouse model; dextran permeability assay; immunofluorescence for VE-cadherin and F-actin; RhoA activation assay; phospho-ERM western blot\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with multiple orthogonal cellular phenotype readouts and defined signaling mechanism\",\n      \"pmids\": [\"27289182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-5100 directly binds to the 3′ UTR of PODXL and post-transcriptionally represses its expression in pancreatic cancer cells; silencing PODXL diminishes cell migration and invasion, demonstrating PODXL's role in promoting pancreatic cancer cell motility.\",\n      \"method\": \"miRNA overexpression; 3′ UTR luciferase reporter assay; siRNA knockdown of PODXL; migration and invasion assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3′ UTR binding demonstrated with reporter assay plus functional loss-of-function phenotype\",\n      \"pmids\": [\"26892887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PODXL carries multiple post-translational modification-dependent pluripotency epitopes (TRA-1-60, TRA-1-81, GCTM2, GP200, mAb84) on human pluripotent stem cells; the universal 3D3 antibody targeting the PODXL protein backbone causes massive necrosis and apoptosis of human pluripotent stem cells, and PODXL expression is activated by the transcription factor KLF4 during reprogramming.\",\n      \"method\": \"Antibody-mediated cytotoxicity assay; flow cytometry; reprogramming time-course with KLF4; immunofluorescence\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods in single study; KLF4 activation and antibody cytotoxicity demonstrated, but single lab\",\n      \"pmids\": [\"26886504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A frameshift mutation (c.89_90insGTCGCCCC) in PODXL exon 1 causing loss of protein is linked to autosomal-recessive juvenile Parkinsonism; functional validation in differentiated PC12 cells showed that mutant PODXL constructs significantly impair neurite branching and length compared to wild-type, establishing a role for PODXL in neural morphology and development.\",\n      \"method\": \"Whole-exome sequencing; Sanger sequencing for segregation; PC12 cell transfection with wild-type vs. mutant PODXL constructs; neurite morphology quantification\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotype in relevant neuronal cell model; single lab\",\n      \"pmids\": [\"26864383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TCF3, a basic helix-loop-helix transcription factor, stimulates proliferation and suppresses apoptosis of human spermatogonial stem cells (SSCs) by directly binding to and regulating the transcription of PODXL; PODXL silencing compromised SSC stem cell activity, placing PODXL downstream of TCF3 in a proliferation/survival pathway.\",\n      \"method\": \"RNA sequencing; chromatin immunoprecipitation (ChIP) assay; PODXL siRNA knockdown; proliferation and apoptosis assays in human SSCs\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct TCF3 binding to PODXL locus; loss-of-function with defined cellular phenotype; single lab\",\n      \"pmids\": [\"34422820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"lncRNA BBOX1-AS1 acts as a competing endogenous RNA (ceRNA) that sequesters miR-361-3p to upregulate PODXL expression in ovarian cancer cells; elevated PODXL promotes ovarian cancer cell proliferation and survival, while PODXL depletion counteracts the pro-tumorigenic effects of miR-361-3p inhibition.\",\n      \"method\": \"RNA pulldown/binding assay; luciferase reporter assay for miR-361-3p binding to PODXL 3′ UTR; siRNA knockdown; proliferation and apoptosis assays\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, ceRNA mechanism demonstrated but limited mechanistic depth for PODXL itself\",\n      \"pmids\": [\"33159291\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PODXL (podocalyxin-like) is a heavily glycosylated transmembrane sialomucin that functions as a cell adhesion and barrier-regulatory protein: in vascular endothelium it maintains barrier integrity by modulating RhoA/ERM signaling and VE-cadherin junction recovery after injury; in pluripotent stem cells it carries post-translational pluripotency epitopes (TRA-1-60, TRA-1-81) and its expression is activated by KLF4; in neurons and spermatogonial stem cells it supports morphogenesis and stem cell self-renewal downstream of transcription factors TCF3 and is regulated by miRNAs (miR-5100, miR-361-3p) that modulate its 3′ UTR to control cancer cell migration and invasion.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nThe gene of interest is **PODXL** (podocalyxin-like protein) — a transmembrane sialomucin expressed on podocytes, endothelium, hematopoietic cells, and various stem/cancer cells.\n\n**KEEP papers (about canonical PODXL protein):**\n- [45] miR-5100 targets PODXL in pancreatic cancer → KEEP\n- [46] Conditional knockout of Podxl in endothelial cells → KEEP\n- [53] Frameshift mutation in PODXL causing juvenile Parkinsonism, functional validation in PC12 cells → KEEP\n- [66] PODXL as carrier of pluripotency markers, antibody studies → KEEP\n- [70] lncRNA BBOX1-AS1/miR-361-3p/PODXL axis in OC → KEEP (PODXL is the endpoint target with functional data)\n- [87] TCF3 regulates PODXL in spermatogonial stem cells → KEEP\n- [94] gp200-MR6 on breast epithelium (this is likely IL4R complex, not PODXL) → EXCLUDE (alias collision: gp200-MR6 is associated with IL-4 receptor, not podocalyxin)\n- [14] (gene2pubmed) gp200/GCTM-2 identified as podocalyxin → KEEP (PMID:12504081)\n- [19] (gene2pubmed) Podocalyxin coupled to actin via NHERF2/ezrin → KEEP (PMID:11457882)\n- [20] (gene2pubmed) PCLP as L-selectin ligand on HEV → KEEP (PMID:9625756)\n- [21] (gene2pubmed) mAb 84 cytotoxic to hESC via PODXL → KEEP (PMID:18356574)\n- [22] (gene2pubmed) gp135/podocalyxin and NHERF-2 in MDCK polarization → KEEP (PMID:15642748)\n- [24] (gene2pubmed) PODXL identifies early MSC progenitors → KEEP (PMID:18818395)\n- [25] (gene2pubmed) Podocalyxin overexpression in breast cancer, perturbs cell junctions → KEEP (PMID:15289306)\n- [18] (gene2pubmed) Podocalyxin expression in acquired kidney diseases → KEEP (PMID:12874460) — borderline (expression/IHC), but notes protein reduction\n- All PDX model papers (1-13, 15-17, 29, 33-35, etc.) → EXCLUDE (alias collision: PDX = patient-derived xenograft or PDX-1 pancreatic transcription factor, not PODXL)\n- All PDX-1 transcription factor papers → EXCLUDE\n- PC-12 pheochromocytoma papers → EXCLUDE\n- PC-TP/StARD2 paper → EXCLUDE\n- PC-1/ENPP1 papers → EXCLUDE\n- All other non-PODXL papers → EXCLUDE\n\nFor gene2pubmed papers:\n- PMID:25056061 (schizophrenia GWAS) → EXCLUDE (no mechanistic PODXL data)\n- PMID:15326289 (urinary exosomes) → KEEP for PODXL presence but no mechanism → EXCLUDE\n- PMID:22658674 (RBP interactome) → EXCLUDE\n- PMID:12477932, 14702039, 10737800 (cDNA sequencing) → EXCLUDE\n- PMID:26186194, 28514442, 32296183, 33961781 (interactome networks) → EXCLUDE (large-scale, no specific PODXL mechanism)\n- PMID:29507755, 21873635, 19056867, 8125298, 12690205 → EXCLUDE\n- PMID:26638075, 35271311, 34079125 → EXCLUDE (large-scale, no specific PODXL mechanism)\n- PMID:14702039 → EXCLUDE\n- PMID:15146197 → EXCLUDE\n- PMID:12874460 → borderline expression study → EXCLUDE (no mechanism)\n- PMID:18818395 → KEEP (functional RNAi data)\n- PMID:15289306 → KEEP (forced expression with phenotype)\n- PMID:23376485, 23533145 → EXCLUDE (proteomics, no mechanism)\n- PMID:31871319 (Rho GTPase proximity) → EXCLUDE\n- PMID:30639242 (Ras BioID) → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Podocalyxin (PC) is linked to the actin cytoskeleton via a tripartite complex with NHERF2 (a PDZ-domain scaffold protein) and ezrin (an ERM-family linker). The cytoplasmic tail of PC contains a C-terminal PDZ-binding motif (DTHL) that binds specifically to the second PDZ domain of NHERF2, as demonstrated by yeast two-hybrid and in vitro pull-down assays. PC, NHERF2, and ezrin co-immunoprecipitate, forming a multimeric complex. This PC/NHERF2/ezrin/actin interaction is disrupted in glomerular epithelial cells from puromycin aminonucleoside-, protamine sulfate-, or sialidase-treated rats that show loss of foot processes, establishing that this complex is required for maintaining podocyte architecture.\",\n      \"method\": \"Yeast two-hybrid, in vitro pull-down, co-immunoprecipitation, immunocytochemistry, disease model (puromycin aminonucleoside nephrosis)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (Y2H, pulldown, Co-IP, localization) in one study with functional disease-model validation\",\n      \"pmids\": [\"11457882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Podocalyxin-like protein (PCLP) expressed on high endothelial venules (HEV) functions as a ligand for L-selectin, supporting lymphocyte tethering and rolling under physiological flow conditions in vitro. Purified HEV-derived PCLP bound recombinant L-selectin and the HEV-specific monoclonal antibody MECA-79, demonstrating its role as a sialomucin-type adhesion molecule for leukocyte homing.\",\n      \"method\": \"Protein purification from HEV, recombinant L-selectin binding assay, flow-based lymphocyte rolling assay, MECA-79 immunoreactivity\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted binding assay plus physiological flow assay with purified native protein\",\n      \"pmids\": [\"9625756\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The human embryonal carcinoma tumor antigen gp200 (also known as GCTM-2) was identified as podocalyxin by peptide mass spectrometry and confirmed by reactivity of two distinct anti-podocalyxin monoclonal antibodies, establishing that podocalyxin is expressed on malignant testicular germ cell tumors and is the molecular identity of these previously characterized cancer antigens.\",\n      \"method\": \"Protein sequence analysis of gp200 peptides by mass spectrometry, immunoreactivity with two distinct anti-podocalyxin monoclonal antibodies\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-based protein identification confirmed by two independent antibodies\",\n      \"pmids\": [\"12504081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In MDCK epithelial cells, podocalyxin (gp135) marks a preapical domain that is established before tight junction formation. The C-terminal PDZ-binding motif of podocalyxin is required for targeting it to the free surface of single cells and to a subdomain of the terminally polarized apical membrane. Podocalyxin co-localizes with NHERF-2 at this preapical domain, and RNAi depletion of podocalyxin causes defects in epithelial polarization, demonstrating a functional role in establishing apical polarity.\",\n      \"method\": \"Domain-deletion mutagenesis, RNAi knockdown, immunofluorescence, identification of gp135 as dog podocalyxin orthologue\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus RNAi loss-of-function with defined polarization phenotype\",\n      \"pmids\": [\"15642748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Forced overexpression of podocalyxin in MCF-7 breast carcinoma cells perturbed cell-cell junctions and caused cell shedding from confluent monolayers, demonstrating a direct anti-adhesive function of podocalyxin that can promote tumor cell detachment.\",\n      \"method\": \"Forced expression (overexpression) in MCF-7 cells, cell junction analysis, confluent monolayer shedding assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain-of-function with defined cellular phenotype, single study single method\",\n      \"pmids\": [\"15289306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PODXL (podocalyxin-like protein) is selectively expressed on early progenitor mesenchymal stem cells (MSCs). RNAi-mediated inhibition of PODXL expression caused cell aggregation in culture, indicating that PODXL normally functions to prevent cell-cell aggregation in MSCs. PODXL-high/CD49f-high MSCs showed greater clonogenicity, more efficient differentiation, and preferential homing to infarcted heart after intravenous infusion in mice.\",\n      \"method\": \"FACS isolation, RNA interference (RNAi) knockdown with aggregation phenotype, in vivo intravenous infusion homing assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RNAi loss-of-function with defined cellular phenotype plus in vivo homing data, single study\",\n      \"pmids\": [\"18818395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A monoclonal antibody (mAb 84) targeting podocalyxin-like protein-1 (PODXL) on undifferentiated human embryonic stem cells (hESCs) induces rapid, complement-independent cell death within 30 minutes, selectively killing undifferentiated hESCs but not differentiated derivatives. Immunoprecipitation identified PODXL as the target antigen of mAb 84, and pre-treatment prevented teratoma formation in SCID mice.\",\n      \"method\": \"Immunoprecipitation antigen identification, cytotoxicity assay, complement inhibition, in vivo teratoma suppression assay\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antigen identified by IP, cytotoxicity mechanism characterized, in vivo functional validation\",\n      \"pmids\": [\"18356574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-5100 directly binds the 3′ UTR of PODXL mRNA and post-transcriptionally represses PODXL expression in pancreatic cancer cells. Silencing PODXL phenocopied miR-5100 overexpression, inhibiting cell migration and invasion, establishing PODXL as a pro-metastatic effector downstream of miR-5100 in pancreatic cancer.\",\n      \"method\": \"3′UTR luciferase reporter assay, miRNA overexpression, siRNA knockdown, migration and invasion assays\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — 3′UTR reporter plus siRNA knockdown with functional migration/invasion phenotype, single study\",\n      \"pmids\": [\"26892887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Conditional endothelial-specific deletion of Podxl in mice disrupts endothelial barrier integrity: Podxl-deficient lung endothelial cells show increased permeability to dextran and enhanced macrophage transmigration. After thrombin stimulation, ECs lacking Podxl exhibit delayed recovery of VE-cadherin contacts, persistence of F-actin stress fibers, sustained phosphorylation of the ERM complex, and sustained RhoA activation, indicating that Podxl normally promotes endothelial barrier re-sealing by restraining RhoA activity and facilitating VE-cadherin junction restoration.\",\n      \"method\": \"Conditional knockout mouse, dextran permeability assay, macrophage transmigration assay, VE-cadherin immunofluorescence, F-actin staining, ERM phosphorylation western blot, RhoA activation assay\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple orthogonal cellular readouts establishing mechanism\",\n      \"pmids\": [\"27289182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PODXL carries the major post-translational epitopes responsible for pluripotent surface markers TRA-1-60, TRA-1-81, GCTM2, GP200, and mAb84 in human pluripotent stem cells. PODXL expression is activated by KLF4 during early reprogramming, and a residual PODXL-positive population persists after extended differentiation. A universal anti-PODXL antibody (3D3) causes massive necrosis and apoptosis of human pluripotent stem cells.\",\n      \"method\": \"mRNA and protein expression analysis during reprogramming, KLF4 overexpression, antibody-mediated cytotoxicity, flow cytometry\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — expression studies plus functional antibody cytotoxicity, limited mechanistic depth\",\n      \"pmids\": [\"26886504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A frameshift mutation (c.89_90insGTCGCCCC) in exon 1 of PODXL resulting in loss of protein was identified as causal for autosomal-recessive juvenile Parkinsonism. Functional validation in differentiated PC12 cells showed significant differences in neurite branching and length (p<0.0001) between cells expressing wild-type versus mutant PODXL constructs, establishing a role for PODXL in neural process morphology.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing for segregation, functional assay in differentiated PC12 cells (neurite branching and length measurement)\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — human genetics plus cellular functional validation in neuronal model, single study\",\n      \"pmids\": [\"26864383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Long non-coding RNA BBOX1-AS1 acts as a competing endogenous RNA (ceRNA) that sequesters miR-361-3p, thereby relieving miR-361-3p-mediated repression of PODXL and increasing PODXL expression in ovarian cancer cells. PODXL depletion reversed the pro-tumorigenic effects of BBOX1-AS1 silencing rescue, placing PODXL as a downstream effector in the BBOX1-AS1/miR-361-3p/PODXL regulatory axis promoting ovarian cancer cell proliferation and survival.\",\n      \"method\": \"lncRNA and miRNA overexpression/knockdown, luciferase reporter assays, siRNA-mediated PODXL silencing, proliferation and apoptosis assays\",\n      \"journal\": \"Reproductive sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — reporter assays and epistasis rescue experiment, single study\",\n      \"pmids\": [\"33159291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Transcription factor TCF3 directly regulates PODXL transcription in human spermatogonial stem cells (SSCs). ChIP assay demonstrated TCF3 binding to the PODXL promoter. TCF3 overexpression promoted SSC proliferation and suppressed apoptosis, while PODXL silencing compromised SSC stem cell activity (proliferation and survival), placing PODXL as a direct TCF3 target gene required for SSC self-renewal.\",\n      \"method\": \"RNA sequencing, chromatin immunoprecipitation (ChIP), PODXL siRNA knockdown, proliferation and apoptosis assays, TCF3 overexpression\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP confirms direct promoter binding; functional knockdown with defined phenotype, single study\",\n      \"pmids\": [\"34422820\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PODXL is a transmembrane sialomucin that links to the actin cytoskeleton via a NHERF2/ezrin scaffold (through its C-terminal PDZ-binding motif), functions as an anti-adhesive molecule that maintains podocyte foot process architecture, promotes epithelial apical polarity, serves as an L-selectin ligand on high endothelial venules, restrains RhoA-mediated endothelial contraction to maintain vascular barrier integrity, and is required for neurite outgrowth and spermatogonial stem cell self-renewal, with its expression regulated by KLF4, TCF3, and miR-5100/miR-361-3p post-transcriptional mechanisms.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PODXL (podocalyxin-like) is a transmembrane sialomucin that regulates cell adhesion, barrier integrity, and morphogenesis across multiple tissue contexts. In vascular endothelium, PODXL is required for restoration of barrier function after injury by modulating RhoA/ERM signaling and VE-cadherin junction recovery [PMID:27289182]. On human pluripotent stem cells, PODXL serves as the protein backbone carrying pluripotency-associated glycan epitopes (TRA-1-60, TRA-1-81), its expression is activated by KLF4 during reprogramming, and antibody targeting of the PODXL core induces stem cell death [PMID:26886504]. A loss-of-function frameshift mutation in PODXL is linked to autosomal-recessive juvenile Parkinsonism, consistent with its role in neurite branching and neural morphogenesis demonstrated in PC12 cells [PMID:26864383].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing the molecular identity of PODXL as a surface glycoprotein on malignant stem cells resolved the long-standing question of what the gp200/GCTM-2 tumor antigen was, linking podocalyxin to embryonal carcinoma biology.\",\n      \"evidence\": \"Peptide sequencing of gp200 matched to podocalyxin; confirmed by two independent anti-podocalyxin antibodies on human embryonal carcinoma cells\",\n      \"pmids\": [\"12504081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional significance of PODXL expression on embryonal carcinoma cells was not tested\",\n        \"Whether PODXL contributes to tumor formation or is merely a marker was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditional endothelial knockout revealed that PODXL is not merely a passive glycocalyx component but actively restores barrier integrity after injury by terminating RhoA/ERM signaling and enabling VE-cadherin junction reassembly.\",\n      \"evidence\": \"Endothelial-specific Podxl conditional knockout mouse; dextran permeability, VE-cadherin immunofluorescence, phospho-ERM western blot, RhoA activity assay\",\n      \"pmids\": [\"27289182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct molecular mechanism by which PODXL dampens RhoA signaling was not defined\",\n        \"Whether PODXL's extracellular sialomucin domain or cytoplasmic domain mediates barrier recovery is unknown\",\n        \"In vivo consequences for vascular leak or edema in the knockout mice were not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of PODXL as the protein backbone for multiple pluripotency glycan epitopes and as a KLF4 transcriptional target established its functional role in human pluripotent stem cell identity and survival.\",\n      \"evidence\": \"Flow cytometry with TRA-1-60/TRA-1-81/GCTM2 antibodies; anti-PODXL 3D3 antibody cytotoxicity; KLF4 reprogramming time-course in human iPSCs\",\n      \"pmids\": [\"26886504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PODXL has a signaling role in maintaining pluripotency beyond carrying glycan epitopes is unclear\",\n        \"The mechanism by which 3D3 antibody binding triggers necrosis/apoptosis was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking a PODXL loss-of-function frameshift to juvenile Parkinsonism and demonstrating impaired neurite morphogenesis established PODXL as a gene required for neural development.\",\n      \"evidence\": \"Whole-exome sequencing with Sanger confirmation for segregation; transfection of WT vs. mutant PODXL in differentiated PC12 cells with neurite quantification\",\n      \"pmids\": [\"26864383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Finding derives from a single family; independent replication in additional kindreds is lacking\",\n        \"Mechanism connecting PODXL loss to dopaminergic neuron vulnerability is unknown\",\n        \"No in vivo neuronal phenotyping was performed\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating that miR-5100 directly represses PODXL via its 3′ UTR and that PODXL silencing reduces pancreatic cancer cell migration established PODXL as a pro-migratory effector under post-transcriptional control.\",\n      \"evidence\": \"3′ UTR luciferase reporter assay; miR-5100 overexpression and PODXL siRNA knockdown; Transwell migration and invasion assays in pancreatic cancer cells\",\n      \"pmids\": [\"26892887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling by which PODXL promotes migration was not identified\",\n        \"In vivo relevance to pancreatic cancer metastasis was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ChIP-based demonstration that TCF3 directly activates PODXL transcription to sustain spermatogonial stem cell proliferation and survival placed PODXL in a defined transcriptional hierarchy governing male germline stem cell maintenance.\",\n      \"evidence\": \"ChIP assay for TCF3 binding at PODXL promoter; RNA-seq; PODXL siRNA knockdown with proliferation and apoptosis assays in human SSCs\",\n      \"pmids\": [\"34422820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which PODXL-dependent signaling pathways mediate SSC self-renewal was not determined\",\n        \"In vivo validation in a spermatogonial stem cell niche model is absent\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intracellular signaling mechanism by which PODXL exerts its diverse tissue-specific effects — endothelial barrier regulation, neural morphogenesis, stem cell survival — remains undefined; whether these functions depend on its cytoplasmic domain interactions (e.g., with NHERF/ERM) or its extracellular glycan coat is a central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of full-length PODXL exists\",\n        \"Cytoplasmic domain binding partners mediating RhoA regulation have not been identified in the available literature\",\n        \"Whether the sialomucin ectodomain versus the cytoplasmic tail drives pro-migratory and morphogenetic functions has not been dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:1500931\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KLF4\",\n      \"TCF3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Podocalyxin (PODXL) is a transmembrane sialomucin that functions as a multivalent regulator of cell adhesion, polarity, and cytoskeletal organization across diverse cell types. Its cytoplasmic C-terminal PDZ-binding motif (DTHL) nucleates a tripartite complex with the scaffold NHERF2 and the ERM-family linker ezrin, coupling PODXL to the cortical actin cytoskeleton; disruption of this complex accompanies podocyte foot-process effacement in nephrotic disease models, and conditional endothelial deletion shows that PODXL restrains RhoA activity to maintain vascular barrier integrity and VE-cadherin junction recovery after thrombin challenge [PMID:11457882, PMID:27289182]. PODXL acts as an anti-adhesive charge-barrier that prevents cell–cell aggregation, establishes the preapical membrane domain in polarizing epithelia through its PDZ-binding motif and NHERF2 interaction, and serves as an L-selectin ligand on high endothelial venules to support lymphocyte rolling [PMID:15642748, PMID:9625756, PMID:18818395]. A homozygous frameshift mutation in PODXL causes autosomal-recessive juvenile parkinsonism, and loss of PODXL impairs neurite branching in differentiated PC12 cells, establishing a requirement for neural process morphogenesis [PMID:26864383].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying PODXL as an L-selectin ligand on HEV established it as a functional sialomucin mediating leukocyte tethering and rolling, resolving the molecular identity of a key lymphocyte-homing receptor.\",\n      \"evidence\": \"Purified HEV-derived PODXL bound recombinant L-selectin and supported lymphocyte rolling under physiological flow in vitro\",\n      \"pmids\": [\"9625756\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution relative to other HEV sialomucins (GlyCAM-1, CD34) not dissected\", \"In vivo lymphocyte homing dependence on PODXL not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstration that PODXL links to actin via an NHERF2/ezrin scaffold through its C-terminal PDZ-binding motif provided the first mechanistic explanation for how the extracellular mucin domain is transduced to cytoskeletal architecture in podocytes.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, co-IP, and immunocytochemistry in normal and puromycin aminonucleoside-treated rat podocytes\",\n      \"pmids\": [\"11457882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and direct vs. indirect binding within the trimeric complex not resolved\", \"Whether other ERM proteins substitute for ezrin not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Gain-of-function in MCF-7 cells revealed that PODXL overexpression directly disrupts cell–cell junctions and promotes cell detachment, establishing an intrinsic anti-adhesive activity relevant to tumor cell shedding.\",\n      \"evidence\": \"Forced overexpression in MCF-7 breast carcinoma monolayers with junction analysis and shedding quantification\",\n      \"pmids\": [\"15289306\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Anti-adhesive mechanism (charge repulsion vs. signaling) not distinguished\", \"Relevance to endogenous expression levels in primary tumors uncertain\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"RNAi depletion and domain-deletion studies in MDCK cells demonstrated that PODXL and its PDZ-binding motif are required for apical membrane identity before tight-junction formation, extending its role from podocyte architecture to general epithelial polarity.\",\n      \"evidence\": \"RNAi knockdown and C-terminal deletion mutagenesis in polarizing MDCK cells with immunofluorescence\",\n      \"pmids\": [\"15642748\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PODXL instructs or merely marks the preapical domain not fully resolved\", \"Downstream effectors beyond NHERF2 not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"PODXL was shown to prevent cell–cell aggregation in mesenchymal stem cells and to mark high-clonogenicity progenitors with enhanced in vivo homing capacity, broadening its anti-adhesive role beyond epithelia.\",\n      \"evidence\": \"RNAi knockdown aggregation phenotype in MSCs; FACS-sorted PODXL-high cells showed improved clonogenicity and homing to infarcted heart in mice\",\n      \"pmids\": [\"18818395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Homing mechanism (selectin-based vs. charge-based) not dissected\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Conditional endothelial knockout revealed that PODXL maintains vascular barrier integrity by restraining RhoA activation, facilitating VE-cadherin junction recovery, and limiting stress-fiber persistence after inflammatory challenge.\",\n      \"evidence\": \"Endothelial-specific Podxl conditional KO mice with dextran permeability, macrophage transmigration, RhoA pull-down, and VE-cadherin imaging\",\n      \"pmids\": [\"27289182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular link between PODXL and RhoA inhibition not identified\", \"Whether the NHERF2/ezrin complex mediates this endothelial function not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A homozygous frameshift loss-of-function mutation in PODXL was identified as causal for autosomal-recessive juvenile parkinsonism, and mutant constructs impaired neurite branching in PC12 cells, establishing a neuronal requirement.\",\n      \"evidence\": \"Whole-exome sequencing with Sanger-confirmed segregation; functional rescue in differentiated PC12 cells\",\n      \"pmids\": [\"26864383\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PODXL regulates neurite morphology unknown\", \"Single family — genetic finding awaits replication in independent cohorts\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"PODXL was identified as the carrier of major pluripotency surface epitopes (TRA-1-60, TRA-1-81, GCTM2) and shown to be transcriptionally activated by KLF4 during reprogramming, connecting its expression to the pluripotency network.\",\n      \"evidence\": \"Expression analysis during reprogramming, KLF4 overexpression, antibody-mediated cytotoxicity in hPSCs\",\n      \"pmids\": [\"26886504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KLF4 directly binds the PODXL promoter not determined\", \"Functional role of PODXL in pluripotency maintenance versus as a passive marker not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Post-transcriptional regulation of PODXL by miR-5100 was established, linking PODXL expression levels to pancreatic cancer cell migration and invasion.\",\n      \"evidence\": \"3′UTR luciferase reporter, miR-5100 overexpression, siRNA knockdown with Transwell migration/invasion assays\",\n      \"pmids\": [\"26892887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo metastasis dependence on PODXL not tested\", \"Signal transduction downstream of PODXL in migration not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ChIP-confirmed direct transcriptional regulation of PODXL by TCF3 in spermatogonial stem cells, with PODXL knockdown compromising SSC proliferation and survival, placed PODXL in the SSC self-renewal program.\",\n      \"evidence\": \"ChIP of TCF3 at PODXL promoter, siRNA knockdown of PODXL, proliferation and apoptosis assays in human SSCs\",\n      \"pmids\": [\"34422820\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PODXL acts via anti-adhesion or distinct signaling in SSCs is unknown\", \"Single study without in vivo validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular mechanism by which PODXL restrains RhoA activity in endothelial cells and the structural basis of its cytoplasmic interactions remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the PODXL cytoplasmic domain or its NHERF2 complex\", \"Mechanism linking PODXL to RhoA inhibition not identified\", \"Whether PODXL neuronal and endothelial functions share a common NHERF2/ezrin-dependent mechanism is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [1, 4, 5, 8]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 3, 4, 8]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NHERF2\", \"EZR\", \"L-selectin\", \"VE-cadherin\", \"KLF4\", \"TCF3\"],\n    \"other_free_text\": []\n  }\n}\n```"}