{"gene":"PDPN","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":1999,"finding":"PA2.26 (podoplanin/PDPN) is a mucin-like transmembrane glycoprotein concentrated in actin-rich microvilli and plasma membrane projections (filopodia, lamellipodia, ruffles) where it co-localizes with ERM family proteins; ezrin and moesin (but not radixin) co-immunoprecipitate with PA2.26. Ectopic expression in keratinocytes induces fibroblastoid morphological conversion, major actin cytoskeleton reorganization, redistribution of ezrin to cell-surface projections, and enhanced motility.","method":"Co-immunoprecipitation, confocal/immunoelectron microscopy, ectopic expression in keratinocytes with phenotypic readout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus direct localization with functional consequence (motility), replicated in multiple cell systems","pmids":["10574709"],"is_preprint":false},{"year":2003,"finding":"Aggrus/podoplanin (PDPN) is a platelet aggregation-inducing sialoglycoprotein; its platelet aggregation-stimulating (PLAG) domain containing O-glycosylated threonine residues (Thr34 and Thr52) is the critical determinant for platelet aggregation-inducing activity. Purified Aggrus induces platelet aggregation without requiring plasma components.","method":"Antibody-affinity purification of native protein, expression in CHO cells, point mutagenesis of PLAG domain threonines, platelet aggregation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — purification, functional assay, and mutagenesis identifying critical residues, foundational study","pmids":["14522983"],"is_preprint":false},{"year":2004,"finding":"Sialylated O-glycans (specifically sialic acid plus Gal-β1,3-GalNAc-Ser/Thr, i.e., sialylated core 1 structure) on Aggrus/podoplanin are critical for its platelet aggregation-inducing activity. CMP-sialic acid transporter-deficient and UDP-galactose transporter-deficient CHO cells expressing Aggrus lost platelet aggregation activity, while N-glycan-deficient cells retained it.","method":"Stable expression in CHO glycosylation-deficient mutant cell lines (Lec1, Lec2, Lec8), lectin blotting, platelet aggregation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — reconstitution in defined glycosylation-deficient cells with orthogonal lectin blotting, clear mechanistic conclusion","pmids":["15231832"],"is_preprint":false},{"year":2005,"finding":"Human PA2.26/podoplanin co-localizes with ezrin at the surface of tumor cells and its presence in oral squamous cell carcinoma is associated with downregulation of membrane E-cadherin. Ectopic expression in HeLa and HaCaT cells promotes redistribution of ezrin to cell edges, formation of cell-surface protrusions, and reduced Ca2+-dependent cell-cell adhesiveness.","method":"Double immunofluorescence, confocal microscopy, ectopic expression with phenotypic readouts (protrusion formation, adhesion assay)","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — localization with functional consequence, single lab, multiple readouts","pmids":["15515019"],"is_preprint":false},{"year":2006,"finding":"E11/gp38 (podoplanin/PDPN) is selectively expressed in osteocytes and is required for dendrite elongation; fluid flow shear stress increases E11 mRNA in osteocyte-like cells (MLO-Y4), and siRNA knockdown of E11 blocks shear stress-induced dendricity and dendrite elongation.","method":"siRNA knockdown, fluid flow shear stress assay, MLO-Y4 osteocyte-like cell culture, in vivo mechanical loading","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean siRNA KD with specific morphological phenotype, confirmed in vivo, mechanosensory function defined","pmids":["16738320"],"is_preprint":false},{"year":2006,"finding":"Podoplanin directly interacts in vitro and in vivo with ezrin (and moesin) through a cluster of basic amino acids within its cytoplasmic tail, primarily through the juxtamembrane dipeptide RK. This interaction is required for podoplanin-induced RhoA activation and epithelial-mesenchymal transition (EMT) in MDCK cells. Dominant-negative truncated ezrin or dominant-negative RhoA blocked these effects.","method":"In vitro pull-down, co-immunoprecipitation, GFP-tagged cytoplasmic tail mutants, RhoA activity assay (pull-down), dominant-negative constructs, fluorescence time-lapse video microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1/2 — direct in vitro interaction confirmed, mutagenesis of binding domain, epistasis via dominant-negatives, multiple orthogonal methods","pmids":["17046996"],"is_preprint":false},{"year":2006,"finding":"Podoplanin promotes tumor cell invasion via downregulation of small Rho family GTPase activities leading to filopodia formation and collective cell migration, in a manner that does not require epithelial-mesenchymal transition (E-cadherin expression maintained).","method":"Overexpression in cultured human breast cancer cells, mouse pancreatic beta-cell carcinogenesis model, Rho GTPase activity assays, in vitro invasion assays, human cancer biopsy analysis","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 — multiple model systems, Rho GTPase mechanistic assays, in vivo validation","pmids":["16616332"],"is_preprint":false},{"year":2006,"finding":"The PLAG (platelet aggregation-stimulating) domain of Aggrus/podoplanin is conserved across mammalian species with three tandem repeats; the first or last (but not middle) PLAG domain is critical for platelet aggregation-inducing activity. Bovine Aggrus with a deletion in the first PLAG domain lacks platelet aggregation activity. Point mutations in PLAG domains confirmed their functional importance.","method":"Cross-species cDNA cloning, point mutagenesis, platelet aggregation assay, phylogenetic analysis","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1/2 — systematic mutagenesis across species with functional platelet aggregation readout","pmids":["16766141"],"is_preprint":false},{"year":2007,"finding":"PDPN/Aggrus promotes pulmonary metastasis by inducing platelet aggregation via its PLAG domain (specifically Thr34 and Thr52); point mutation at these residues abolishes both platelet aggregation and metastasis. Aggrus-expressing cells become covered with platelets and arrest in lung microvasculature within 30 minutes post-injection.","method":"Point mutagenesis, experimental and spontaneous metastasis mouse models, intravital observation of platelet-tumor cell interactions, aspirin treatment","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis with in vivo functional validation, mechanistic link between PLAG domain, platelet aggregation, and metastasis established","pmids":["17392172"],"is_preprint":false},{"year":2007,"finding":"CLEC-2 is identified as the platelet receptor for podoplanin; their association is sialic acid-dependent (on O-glycans of podoplanin). Recombinant CLEC-2 inhibits platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, and CLEC-2-mediated signaling involves Src and phospholipase Cγ2 activation.","method":"Flow cytometry binding assay, recombinant CLEC-2 inhibition of platelet aggregation, signaling inhibitor studies (Src, PLCγ2)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — binding confirmed by flow cytometry, functional inhibition with recombinant receptor, signaling pathway defined; widely replicated","pmids":["17616532"],"is_preprint":false},{"year":2008,"finding":"CD9 (tetraspanin) forms a complex with Aggrus/podoplanin via transmembrane domains 1 and 2 (TM1 and TM2) of CD9. CD9 and Aggrus interact homophilically and co-localize in low-density membrane fractions. CD9 expression suppresses Aggrus-induced platelet aggregation and metastasis; deletion of TM1 and TM2 abolishes these inhibitory effects.","method":"Co-immunoprecipitation, low-density membrane fractionation, TM domain deletion constructs, platelet aggregation assay, experimental metastasis model","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, domain-deletion mutagenesis, functional platelet aggregation and in vivo metastasis readouts","pmids":["18541721"],"is_preprint":false},{"year":2008,"finding":"Podoplanin expression is regulated post-translationally by calpain-mediated proteolysis; calpain-1 cleaves podoplanin in vitro, and calpain inhibition leads to podoplanin accumulation in tumor cells that transcribe but do not accumulate podoplanin protein. A novel podoplanin isoform lacking the cytoplasmic YS dipeptide (generated by alternative splicing) was identified; this YS motif is highly conserved across species.","method":"Western blot with protease inhibitors (calpeptin, lactacystin), in vitro calpain-1 cleavage assay, alternative splicing analysis","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro cleavage assay confirmed calpain as the protease; inhibitor studies in multiple cell lines","pmids":["19146981"],"is_preprint":false},{"year":2010,"finding":"Podoplanin on lymphatic endothelial cells activates circulating platelets from the cardinal vein via CLEC-2 interaction, and this platelet activation is required for separation of the lymphatic from the blood vascular system during embryonic development. Platelet aggregates form at the separation zone in wild-type but not podoplanin-knockout embryos; the same blood-filled lymphatic phenotype is induced by podoplanin-blocking antibodies, aspirin, or kindlin-3 knockout (which impairs platelet aggregation).","method":"Podoplanin knockout mouse embryo analysis, aspirin treatment of pregnant mice, podoplanin-blocking antibody administration, kindlin-3 knockout, immunohistochemistry of embryonic platelet aggregates","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple independent genetic and pharmacological perturbations converge on same phenotype; epistasis between podoplanin and platelet activation established in vivo","pmids":["20110424"],"is_preprint":false},{"year":2012,"finding":"IMP-3 (IGF2BP3) stabilizes PDPN mRNA through binding to the 3'UTR of PDPN, maintaining podoplanin levels required for functional invadopodia formation and extracellular matrix degradation in oral squamous cell carcinoma cells. IMP-3 depletion reduces PDPN mRNA stability and abolishes invadopodia-mediated ECM degradation. TGF-β1 increases PDPN expression, potentiating cancer invasion via invadopodia.","method":"RNA in situ hybridization with 3'UTR probe, luciferase reporter assay with PDPN 3'UTR, siRNA knockdown, Transwell invasion assay, xenograft model","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2/3 — reporter assay establishes mRNA stabilization mechanism, functional invasion readout, in vivo validation","pmids":["22859271"],"is_preprint":false},{"year":2013,"finding":"The two conserved intracellular serine residues of podoplanin (PDPN) can be phosphorylated by PKA (protein kinase A). Conversion of these serines to non-phosphorylatable alanines enhances cell migration, while conversion to phosphomimetic aspartates decreases cell migration, indicating that PKA-mediated phosphorylation of PDPN inhibits cell motility. PDPN expression in fibroblasts facilitates motility and viability of neighboring melanoma cells in co-culture.","method":"Knockout MEFs from Pdpn-null mice, site-directed mutagenesis (Ser→Ala and Ser→Asp), in vitro PKA phosphorylation assay, migration assays, co-culture experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 — in vitro kinase assay plus mutagenesis of specific residues with migration phenotype on null background","pmids":["23530051"],"is_preprint":false},{"year":2013,"finding":"Aggrus/podoplanin promotes tumor growth in addition to metastasis through platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth in vivo. The anti-Aggrus monoclonal antibody MS-1 suppresses Aggrus-CLEC-2 binding, platelet aggregation, and metastasis, and exhibits ADCC and CDC activities against Aggrus-positive tumors.","method":"siRNA knockdown, in vitro platelet co-culture proliferation assay, xenograft tumor growth model, antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2/3 — KD with defined in vitro and in vivo phenotypes, mechanism (platelet secretion) partially defined","pmids":["23991201"],"is_preprint":false},{"year":2015,"finding":"Both PKA and CDK5 phosphorylate podoplanin (PDPN) on its two conserved intracellular serine residues, and they cooperate to phosphorylate both serines to decrease cell motility. CDK5 phosphorylation of PDPN was demonstrated in addition to the previously characterized PKA phosphorylation.","method":"In vitro kinase assays with PKA and CDK5, site-directed mutagenesis of intracellular serines, cell migration assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assays with mutagenesis confirming specific phosphorylation sites and functional consequence","pmids":["25959509"],"is_preprint":false},{"year":2019,"finding":"PDPN induces phosphorylation of ERM (ezrin, radixin, moesin) proteins and is associated with expression and activity of MMP-2 and MMP-9, actin cytoskeleton remodeling, and cellular protrusion formation in thyroid carcinoma cells. Inhibition of the MAPK pathway (with U0126 or PLX4720) decreases PDPN expression and increases E/R/M phosphorylation, reducing cell migration.","method":"siRNA knockdown of PDPN, Western blotting for ERM phosphorylation, gelatin zymography for MMP activity, scratch and Transwell migration/invasion assays, MAPK pathway inhibitors","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2/3 — KD with defined molecular phenotypes (ERM phosphorylation, MMP activity), mechanistic link to MAPK pathway established","pmids":["30654768"],"is_preprint":false},{"year":2021,"finding":"CD177 (neutrophil protein) is identified as a novel binding partner/receptor of PDPN on cancer-associated fibroblasts using a high-throughput cell surface interactome screen. CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs. Quantitative phosphoproteomics of PDPN-deficient CAFs reveals PDPN regulates cell signaling, growth, and actomyosin contractility.","method":"High-throughput extracellular interactome screen, quantitative phosphoproteomics (MS), cellular assays with PDPN-deficient CAFs and CD177 treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2/3 — unbiased interactome screen with functional validation and phosphoproteomics; single lab","pmids":["34879110"],"is_preprint":false},{"year":2022,"finding":"UGRP1 binds to cell-surface PDPN and activates RhoA, enhancing interaction of IKKγ and IKKβ to slightly activate NF-κB, which upregulates expression of TLR2, MyD88, NOD2, and NLRP3, thereby promoting inflammatory cytokine production (IL-6, IL-1β, TNF-α) in macrophages during Streptococcus pneumoniae infection. Blocking UGRP1-PDPN interaction protected mice from severe pneumococcal pneumonia.","method":"Co-immunoprecipitation (UGRP1-PDPN binding), RhoA activation assay, NF-κB reporter/Western blot, siRNA/antibody blocking, in vivo mouse infection model with RhoA agonist rescue","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP confirms binding, RhoA assay defines signaling step, in vivo rescue with RhoA agonist provides epistasis","pmids":["35652821"],"is_preprint":false},{"year":2024,"finding":"The PDPN/CLEC-2 axis modulates megakaryocyte subtype differentiation; stromal PDPN interacting with CLEC-2 on megakaryocyte progenitors drives differentiation toward MYLK4-positive HSC-regulating megakaryocytes (with higher ploidy) at the expense of BMAL1-positive platelet-producing megakaryocytes, thus increasing megakaryocyte number while decreasing platelet output.","method":"Co-culture of hematopoietic progenitors with PDPN-expressing or PDPN-knockout immortalized stromal feeder cells, CLEC-2 conditional KO megakaryocytes, flow cytometry for megakaryocyte subtype markers and ploidy","journal":"Thrombosis research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO of both PDPN (stromal) and CLEC-2 (megakaryocyte) with defined subtype differentiation phenotype","pmids":["39615442"],"is_preprint":false},{"year":2024,"finding":"MMP13 upregulates PDPN expression in endothelial cells, and PDPN mediates the platelet aggregation-promoting effect of MMP13 in HUVECs; PDPN-siRNA knockdown attenuates MMP13-induced platelet aggregation. In a DVT mouse model, MMP13 inhibition reduces PDPN expression and decreases deep vein thrombosis burden.","method":"MMP13 overexpression and siRNA knockdown in HUVECs, PDPN-siRNA knockdown, platelet aggregation assay, in vivo DVT mouse model with transcriptome analysis","journal":"Current medical science","confidence":"Medium","confidence_rationale":"Tier 2/3 — siRNA epistasis (PDPN KD rescues MMP13 effect) with functional platelet aggregation readout and in vivo confirmation","pmids":["38619683"],"is_preprint":false},{"year":2024,"finding":"PDPN promotes melanoma cell growth and metastasis through activation of the Wnt/β-catenin pathway, and this pathway also mediates PDPN-dependent upregulation of PD-L1. A PDPN antagonist peptide (CY12-RP2) suppresses these effects, reduces tumor growth, restores CD8+ T-cell anti-tumor activity, and its efficacy is entirely CD8+ T-cell dependent.","method":"Functional assays (proliferation, migration, metastasis), Western blotting (β-catenin, PD-L1), in vivo xenograft and allogeneic mouse models, CD8+ T-cell depletion experiments, flow cytometry","journal":"Journal of experimental & clinical cancer research / Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2/3 — β-catenin/PD-L1 signaling established by WB, CD8-depletion epistasis; two papers converge on same pathway","pmids":["38167452","41573582"],"is_preprint":false}],"current_model":"Podoplanin (PDPN) is a mucin-type transmembrane glycoprotein that localizes to actin-rich membrane protrusions (filopodia, lamellipodia) by directly binding ERM proteins (ezrin/moesin) via basic residues in its cytoplasmic tail; this interaction activates RhoA to drive EMT, collective invasion, and dendrite elongation. Its sialylated O-glycan PLAG domain (containing Thr34/Thr52) engages the platelet receptor CLEC-2, inducing platelet aggregation that promotes hematogenous metastasis, blood-lymphatic separation during development, and megakaryocyte subtype polarization. Two conserved intracellular serines are phosphorylated by PKA and CDK5 to inhibit cell motility; calpain-1 mediates post-translational proteolysis of PDPN, while IMP-3 stabilizes PDPN mRNA. CD9 suppresses PDPN-CLEC-2 signaling by forming a complex with PDPN, and CD177 acts as an extracellular antagonistic binding partner; additionally, PDPN activates Wnt/β-catenin-mediated PD-L1 upregulation and, upon binding UGRP1, activates RhoA-NF-κB inflammatory signaling."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that PDPN is a membrane glycoprotein concentrated at actin-rich protrusions that physically associates with ERM proteins and remodels the cytoskeleton answered the foundational question of where PDPN acts and what immediate intracellular partners it engages.","evidence":"Co-immunoprecipitation of ezrin/moesin with PA2.26, confocal/immunoelectron microscopy in keratinocytes with ectopic expression","pmids":["10574709"],"confidence":"High","gaps":["Direct binding site on PDPN not mapped","RhoA pathway not yet implicated","No glycan function addressed"]},{"year":2003,"claim":"Identification of the PLAG domain with its O-glycosylated Thr34/Thr52 as the critical determinant for platelet aggregation revealed the extracellular functional module of PDPN and established a mechanistic basis for its thrombogenic activity.","evidence":"Purified Aggrus/PDPN from CHO cells, point mutagenesis of PLAG threonines, platelet aggregation assay","pmids":["14522983"],"confidence":"High","gaps":["Platelet receptor not yet identified","In vivo relevance to metastasis untested"]},{"year":2004,"claim":"Demonstrating that sialylated core 1 O-glycans—but not N-glycans—are required for platelet aggregation defined the glycan code that activates the platelet interaction, narrowing the molecular requirements for PLAG domain function.","evidence":"Expression in CHO glycosylation-deficient mutant lines (Lec1/Lec2/Lec8), lectin blotting, platelet aggregation","pmids":["15231832"],"confidence":"High","gaps":["Identity of the platelet-side receptor still unknown","Structural basis of glycan recognition unresolved"]},{"year":2006,"claim":"Mapping the ERM-binding site to juxtamembrane basic residues and showing this interaction is required for RhoA activation and EMT established the signaling axis downstream of PDPN's cytoplasmic tail, while parallel work demonstrated PDPN drives collective invasion via modulation of Rho GTPases even without full EMT.","evidence":"In vitro pull-down/co-IP with cytoplasmic tail mutants, RhoA activity assays, dominant-negative ezrin/RhoA epistasis in MDCK cells; Rho GTPase assays and invasion assays in breast cancer cells and mouse pancreatic carcinogenesis","pmids":["17046996","16616332"],"confidence":"High","gaps":["Relative contributions of RhoA activation vs. other Rho family members unclear","Structural basis of ERM–PDPN binding unresolved"]},{"year":2006,"claim":"Showing that PDPN/E11 is required for osteocyte dendrite elongation under mechanical shear stress extended PDPN's cytoskeletal function beyond cancer to a physiological mechanosensory context.","evidence":"siRNA knockdown in MLO-Y4 osteocyte-like cells, fluid flow shear stress assays, in vivo mechanical loading","pmids":["16738320"],"confidence":"High","gaps":["Downstream signaling pathway in osteocytes not fully delineated","Whether ERM binding is required for dendricity not tested"]},{"year":2007,"claim":"Identification of CLEC-2 as the platelet receptor for PDPN and demonstration that their sialic acid-dependent interaction triggers Src/PLCγ2 signaling on platelets resolved the receptor–ligand pair governing PDPN-induced platelet activation, while in vivo mutagenesis of PLAG Thr34/Thr52 proved this axis drives pulmonary metastasis.","evidence":"Flow cytometry binding, recombinant CLEC-2 inhibition of platelet aggregation, Src/PLCγ2 inhibitor studies; PLAG point mutant cells in experimental metastasis mouse models with intravital imaging","pmids":["17616532","17392172"],"confidence":"High","gaps":["Crystal structure of PDPN–CLEC-2 complex not available","Whether CLEC-2 is the sole platelet receptor not excluded"]},{"year":2008,"claim":"Discovery that CD9 complexes with PDPN through its transmembrane domains and suppresses CLEC-2-dependent platelet aggregation and metastasis identified the first negative cis-regulator of PDPN, while calpain-1 was shown to mediate PDPN proteolytic turnover, revealing a second layer of post-translational control.","evidence":"Reciprocal co-IP, TM domain deletion mutagenesis, platelet aggregation and metastasis assays; in vitro calpain-1 cleavage, calpain inhibitor accumulation studies","pmids":["18541721","19146981"],"confidence":"High","gaps":["Structural detail of CD9–PDPN TM interaction unknown","Calpain cleavage site on PDPN not mapped","Physiological triggers of calpain-mediated PDPN turnover undefined"]},{"year":2010,"claim":"Genetic and pharmacological ablation of PDPN–CLEC-2 signaling in mouse embryos producing blood-filled lymphatics established the physiological requirement for this axis in blood–lymphatic vascular separation during development.","evidence":"Podoplanin-knockout embryos, blocking antibodies, aspirin treatment, kindlin-3 KO; immunohistochemistry of platelet aggregates at separation zone","pmids":["20110424"],"confidence":"High","gaps":["Downstream lymphatic-intrinsic signaling consequences not addressed","Whether platelet aggregation is sufficient or other PDPN functions contribute is unclear"]},{"year":2013,"claim":"Demonstrating that PKA phosphorylates the two conserved intracellular serines of PDPN to inhibit motility—on a Pdpn-null background—defined a kinase-dependent off-switch for PDPN-driven migration, later extended to CDK5 cooperation.","evidence":"In vitro PKA and CDK5 kinase assays, phosphomimetic/non-phosphorylatable mutagenesis on Pdpn-null MEFs, migration assays","pmids":["23530051","25959509"],"confidence":"High","gaps":["In vivo phosphorylation stoichiometry unknown","Phosphatase that reverses this modification not identified"]},{"year":2012,"claim":"Identification of IMP-3/IGF2BP3 as a stabilizer of PDPN mRNA via its 3′UTR revealed a post-transcriptional regulatory layer that sustains PDPN levels required for invadopodia formation and extracellular matrix degradation.","evidence":"3′UTR luciferase reporter, RNA in situ hybridization, siRNA knockdown with invasion and xenograft readouts in oral SCC cells","pmids":["22859271"],"confidence":"Medium","gaps":["Exact IMP-3 binding site in PDPN 3′UTR not mapped","Other RNA-binding proteins that regulate PDPN mRNA not explored"]},{"year":2021,"claim":"High-throughput interactome screening identified CD177 as an extracellular antagonist of PDPN on cancer-associated fibroblasts, phenocopying PDPN loss and revealing a trans-cellular regulatory mechanism in the tumor stroma.","evidence":"Extracellular interactome screen, quantitative phosphoproteomics of PDPN-deficient CAFs, functional assays with recombinant CD177","pmids":["34879110"],"confidence":"Medium","gaps":["Binding interface between CD177 and PDPN not mapped","Physiological relevance in non-tumor contexts untested","Single-lab finding awaiting independent replication"]},{"year":2022,"claim":"Showing that UGRP1 binds PDPN to activate RhoA–NF-κB signaling and amplify innate immune receptor expression in macrophages during pneumococcal infection extended PDPN function to inflammatory innate immunity beyond its established roles in platelets and motility.","evidence":"Co-IP of UGRP1–PDPN, RhoA activity assay, NF-κB reporter, siRNA/antibody blocking, in vivo mouse pneumonia model with RhoA agonist rescue","pmids":["35652821"],"confidence":"Medium","gaps":["Whether PDPN on macrophages signals via ERM in this context not tested","Specificity of UGRP1 for PDPN versus other receptors not fully excluded"]},{"year":2024,"claim":"Recent work revealed that PDPN–CLEC-2 signaling directs megakaryocyte subtype differentiation and that PDPN activates Wnt/β-catenin to upregulate PD-L1, linking PDPN to hematopoietic lineage decisions and immune evasion.","evidence":"PDPN-KO and CLEC-2-cKO co-culture systems with megakaryocyte progenitors; β-catenin/PD-L1 Western blotting, CD8+ T-cell depletion epistasis in melanoma models","pmids":["39615442","38167452"],"confidence":"Medium","gaps":["Wnt/β-catenin activation mechanism by PDPN not elucidated at the molecular level","Whether megakaryocyte subtype polarization occurs in vivo in bone marrow niches not confirmed","Structural basis of PDPN antagonist peptide CY12-RP2 binding unknown"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of the PDPN–CLEC-2 complex, how PDPN simultaneously engages ERM proteins and activates distinct downstream pathways (RhoA, Wnt/β-catenin, NF-κB) in different cell types, and the identity of phosphatases that reverse PKA/CDK5-mediated inhibition of PDPN motility function.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of PDPN or its complexes","Cell-type-specific signaling logic downstream of PDPN not resolved","Calpain cleavage site and degradation kinetics in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,3,5,6]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,9,12,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,6,17,22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,5,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5,6]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,2,8,9,12,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,15,22]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[19,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,9,19,22]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,20]}],"complexes":["PDPN–CD9 complex","PDPN–ERM complex"],"partners":["CLEC2","EZR","MSN","CD9","CD177","UGRP1","IGF2BP3","CAPN1"],"other_free_text":[]},"mechanistic_narrative":"Podoplanin (PDPN) is a mucin-type transmembrane glycoprotein that couples extracellular glycan-mediated receptor engagement to intracellular cytoskeletal remodeling, thereby governing platelet activation, cell motility, and tissue morphogenesis. Its extracellular sialylated O-glycan PLAG domains (centered on Thr34/Thr52) engage the platelet C-type lectin receptor CLEC-2 to induce platelet aggregation, a function essential for developmental blood–lymphatic vascular separation, hematogenous metastasis, megakaryocyte subtype polarization, and inflammatory signaling upon UGRP1 co-ligation [PMID:14522983, PMID:17616532, PMID:20110424, PMID:39615442, PMID:35652821]. The short cytoplasmic tail binds ERM proteins (ezrin/moesin) via juxtamembrane basic residues to activate RhoA, driving epithelial–mesenchymal transition, filopodia-based collective invasion, and osteocyte dendrite elongation; PKA and CDK5 phosphorylate two conserved intracellular serines to inhibit this motility program [PMID:17046996, PMID:16616332, PMID:16738320, PMID:25959509]. PDPN function is modulated by CD9, which suppresses CLEC-2 engagement via transmembrane domain interaction, by CD177, which acts as an extracellular antagonist on cancer-associated fibroblasts, and by calpain-1-mediated proteolytic turnover [PMID:18541721, PMID:34879110, PMID:19146981]."},"prefetch_data":{"uniprot":{"accession":"Q86YL7","full_name":"Podoplanin","aliases":["Aggrus","Glycoprotein 36","Gp36","PA2.26 antigen","T1-alpha","T1A"],"length_aa":162,"mass_kda":16.7,"function":"Mediates effects on cell migration and adhesion through its different partners. During development plays a role in blood and lymphatic vessels separation by binding CLEC1B, triggering CLEC1B activation in platelets and leading to platelet activation and/or aggregation (PubMed:14522983, PubMed:15231832, PubMed:17222411, PubMed:17616532, PubMed:18215137). Interaction with CD9, on the contrary, attenuates platelet aggregation induced by PDPN (PubMed:18541721). Through MSN or EZR interaction promotes epithelial-mesenchymal transition (EMT) leading to ERZ phosphorylation and triggering RHOA activation leading to cell migration increase and invasiveness (PubMed:17046996, PubMed:21376833). Interaction with CD44 promotes directional cell migration in epithelial and tumor cells (PubMed:20962267). In lymph nodes (LNs), controls fibroblastic reticular cells (FRCs) adhesion to the extracellular matrix (ECM) and contraction of the actomyosin by maintaining ERM proteins (EZR; MSN and RDX) and MYL9 activation through association with unknown transmembrane proteins. Engagement of CLEC1B by PDPN promotes FRCs relaxation by blocking lateral membrane interactions leading to reduction of ERM proteins (EZR; MSN and RDX) and MYL9 activation (By similarity). Through binding with LGALS8 may participate in connection of the lymphatic endothelium to the surrounding extracellular matrix (PubMed:19268462). In keratinocytes, induces changes in cell morphology showing an elongated shape, numerous membrane protrusions, major reorganization of the actin cytoskeleton, increased motility and decreased cell adhesion (PubMed:15515019). Controls invadopodia stability and maturation leading to efficient degradation of the extracellular matrix (ECM) in tumor cells through modulation of RHOC activity in order to activate ROCK1/ROCK2 and LIMK1/LIMK2 and inactivation of CFL1 (PubMed:25486435). Required for normal lung cell proliferation and alveolus formation at birth (By similarity). Does not function as a water channel or as a regulator of aquaporin-type water channels (PubMed:9651190). Does not have any effect on folic acid or amino acid transport (By similarity)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/Q86YL7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDPN","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDPN","total_profiled":1310},"omim":[{"mim_id":"608863","title":"PODOPLANIN; PDPN","url":"https://www.omim.org/entry/608863"},{"mim_id":"606783","title":"C-TYPE LECTIN DOMAIN FAMILY 1, MEMBER B; CLEC1B","url":"https://www.omim.org/entry/606783"},{"mim_id":"603423","title":"PR DOMAIN-CONTAINING PROTEIN 1; PRDM1","url":"https://www.omim.org/entry/603423"},{"mim_id":"600646","title":"PROTEIN C RECEPTOR; 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Expression of mouse and human PDPN in cells induced platelet aggregation without requiring plasma components. A highly conserved platelet aggregation-stimulating domain with putative O-glycosylated threonine residues was identified as the critical determinant for this activity, using a neutralizing monoclonal antibody (8F11) that blocked platelet aggregation.\",\n      \"method\": \"Affinity purification, cell expression assays, platelet aggregation assays, monoclonal antibody blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including purification, functional assays, and antibody neutralization; replicated across subsequent studies\",\n      \"pmids\": [\"14522983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sialylated O-glycans (specifically sialylated core 1 structures: sialic acid plus Galbeta1,3GalNAc-Ser/Thr) on PDPN are critical for its platelet aggregation-inducing activity. Expression in CMP-sialic acid transporter-deficient (Lec2) and UDP-galactose transporter-deficient (Lec8) CHO cells abolished platelet aggregation, while N-glycan-deficient (Lec1) cells retained activity.\",\n      \"method\": \"Stable expression in glycosylation-deficient CHO cell mutants, platelet aggregation assays, lectin blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution in defined glycosylation-mutant cell lines with clear mechanistic readout\",\n      \"pmids\": [\"15231832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PDPN (PA2.26) is concentrated in actin-rich microvilli and plasma membrane projections (filopodia, lamellipodia, ruffles) where it colocalizes with ERM family proteins. Ezrin and moesin (but not radixin) co-immunoprecipitate with PA2.26. Ectopic expression in non-tumorigenic keratinocytes induces epithelial-fibroblastoid morphological conversion with increased plasma membrane extensions, actin cytoskeleton reorganization, redistribution of ezrin to cell-surface projections, and enhanced motility.\",\n      \"method\": \"Confocal and immunoelectron microscopy, co-immunoprecipitation, ectopic expression, cell motility assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional rescue with defined cellular phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"10574709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human PDPN (PA2.26) colocalizes with ezrin at the surface of tumor cells. Ectopic expression of human PDPN in HeLa cells and HaCaT keratinocytes promoted redistribution of ezrin to cell edges, formation of cell-surface protrusions, and reduced Ca2+-dependent cell-cell adhesiveness.\",\n      \"method\": \"Double immunofluorescence, confocal microscopy, ectopic expression, cell adhesion assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods but single lab, confirms prior ezrin interaction data\",\n      \"pmids\": [\"15515019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Three tandem repeats of the platelet aggregation-stimulating (PLAG) domain are conserved across mammalian PDPN homologues. Either the first or last PLAG domain is critical for platelet aggregation-inducing activity (not the middle domain), established by point mutagenesis. A conserved EDxxVTPG motif within the PLAG domains is critical for activity. The PLAG domain and its activity appeared after divergence of avians and mammals.\",\n      \"method\": \"Cloning of homologues, point mutagenesis, platelet aggregation assays, evolutionary analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis with functional readout, multiple species tested\",\n      \"pmids\": [\"16766141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PDPN (Aggrus) promotes pulmonary metastasis by inducing platelet aggregation. Point mutations at the platelet aggregation-stimulating domain residues Thr34 and Thr52 abolished both platelet aggregation and metastasis. Aggrus-expressing cells were covered with platelets and arrested in lung microvasculature 30 minutes after injection.\",\n      \"method\": \"Point mutagenesis, experimental and spontaneous mouse metastasis models, in vivo imaging\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis linked to both biochemical and in vivo metastasis phenotype\",\n      \"pmids\": [\"17392172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD9 (tetraspanin) forms a complex with PDPN (Aggrus) via CD9 transmembrane domains 1 and 2 (TM1 and TM2). CD9 and PDPN colocalize in low-density membrane fractions. CD9 expression inhibits PDPN-induced platelet aggregation and suppresses pulmonary metastasis; deleting TM1 and TM2 abolishes CD9's ability to interact with PDPN or suppress its activity.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutants, platelet aggregation assays, in vivo metastasis model, fractionation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP with domain mapping plus functional in vivo validation\",\n      \"pmids\": [\"18541721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PDPN promotes tumor growth and metastasis via direct interaction with platelet receptor CLEC-2. Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth in vivo. A neutralizing anti-Aggrus antibody (MS-1) that blocked Aggrus-CLEC-2 binding attenuated platelet aggregation, tumor cell growth, and metastasis.\",\n      \"method\": \"Knockdown, in vitro platelet aggregation assays, in vivo xenograft models, neutralizing antibody\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO/KD with multiple mechanistic readouts, antibody blockade confirms CLEC-2 interaction\",\n      \"pmids\": [\"23991201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The intracellular serines of PDPN regulate cell motility. Conversion of these serines to non-phosphorylatable alanine residues enhances cell migration, while conversion to phosphomimetic aspartate residues decreases cell migration. PKA (protein kinase A) can phosphorylate PDPN on these serines to decrease cell migration. PDPN expression in fibroblasts facilitates the motility and viability of neighboring melanoma cells in coculture.\",\n      \"method\": \"Site-directed mutagenesis, knockout mouse embryonic cells, cell migration assays, kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with defined phosphomimetic and phospho-null mutants on null background, functional migration readout\",\n      \"pmids\": [\"23530051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Both PKA and CDK5 can phosphorylate PDPN on its two conserved intracellular serine residues to inhibit cell motility. PKA and CDK5 cooperate to phosphorylate both serines and decrease cell migration.\",\n      \"method\": \"In vitro kinase assays, mutagenesis, cell motility assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay with mutagenesis, single lab\",\n      \"pmids\": [\"25959509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"E11/gp38 (PDPN) is the earliest osteocyte-selective protein expressed as osteoblasts differentiate into osteocytes, appearing first on forming dendritic processes. Fluid flow shear stress increases E11 mRNA expression in osteocyte-like cells. siRNA knockdown of E11 blocks the shear stress-induced increase in dendricity and dendrite elongation in MLO-Y4 cells, establishing a direct role for PDPN in osteocyte dendrite formation.\",\n      \"method\": \"siRNA knockdown, fluid flow shear stress assay, immunostaining, in vivo mechanical loading\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean siRNA KD with defined cellular phenotype (dendrite elongation), confirmed in vivo\",\n      \"pmids\": [\"16738320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Podoplanin protein levels are regulated post-translationally by calpain-mediated proteolysis. Treatment with the calpain inhibitor calpeptin causes podoplanin accumulation in tumor cell lines, while proteasome inhibition has no effect. In vitro experiments showed podoplanin is a direct substrate of calpain-1. A novel podoplanin isoform lacking the cytoplasmic YS dipeptide was identified via alternative splicing.\",\n      \"method\": \"Pharmacological inhibitors (calpeptin, lactacystin), in vitro calpain assay, Western blotting, RT-PCR\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro substrate assay plus pharmacological confirmation, single lab\",\n      \"pmids\": [\"19146981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IMP-3 (IGF2BP3) stabilizes PDPN mRNA through binding to the 3'UTR of PDPN, regulating PDPN protein levels. IMP-3 depletion downregulates PDPN and results in loss of extracellular matrix degradation and invadopodia function. TGF-β1 increases PDPN expression, which potentiates cancer invasion through invadopodia formation.\",\n      \"method\": \"siRNA knockdown, RNA in situ hybridization, 3'UTR reporter assay, xenograft model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus KD phenotype, but single lab\",\n      \"pmids\": [\"22859271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDPN silencing in thyroid cancer cells reduces ERM (ezrin, radixin, moesin) phosphorylation and decreases MMP2 and MMP9 activity, leading to reduced cell migration and invasion. PDPN is associated with the MAPK signaling pathway; inhibition of MEK1/2 or BRAF results in decreased PDPN expression and increased E/R/M phosphorylation. PDPN regulates actin cytoskeleton remodeling and cellular protrusions.\",\n      \"method\": \"siRNA knockdown, zymography, scratch test, Transwell assay, Western blotting, kinase inhibitors\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays but single lab, no reconstitution\",\n      \"pmids\": [\"30654768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD177 (neutrophil protein) was identified as a novel PDPN binding partner and functional antagonist using a high-throughput cell surface interaction platform. Quantitative phosphoproteomics of CAFs revealed PDPN's role in cell signaling, growth, and actomyosin contractility. CD177 recapitulates the phenotype observed in PDPN-deficient CAFs, acting as a functional antagonist.\",\n      \"method\": \"High-throughput cell surface interactome screen, quantitative phosphoproteomics, cellular functional assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — unbiased proteomics plus functional validation, single lab\",\n      \"pmids\": [\"34879110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UGRP1 binds PDPN on the cell surface and, upon binding, activates RhoA to enhance the interaction of IKKγ and IKKβ, which activates NF-κB and promotes expression of TLR2, MyD88, NOD2, and NLRP3, enhancing inflammatory cytokine secretion during S. pneumoniae infection. Blocking UGRP1-PDPN interaction or deleting UGRP1 protected mice from severe pneumococcal pneumonia. RhoA agonist in UGRP1-deficient mice restored IL-6 production.\",\n      \"method\": \"Co-IP, in vivo mouse infection model, genetic KO, RhoA agonist/antagonist, cytokine assays\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with mechanistic pathway placement, single lab\",\n      \"pmids\": [\"35652821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CircITGB6 (a TGFβ-induced circular RNA) enhances PDPN mRNA stability by directly interacting with IGF2BP3, promoting EMT and tumor metastasis. PDPN is identified as an EMT-promoting downstream effector of the circITGB6/IGF2BP3 axis.\",\n      \"method\": \"Gain/loss-of-function assays, RNA-protein interaction assays, in vivo metastasis models, siRNA knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA-protein interaction with functional in vivo validation, single lab\",\n      \"pmids\": [\"37898647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDPN promotes melanoma cell growth and metastasis through activation of the Wnt/β-catenin pathway. An antagonist peptide (CY12-RP2) targeting PDPN suppressed melanoma growth and metastasis by blocking EMT and Wnt/β-catenin pathway, and reversed immunosuppression by modulating immune cell populations.\",\n      \"method\": \"SPR assay (peptide-PDPN binding), in vivo xenograft/allograft models, Western blotting, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — SPR binding plus in vivo functional validation, single lab\",\n      \"pmids\": [\"38167452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDPN-expressing stromal cells interact with CLEC-2 on megakaryocyte progenitors via the PDPN/CLEC-2 axis to modulate megakaryocyte subtype differentiation, favoring MYLK4-positive HSC-regulating megakaryocytes over BMAL1-positive platelet-producing megakaryocytes. PDPN KO feeder cells reduced megakaryocyte number and ploidy and increased platelet production. This was confirmed using CLEC-2 conditional KO megakaryocytes.\",\n      \"method\": \"Co-culture with PDPN WT vs. KO stromal cell lines, CLEC-2 conditional KO, flow cytometry\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO of both PDPN and CLEC-2 with defined cellular phenotype, single lab\",\n      \"pmids\": [\"39615442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDPN promotes immune evasion in melanoma via β-catenin-mediated upregulation of PD-L1. Targeting PDPN with the inhibitory peptide CY12-RP2 reduced β-catenin-dependent PD-L1 expression, increased intratumoral CD8+ T cell infiltration and granzyme B production, and its antitumor efficacy was entirely dependent on CD8+ T cells in depletion experiments.\",\n      \"method\": \"Western blotting, ELISA, flow cytometry, in vivo depletion experiments, immunocompetent mouse models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (β-catenin/PD-L1) with in vivo CD8+ T cell depletion validation, single lab\",\n      \"pmids\": [\"41573582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ectopic expression of PA2.26 (PDPN) in premalignant keratinocytes induced destabilization of adherens junctions, downregulation of E- and P-cadherin protein (via proteolytic degradation), vimentin and K8 upregulation, and acquisition of a fully transformed and metastatic phenotype including lymphatic vessel infiltration and lymph node metastasis in nude mice.\",\n      \"method\": \"Ectopic expression, Western blotting, immunofluorescence, nude mouse transplantation, immunohistochemistry\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ectopic expression with defined molecular and in vivo phenotype, single lab\",\n      \"pmids\": [\"11092535\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDPN (podoplanin) is a mucin-type transmembrane glycoprotein that promotes tumor metastasis by inducing platelet aggregation through its sialylated PLAG domains binding to the platelet receptor CLEC-2; its cytoplasmic serines are phosphorylated by PKA and CDK5 to inhibit cell motility; it associates with ERM proteins (ezrin/moesin) to regulate actin cytoskeleton organization and cell migration; it promotes osteocyte dendrite elongation; its activity is antagonized by CD9 (which forms a transmembrane complex with PDPN) and by CD177; its protein levels are regulated post-translationally by calpain-1; and it activates downstream signaling through RhoA, Wnt/β-catenin, and MAPK pathways to drive invasion, EMT, immune evasion via PD-L1 upregulation, and cancer-associated fibroblast functions.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"PA2.26 (podoplanin/PDPN) is a mucin-like transmembrane glycoprotein concentrated in actin-rich microvilli and plasma membrane projections (filopodia, lamellipodia, ruffles) where it co-localizes with ERM family proteins; ezrin and moesin (but not radixin) co-immunoprecipitate with PA2.26. Ectopic expression in keratinocytes induces fibroblastoid morphological conversion, major actin cytoskeleton reorganization, redistribution of ezrin to cell-surface projections, and enhanced motility.\",\n      \"method\": \"Co-immunoprecipitation, confocal/immunoelectron microscopy, ectopic expression in keratinocytes with phenotypic readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus direct localization with functional consequence (motility), replicated in multiple cell systems\",\n      \"pmids\": [\"10574709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Aggrus/podoplanin (PDPN) is a platelet aggregation-inducing sialoglycoprotein; its platelet aggregation-stimulating (PLAG) domain containing O-glycosylated threonine residues (Thr34 and Thr52) is the critical determinant for platelet aggregation-inducing activity. Purified Aggrus induces platelet aggregation without requiring plasma components.\",\n      \"method\": \"Antibody-affinity purification of native protein, expression in CHO cells, point mutagenesis of PLAG domain threonines, platelet aggregation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — purification, functional assay, and mutagenesis identifying critical residues, foundational study\",\n      \"pmids\": [\"14522983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Sialylated O-glycans (specifically sialic acid plus Gal-β1,3-GalNAc-Ser/Thr, i.e., sialylated core 1 structure) on Aggrus/podoplanin are critical for its platelet aggregation-inducing activity. CMP-sialic acid transporter-deficient and UDP-galactose transporter-deficient CHO cells expressing Aggrus lost platelet aggregation activity, while N-glycan-deficient cells retained it.\",\n      \"method\": \"Stable expression in CHO glycosylation-deficient mutant cell lines (Lec1, Lec2, Lec8), lectin blotting, platelet aggregation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — reconstitution in defined glycosylation-deficient cells with orthogonal lectin blotting, clear mechanistic conclusion\",\n      \"pmids\": [\"15231832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human PA2.26/podoplanin co-localizes with ezrin at the surface of tumor cells and its presence in oral squamous cell carcinoma is associated with downregulation of membrane E-cadherin. Ectopic expression in HeLa and HaCaT cells promotes redistribution of ezrin to cell edges, formation of cell-surface protrusions, and reduced Ca2+-dependent cell-cell adhesiveness.\",\n      \"method\": \"Double immunofluorescence, confocal microscopy, ectopic expression with phenotypic readouts (protrusion formation, adhesion assay)\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — localization with functional consequence, single lab, multiple readouts\",\n      \"pmids\": [\"15515019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"E11/gp38 (podoplanin/PDPN) is selectively expressed in osteocytes and is required for dendrite elongation; fluid flow shear stress increases E11 mRNA in osteocyte-like cells (MLO-Y4), and siRNA knockdown of E11 blocks shear stress-induced dendricity and dendrite elongation.\",\n      \"method\": \"siRNA knockdown, fluid flow shear stress assay, MLO-Y4 osteocyte-like cell culture, in vivo mechanical loading\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean siRNA KD with specific morphological phenotype, confirmed in vivo, mechanosensory function defined\",\n      \"pmids\": [\"16738320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Podoplanin directly interacts in vitro and in vivo with ezrin (and moesin) through a cluster of basic amino acids within its cytoplasmic tail, primarily through the juxtamembrane dipeptide RK. This interaction is required for podoplanin-induced RhoA activation and epithelial-mesenchymal transition (EMT) in MDCK cells. Dominant-negative truncated ezrin or dominant-negative RhoA blocked these effects.\",\n      \"method\": \"In vitro pull-down, co-immunoprecipitation, GFP-tagged cytoplasmic tail mutants, RhoA activity assay (pull-down), dominant-negative constructs, fluorescence time-lapse video microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct in vitro interaction confirmed, mutagenesis of binding domain, epistasis via dominant-negatives, multiple orthogonal methods\",\n      \"pmids\": [\"17046996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Podoplanin promotes tumor cell invasion via downregulation of small Rho family GTPase activities leading to filopodia formation and collective cell migration, in a manner that does not require epithelial-mesenchymal transition (E-cadherin expression maintained).\",\n      \"method\": \"Overexpression in cultured human breast cancer cells, mouse pancreatic beta-cell carcinogenesis model, Rho GTPase activity assays, in vitro invasion assays, human cancer biopsy analysis\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems, Rho GTPase mechanistic assays, in vivo validation\",\n      \"pmids\": [\"16616332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The PLAG (platelet aggregation-stimulating) domain of Aggrus/podoplanin is conserved across mammalian species with three tandem repeats; the first or last (but not middle) PLAG domain is critical for platelet aggregation-inducing activity. Bovine Aggrus with a deletion in the first PLAG domain lacks platelet aggregation activity. Point mutations in PLAG domains confirmed their functional importance.\",\n      \"method\": \"Cross-species cDNA cloning, point mutagenesis, platelet aggregation assay, phylogenetic analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — systematic mutagenesis across species with functional platelet aggregation readout\",\n      \"pmids\": [\"16766141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PDPN/Aggrus promotes pulmonary metastasis by inducing platelet aggregation via its PLAG domain (specifically Thr34 and Thr52); point mutation at these residues abolishes both platelet aggregation and metastasis. Aggrus-expressing cells become covered with platelets and arrest in lung microvasculature within 30 minutes post-injection.\",\n      \"method\": \"Point mutagenesis, experimental and spontaneous metastasis mouse models, intravital observation of platelet-tumor cell interactions, aspirin treatment\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis with in vivo functional validation, mechanistic link between PLAG domain, platelet aggregation, and metastasis established\",\n      \"pmids\": [\"17392172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CLEC-2 is identified as the platelet receptor for podoplanin; their association is sialic acid-dependent (on O-glycans of podoplanin). Recombinant CLEC-2 inhibits platelet aggregation induced by podoplanin-expressing tumor cells or lymphatic endothelial cells, and CLEC-2-mediated signaling involves Src and phospholipase Cγ2 activation.\",\n      \"method\": \"Flow cytometry binding assay, recombinant CLEC-2 inhibition of platelet aggregation, signaling inhibitor studies (Src, PLCγ2)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding confirmed by flow cytometry, functional inhibition with recombinant receptor, signaling pathway defined; widely replicated\",\n      \"pmids\": [\"17616532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD9 (tetraspanin) forms a complex with Aggrus/podoplanin via transmembrane domains 1 and 2 (TM1 and TM2) of CD9. CD9 and Aggrus interact homophilically and co-localize in low-density membrane fractions. CD9 expression suppresses Aggrus-induced platelet aggregation and metastasis; deletion of TM1 and TM2 abolishes these inhibitory effects.\",\n      \"method\": \"Co-immunoprecipitation, low-density membrane fractionation, TM domain deletion constructs, platelet aggregation assay, experimental metastasis model\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, domain-deletion mutagenesis, functional platelet aggregation and in vivo metastasis readouts\",\n      \"pmids\": [\"18541721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Podoplanin expression is regulated post-translationally by calpain-mediated proteolysis; calpain-1 cleaves podoplanin in vitro, and calpain inhibition leads to podoplanin accumulation in tumor cells that transcribe but do not accumulate podoplanin protein. A novel podoplanin isoform lacking the cytoplasmic YS dipeptide (generated by alternative splicing) was identified; this YS motif is highly conserved across species.\",\n      \"method\": \"Western blot with protease inhibitors (calpeptin, lactacystin), in vitro calpain-1 cleavage assay, alternative splicing analysis\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro cleavage assay confirmed calpain as the protease; inhibitor studies in multiple cell lines\",\n      \"pmids\": [\"19146981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Podoplanin on lymphatic endothelial cells activates circulating platelets from the cardinal vein via CLEC-2 interaction, and this platelet activation is required for separation of the lymphatic from the blood vascular system during embryonic development. Platelet aggregates form at the separation zone in wild-type but not podoplanin-knockout embryos; the same blood-filled lymphatic phenotype is induced by podoplanin-blocking antibodies, aspirin, or kindlin-3 knockout (which impairs platelet aggregation).\",\n      \"method\": \"Podoplanin knockout mouse embryo analysis, aspirin treatment of pregnant mice, podoplanin-blocking antibody administration, kindlin-3 knockout, immunohistochemistry of embryonic platelet aggregates\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple independent genetic and pharmacological perturbations converge on same phenotype; epistasis between podoplanin and platelet activation established in vivo\",\n      \"pmids\": [\"20110424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IMP-3 (IGF2BP3) stabilizes PDPN mRNA through binding to the 3'UTR of PDPN, maintaining podoplanin levels required for functional invadopodia formation and extracellular matrix degradation in oral squamous cell carcinoma cells. IMP-3 depletion reduces PDPN mRNA stability and abolishes invadopodia-mediated ECM degradation. TGF-β1 increases PDPN expression, potentiating cancer invasion via invadopodia.\",\n      \"method\": \"RNA in situ hybridization with 3'UTR probe, luciferase reporter assay with PDPN 3'UTR, siRNA knockdown, Transwell invasion assay, xenograft model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — reporter assay establishes mRNA stabilization mechanism, functional invasion readout, in vivo validation\",\n      \"pmids\": [\"22859271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The two conserved intracellular serine residues of podoplanin (PDPN) can be phosphorylated by PKA (protein kinase A). Conversion of these serines to non-phosphorylatable alanines enhances cell migration, while conversion to phosphomimetic aspartates decreases cell migration, indicating that PKA-mediated phosphorylation of PDPN inhibits cell motility. PDPN expression in fibroblasts facilitates motility and viability of neighboring melanoma cells in co-culture.\",\n      \"method\": \"Knockout MEFs from Pdpn-null mice, site-directed mutagenesis (Ser→Ala and Ser→Asp), in vitro PKA phosphorylation assay, migration assays, co-culture experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro kinase assay plus mutagenesis of specific residues with migration phenotype on null background\",\n      \"pmids\": [\"23530051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aggrus/podoplanin promotes tumor growth in addition to metastasis through platelet-tumor interaction, platelet activation, and secretion of platelet-derived factors in vivo. Aggrus knockdown suppressed platelet-induced proliferation in vitro and tumor growth in vivo. The anti-Aggrus monoclonal antibody MS-1 suppresses Aggrus-CLEC-2 binding, platelet aggregation, and metastasis, and exhibits ADCC and CDC activities against Aggrus-positive tumors.\",\n      \"method\": \"siRNA knockdown, in vitro platelet co-culture proliferation assay, xenograft tumor growth model, antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — KD with defined in vitro and in vivo phenotypes, mechanism (platelet secretion) partially defined\",\n      \"pmids\": [\"23991201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Both PKA and CDK5 phosphorylate podoplanin (PDPN) on its two conserved intracellular serine residues, and they cooperate to phosphorylate both serines to decrease cell motility. CDK5 phosphorylation of PDPN was demonstrated in addition to the previously characterized PKA phosphorylation.\",\n      \"method\": \"In vitro kinase assays with PKA and CDK5, site-directed mutagenesis of intracellular serines, cell migration assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assays with mutagenesis confirming specific phosphorylation sites and functional consequence\",\n      \"pmids\": [\"25959509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDPN induces phosphorylation of ERM (ezrin, radixin, moesin) proteins and is associated with expression and activity of MMP-2 and MMP-9, actin cytoskeleton remodeling, and cellular protrusion formation in thyroid carcinoma cells. Inhibition of the MAPK pathway (with U0126 or PLX4720) decreases PDPN expression and increases E/R/M phosphorylation, reducing cell migration.\",\n      \"method\": \"siRNA knockdown of PDPN, Western blotting for ERM phosphorylation, gelatin zymography for MMP activity, scratch and Transwell migration/invasion assays, MAPK pathway inhibitors\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — KD with defined molecular phenotypes (ERM phosphorylation, MMP activity), mechanistic link to MAPK pathway established\",\n      \"pmids\": [\"30654768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD177 (neutrophil protein) is identified as a novel binding partner/receptor of PDPN on cancer-associated fibroblasts using a high-throughput cell surface interactome screen. CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs. Quantitative phosphoproteomics of PDPN-deficient CAFs reveals PDPN regulates cell signaling, growth, and actomyosin contractility.\",\n      \"method\": \"High-throughput extracellular interactome screen, quantitative phosphoproteomics (MS), cellular assays with PDPN-deficient CAFs and CD177 treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — unbiased interactome screen with functional validation and phosphoproteomics; single lab\",\n      \"pmids\": [\"34879110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"UGRP1 binds to cell-surface PDPN and activates RhoA, enhancing interaction of IKKγ and IKKβ to slightly activate NF-κB, which upregulates expression of TLR2, MyD88, NOD2, and NLRP3, thereby promoting inflammatory cytokine production (IL-6, IL-1β, TNF-α) in macrophages during Streptococcus pneumoniae infection. Blocking UGRP1-PDPN interaction protected mice from severe pneumococcal pneumonia.\",\n      \"method\": \"Co-immunoprecipitation (UGRP1-PDPN binding), RhoA activation assay, NF-κB reporter/Western blot, siRNA/antibody blocking, in vivo mouse infection model with RhoA agonist rescue\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP confirms binding, RhoA assay defines signaling step, in vivo rescue with RhoA agonist provides epistasis\",\n      \"pmids\": [\"35652821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The PDPN/CLEC-2 axis modulates megakaryocyte subtype differentiation; stromal PDPN interacting with CLEC-2 on megakaryocyte progenitors drives differentiation toward MYLK4-positive HSC-regulating megakaryocytes (with higher ploidy) at the expense of BMAL1-positive platelet-producing megakaryocytes, thus increasing megakaryocyte number while decreasing platelet output.\",\n      \"method\": \"Co-culture of hematopoietic progenitors with PDPN-expressing or PDPN-knockout immortalized stromal feeder cells, CLEC-2 conditional KO megakaryocytes, flow cytometry for megakaryocyte subtype markers and ploidy\",\n      \"journal\": \"Thrombosis research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO of both PDPN (stromal) and CLEC-2 (megakaryocyte) with defined subtype differentiation phenotype\",\n      \"pmids\": [\"39615442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MMP13 upregulates PDPN expression in endothelial cells, and PDPN mediates the platelet aggregation-promoting effect of MMP13 in HUVECs; PDPN-siRNA knockdown attenuates MMP13-induced platelet aggregation. In a DVT mouse model, MMP13 inhibition reduces PDPN expression and decreases deep vein thrombosis burden.\",\n      \"method\": \"MMP13 overexpression and siRNA knockdown in HUVECs, PDPN-siRNA knockdown, platelet aggregation assay, in vivo DVT mouse model with transcriptome analysis\",\n      \"journal\": \"Current medical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — siRNA epistasis (PDPN KD rescues MMP13 effect) with functional platelet aggregation readout and in vivo confirmation\",\n      \"pmids\": [\"38619683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDPN promotes melanoma cell growth and metastasis through activation of the Wnt/β-catenin pathway, and this pathway also mediates PDPN-dependent upregulation of PD-L1. A PDPN antagonist peptide (CY12-RP2) suppresses these effects, reduces tumor growth, restores CD8+ T-cell anti-tumor activity, and its efficacy is entirely CD8+ T-cell dependent.\",\n      \"method\": \"Functional assays (proliferation, migration, metastasis), Western blotting (β-catenin, PD-L1), in vivo xenograft and allogeneic mouse models, CD8+ T-cell depletion experiments, flow cytometry\",\n      \"journal\": \"Journal of experimental & clinical cancer research / Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — β-catenin/PD-L1 signaling established by WB, CD8-depletion epistasis; two papers converge on same pathway\",\n      \"pmids\": [\"38167452\", \"41573582\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Podoplanin (PDPN) is a mucin-type transmembrane glycoprotein that localizes to actin-rich membrane protrusions (filopodia, lamellipodia) by directly binding ERM proteins (ezrin/moesin) via basic residues in its cytoplasmic tail; this interaction activates RhoA to drive EMT, collective invasion, and dendrite elongation. Its sialylated O-glycan PLAG domain (containing Thr34/Thr52) engages the platelet receptor CLEC-2, inducing platelet aggregation that promotes hematogenous metastasis, blood-lymphatic separation during development, and megakaryocyte subtype polarization. Two conserved intracellular serines are phosphorylated by PKA and CDK5 to inhibit cell motility; calpain-1 mediates post-translational proteolysis of PDPN, while IMP-3 stabilizes PDPN mRNA. CD9 suppresses PDPN-CLEC-2 signaling by forming a complex with PDPN, and CD177 acts as an extracellular antagonistic binding partner; additionally, PDPN activates Wnt/β-catenin-mediated PD-L1 upregulation and, upon binding UGRP1, activates RhoA-NF-κB inflammatory signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDPN (podoplanin) is a mucin-type transmembrane glycoprotein that functions as a platelet aggregation-inducing factor and a regulator of actin cytoskeleton dynamics, with roles spanning tumor metastasis, immune modulation, and osteocyte dendrite formation. Its extracellular PLAG domains require sialylated O-glycans to engage the platelet receptor CLEC-2, triggering platelet aggregation that facilitates tumor cell arrest in the microvasculature and promotes pulmonary metastasis; this activity is antagonized by CD9, which binds PDPN via its transmembrane domains, and by CD177 [PMID:14522983, PMID:15231832, PMID:17392172, PMID:18541721, PMID:23991201, PMID:34879110]. Intracellularly, PDPN associates with ezrin and moesin to drive actin remodeling, plasma membrane protrusion formation, and cell migration, while phosphorylation of its conserved cytoplasmic serines by PKA and CDK5 inhibits motility; PDPN expression destabilizes adherens junctions, promotes EMT, and activates downstream Wnt/β-catenin and RhoA/NF-κB signaling [PMID:10574709, PMID:23530051, PMID:25959509, PMID:11092535, PMID:38167452, PMID:35652821]. PDPN protein levels are regulated post-translationally by calpain-1-mediated proteolysis and at the mRNA level through IGF2BP3-dependent stabilization of its 3′UTR [PMID:19146981, PMID:22859271, PMID:37898647].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that PDPN localizes to actin-rich membrane projections and physically associates with ERM proteins resolved how a small transmembrane glycoprotein could reorganize the cytoskeleton and promote cell motility.\",\n      \"evidence\": \"Co-immunoprecipitation with ezrin/moesin, confocal and immunoelectron microscopy, ectopic expression in keratinocytes\",\n      \"pmids\": [\"10574709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of PDPN–ERM interaction not defined\", \"Signaling intermediates between PDPN–ERM binding and actin remodeling unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrating that PDPN expression induces EMT hallmarks—cadherin downregulation, vimentin upregulation, and metastatic competence—established it as an active driver of malignant transformation rather than a passive tumor marker.\",\n      \"evidence\": \"Ectopic expression in premalignant keratinocytes with Western blotting, immunofluorescence, and nude mouse transplantation\",\n      \"pmids\": [\"11092535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cadherin proteolytic degradation downstream of PDPN not identified\", \"Whether EMT induction requires ERM binding was untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identifying PDPN as the tumor cell-surface factor responsible for platelet aggregation, and mapping a conserved O-glycosylated domain required for this activity, provided the first molecular mechanism linking PDPN to metastasis via platelet interaction.\",\n      \"evidence\": \"Affinity purification, cell expression assays, platelet aggregation assays, neutralizing antibody (8F11)\",\n      \"pmids\": [\"14522983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Platelet receptor for PDPN not yet identified\", \"In vivo metastatic relevance not yet tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Using glycosylation-deficient cell lines to show that sialylated core 1 O-glycans are essential for platelet aggregation defined the precise glycan modification required for PDPN's extracellular function.\",\n      \"evidence\": \"Stable expression in Lec2, Lec8, and Lec1 CHO mutant cells with platelet aggregation readout\",\n      \"pmids\": [\"15231832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether specific sialyltransferases are rate-limiting in vivo was unknown\", \"Glycan-receptor binding stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapping three tandem PLAG domains across mammalian homologues and showing that mutagenesis of the conserved EDxxVTPG motif abolished platelet aggregation established the modular structural logic of PDPN's extracellular activity; concurrently, PDPN was shown to be the earliest osteocyte-selective protein required for dendrite elongation, broadening its physiological roles beyond cancer.\",\n      \"evidence\": \"Point mutagenesis with aggregation assays across species (PLAG); siRNA knockdown under fluid flow shear stress in MLO-Y4 osteocyte-like cells (dendrite)\",\n      \"pmids\": [\"16766141\", \"16738320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic structure of PLAG domain–receptor interface not resolved\", \"Downstream signaling linking PDPN to dendrite extension in osteocytes not characterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that Thr34/Thr52 point mutations abolished both platelet aggregation and pulmonary metastasis in vivo causally linked PLAG domain glycosylation to the metastatic process.\",\n      \"evidence\": \"Point mutagenesis with experimental and spontaneous metastasis mouse models and intravital imaging\",\n      \"pmids\": [\"17392172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether blocking platelet aggregation is sufficient or whether additional PDPN functions contribute to metastasis was unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying CD9 as a transmembrane complex partner that antagonizes PDPN-induced platelet aggregation and metastasis revealed a cis-regulatory mechanism operating within the tumor cell membrane; separately, calpain-1 was identified as a post-translational regulator of PDPN protein levels.\",\n      \"evidence\": \"Co-IP with domain deletion mutants of CD9 TM1/TM2, in vivo metastasis model (CD9); pharmacological calpain inhibition plus in vitro calpain-1 substrate assay (calpain)\",\n      \"pmids\": [\"18541721\", \"19146981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD9 inhibits PDPN by steric blockade of CLEC-2 or conformational change unknown\", \"Calpain cleavage site on PDPN not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that IGF2BP3 (IMP-3) stabilizes PDPN mRNA via its 3′UTR identified a key upstream regulatory axis controlling PDPN expression during TGFβ-driven invasion and invadopodia formation.\",\n      \"evidence\": \"siRNA knockdown of IMP-3, 3′UTR reporter assay, xenograft model\",\n      \"pmids\": [\"22859271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific RNA motifs bound by IGF2BP3 in PDPN 3′UTR not defined\", \"Whether other RBPs co-regulate PDPN mRNA stability unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Two key advances: CLEC-2 was confirmed as the platelet receptor directly engaging PDPN, and phosphorylation of PDPN's cytoplasmic serines by PKA was shown to inhibit cell motility, revealing bidirectional regulation (extracellular glycan-dependent platelet activation and intracellular phosphorylation-dependent motility control).\",\n      \"evidence\": \"Neutralizing anti-PDPN antibody blocking CLEC-2 binding with in vivo xenograft validation; site-directed mutagenesis of cytoplasmic serines to phosphomimetic/null residues on KO background with migration assays\",\n      \"pmids\": [\"23991201\", \"23530051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of PDPN–CLEC-2 signaling in platelets not resolved\", \"In vivo relevance of serine phosphorylation to metastasis not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identifying CDK5 as a second kinase phosphorylating PDPN cytoplasmic serines, cooperating with PKA, established that multiple signaling inputs converge on PDPN to fine-tune cell motility.\",\n      \"evidence\": \"In vitro kinase assays with mutagenesis and cell motility assays\",\n      \"pmids\": [\"25959509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent regulation of CDK5 vs. PKA phosphorylation in vivo not explored\", \"Phosphatases that reverse PDPN phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linking PDPN silencing to reduced ERM phosphorylation and MMP2/9 activity in thyroid cancer cells, and showing MAPK pathway regulation of PDPN expression, placed PDPN within a signaling network connecting BRAF/MEK to cytoskeletal remodeling and matrix degradation.\",\n      \"evidence\": \"siRNA knockdown, zymography, Transwell assay, MEK1/2 and BRAF kinase inhibitors\",\n      \"pmids\": [\"30654768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PDPN directly activates ERM phosphorylation or acts indirectly unknown\", \"Generalizability beyond thyroid cancer cells not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery of CD177 as a second extracellular antagonist of PDPN, mimicking PDPN-deficient CAF phenotypes and altering phospho-signaling, expanded the repertoire of physiological PDPN inhibitors beyond CD9.\",\n      \"evidence\": \"High-throughput cell surface interaction screen, quantitative phosphoproteomics of CAFs, functional assays\",\n      \"pmids\": [\"34879110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface of CD177–PDPN not mapped\", \"In vivo relevance of CD177 antagonism in tumor stroma not demonstrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that UGRP1 binding to PDPN activates RhoA, which enhances IKKγ/IKKβ interaction and NF-κB-driven inflammatory cytokine expression during pneumococcal infection, established PDPN as an innate immune signaling receptor beyond its known roles in cancer.\",\n      \"evidence\": \"Co-IP, UGRP1 KO mouse infection model, RhoA agonist rescue of IL-6 in KO mice\",\n      \"pmids\": [\"35652821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PDPN directly activates RhoA or requires intermediate adaptors unknown\", \"Relevance to other infectious or inflammatory contexts not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying circITGB6 as a TGFβ-induced circular RNA that enhances PDPN mRNA stability via IGF2BP3 confirmed the IGF2BP3–PDPN regulatory axis and placed it downstream of a non-coding RNA layer of regulation during EMT.\",\n      \"evidence\": \"Gain/loss-of-function assays, RNA-protein interaction assays, in vivo metastasis models\",\n      \"pmids\": [\"37898647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether circITGB6 is the sole RNA scaffold for IGF2BP3–PDPN mRNA stabilization unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Two studies extended PDPN's downstream signaling: PDPN drives melanoma metastasis through Wnt/β-catenin pathway activation and β-catenin-dependent PD-L1 upregulation leading to immune evasion; separately, the PDPN/CLEC-2 axis on stromal cells was shown to modulate megakaryocyte subtype differentiation, expanding physiological roles to hematopoiesis.\",\n      \"evidence\": \"SPR binding assay plus in vivo xenograft/allograft models with antagonist peptide CY12-RP2 (melanoma); co-culture with PDPN KO stromal cells and CLEC-2 conditional KO megakaryocytes (megakaryopoiesis); in vivo CD8+ T cell depletion (immune evasion)\",\n      \"pmids\": [\"38167452\", \"39615442\", \"41573582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism by which PDPN activates β-catenin signaling not delineated\", \"Physiological relevance of PDPN/CLEC-2 megakaryocyte regulation in vivo not fully established\", \"Whether PD-L1 upregulation is universal across PDPN-expressing tumors unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PDPN's short cytoplasmic tail mechanistically couples to RhoA, Wnt/β-catenin, and MAPK pathways—and which adaptor proteins mediate these connections—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for PDPN or PDPN–CLEC-2 complex\", \"Adaptor proteins linking cytoplasmic tail to RhoA/β-catenin not identified\", \"Relative contribution of platelet-dependent vs. platelet-independent functions to metastasis in physiological settings not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 4, 5, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 3, 13]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 7, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 3, 6, 14]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 3, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [0, 1, 4, 5, 7, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 19]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 7, 17, 20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CLEC2\", \"CD9\", \"EZR\", \"MSN\", \"CD177\", \"UGRP1\", \"IGF2BP3\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Podoplanin (PDPN) is a mucin-type transmembrane glycoprotein that couples extracellular glycan-mediated receptor engagement to intracellular cytoskeletal remodeling, thereby governing platelet activation, cell motility, and tissue morphogenesis. Its extracellular sialylated O-glycan PLAG domains (centered on Thr34/Thr52) engage the platelet C-type lectin receptor CLEC-2 to induce platelet aggregation, a function essential for developmental blood–lymphatic vascular separation, hematogenous metastasis, megakaryocyte subtype polarization, and inflammatory signaling upon UGRP1 co-ligation [PMID:14522983, PMID:17616532, PMID:20110424, PMID:39615442, PMID:35652821]. The short cytoplasmic tail binds ERM proteins (ezrin/moesin) via juxtamembrane basic residues to activate RhoA, driving epithelial–mesenchymal transition, filopodia-based collective invasion, and osteocyte dendrite elongation; PKA and CDK5 phosphorylate two conserved intracellular serines to inhibit this motility program [PMID:17046996, PMID:16616332, PMID:16738320, PMID:25959509]. PDPN function is modulated by CD9, which suppresses CLEC-2 engagement via transmembrane domain interaction, by CD177, which acts as an extracellular antagonist on cancer-associated fibroblasts, and by calpain-1-mediated proteolytic turnover [PMID:18541721, PMID:34879110, PMID:19146981].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that PDPN is a membrane glycoprotein concentrated at actin-rich protrusions that physically associates with ERM proteins and remodels the cytoskeleton answered the foundational question of where PDPN acts and what immediate intracellular partners it engages.\",\n      \"evidence\": \"Co-immunoprecipitation of ezrin/moesin with PA2.26, confocal/immunoelectron microscopy in keratinocytes with ectopic expression\",\n      \"pmids\": [\"10574709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding site on PDPN not mapped\", \"RhoA pathway not yet implicated\", \"No glycan function addressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of the PLAG domain with its O-glycosylated Thr34/Thr52 as the critical determinant for platelet aggregation revealed the extracellular functional module of PDPN and established a mechanistic basis for its thrombogenic activity.\",\n      \"evidence\": \"Purified Aggrus/PDPN from CHO cells, point mutagenesis of PLAG threonines, platelet aggregation assay\",\n      \"pmids\": [\"14522983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Platelet receptor not yet identified\", \"In vivo relevance to metastasis untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that sialylated core 1 O-glycans—but not N-glycans—are required for platelet aggregation defined the glycan code that activates the platelet interaction, narrowing the molecular requirements for PLAG domain function.\",\n      \"evidence\": \"Expression in CHO glycosylation-deficient mutant lines (Lec1/Lec2/Lec8), lectin blotting, platelet aggregation\",\n      \"pmids\": [\"15231832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the platelet-side receptor still unknown\", \"Structural basis of glycan recognition unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapping the ERM-binding site to juxtamembrane basic residues and showing this interaction is required for RhoA activation and EMT established the signaling axis downstream of PDPN's cytoplasmic tail, while parallel work demonstrated PDPN drives collective invasion via modulation of Rho GTPases even without full EMT.\",\n      \"evidence\": \"In vitro pull-down/co-IP with cytoplasmic tail mutants, RhoA activity assays, dominant-negative ezrin/RhoA epistasis in MDCK cells; Rho GTPase assays and invasion assays in breast cancer cells and mouse pancreatic carcinogenesis\",\n      \"pmids\": [\"17046996\", \"16616332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of RhoA activation vs. other Rho family members unclear\", \"Structural basis of ERM–PDPN binding unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing that PDPN/E11 is required for osteocyte dendrite elongation under mechanical shear stress extended PDPN's cytoskeletal function beyond cancer to a physiological mechanosensory context.\",\n      \"evidence\": \"siRNA knockdown in MLO-Y4 osteocyte-like cells, fluid flow shear stress assays, in vivo mechanical loading\",\n      \"pmids\": [\"16738320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling pathway in osteocytes not fully delineated\", \"Whether ERM binding is required for dendricity not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of CLEC-2 as the platelet receptor for PDPN and demonstration that their sialic acid-dependent interaction triggers Src/PLCγ2 signaling on platelets resolved the receptor–ligand pair governing PDPN-induced platelet activation, while in vivo mutagenesis of PLAG Thr34/Thr52 proved this axis drives pulmonary metastasis.\",\n      \"evidence\": \"Flow cytometry binding, recombinant CLEC-2 inhibition of platelet aggregation, Src/PLCγ2 inhibitor studies; PLAG point mutant cells in experimental metastasis mouse models with intravital imaging\",\n      \"pmids\": [\"17616532\", \"17392172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of PDPN–CLEC-2 complex not available\", \"Whether CLEC-2 is the sole platelet receptor not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that CD9 complexes with PDPN through its transmembrane domains and suppresses CLEC-2-dependent platelet aggregation and metastasis identified the first negative cis-regulator of PDPN, while calpain-1 was shown to mediate PDPN proteolytic turnover, revealing a second layer of post-translational control.\",\n      \"evidence\": \"Reciprocal co-IP, TM domain deletion mutagenesis, platelet aggregation and metastasis assays; in vitro calpain-1 cleavage, calpain inhibitor accumulation studies\",\n      \"pmids\": [\"18541721\", \"19146981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of CD9–PDPN TM interaction unknown\", \"Calpain cleavage site on PDPN not mapped\", \"Physiological triggers of calpain-mediated PDPN turnover undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic and pharmacological ablation of PDPN–CLEC-2 signaling in mouse embryos producing blood-filled lymphatics established the physiological requirement for this axis in blood–lymphatic vascular separation during development.\",\n      \"evidence\": \"Podoplanin-knockout embryos, blocking antibodies, aspirin treatment, kindlin-3 KO; immunohistochemistry of platelet aggregates at separation zone\",\n      \"pmids\": [\"20110424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream lymphatic-intrinsic signaling consequences not addressed\", \"Whether platelet aggregation is sufficient or other PDPN functions contribute is unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that PKA phosphorylates the two conserved intracellular serines of PDPN to inhibit motility—on a Pdpn-null background—defined a kinase-dependent off-switch for PDPN-driven migration, later extended to CDK5 cooperation.\",\n      \"evidence\": \"In vitro PKA and CDK5 kinase assays, phosphomimetic/non-phosphorylatable mutagenesis on Pdpn-null MEFs, migration assays\",\n      \"pmids\": [\"23530051\", \"25959509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo phosphorylation stoichiometry unknown\", \"Phosphatase that reverses this modification not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of IMP-3/IGF2BP3 as a stabilizer of PDPN mRNA via its 3′UTR revealed a post-transcriptional regulatory layer that sustains PDPN levels required for invadopodia formation and extracellular matrix degradation.\",\n      \"evidence\": \"3′UTR luciferase reporter, RNA in situ hybridization, siRNA knockdown with invasion and xenograft readouts in oral SCC cells\",\n      \"pmids\": [\"22859271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Exact IMP-3 binding site in PDPN 3′UTR not mapped\", \"Other RNA-binding proteins that regulate PDPN mRNA not explored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"High-throughput interactome screening identified CD177 as an extracellular antagonist of PDPN on cancer-associated fibroblasts, phenocopying PDPN loss and revealing a trans-cellular regulatory mechanism in the tumor stroma.\",\n      \"evidence\": \"Extracellular interactome screen, quantitative phosphoproteomics of PDPN-deficient CAFs, functional assays with recombinant CD177\",\n      \"pmids\": [\"34879110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding interface between CD177 and PDPN not mapped\", \"Physiological relevance in non-tumor contexts untested\", \"Single-lab finding awaiting independent replication\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that UGRP1 binds PDPN to activate RhoA–NF-κB signaling and amplify innate immune receptor expression in macrophages during pneumococcal infection extended PDPN function to inflammatory innate immunity beyond its established roles in platelets and motility.\",\n      \"evidence\": \"Co-IP of UGRP1–PDPN, RhoA activity assay, NF-κB reporter, siRNA/antibody blocking, in vivo mouse pneumonia model with RhoA agonist rescue\",\n      \"pmids\": [\"35652821\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PDPN on macrophages signals via ERM in this context not tested\", \"Specificity of UGRP1 for PDPN versus other receptors not fully excluded\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Recent work revealed that PDPN–CLEC-2 signaling directs megakaryocyte subtype differentiation and that PDPN activates Wnt/β-catenin to upregulate PD-L1, linking PDPN to hematopoietic lineage decisions and immune evasion.\",\n      \"evidence\": \"PDPN-KO and CLEC-2-cKO co-culture systems with megakaryocyte progenitors; β-catenin/PD-L1 Western blotting, CD8+ T-cell depletion epistasis in melanoma models\",\n      \"pmids\": [\"39615442\", \"38167452\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Wnt/β-catenin activation mechanism by PDPN not elucidated at the molecular level\", \"Whether megakaryocyte subtype polarization occurs in vivo in bone marrow niches not confirmed\", \"Structural basis of PDPN antagonist peptide CY12-RP2 binding unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of the PDPN–CLEC-2 complex, how PDPN simultaneously engages ERM proteins and activates distinct downstream pathways (RhoA, Wnt/β-catenin, NF-κB) in different cell types, and the identity of phosphatases that reverse PKA/CDK5-mediated inhibition of PDPN motility function.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of PDPN or its complexes\", \"Cell-type-specific signaling logic downstream of PDPN not resolved\", \"Calpain cleavage site and degradation kinetics in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 3, 5, 6]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 9, 12, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 6, 17, 22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 5, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 2, 8, 9, 12, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 15, 22]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [19, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 9, 19, 22]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 20]}\n    ],\n    \"complexes\": [\n      \"PDPN–CD9 complex\",\n      \"PDPN–ERM complex\"\n    ],\n    \"partners\": [\n      \"CLEC2\",\n      \"EZR\",\n      \"MSN\",\n      \"CD9\",\n      \"CD177\",\n      \"UGRP1\",\n      \"IGF2BP3\",\n      \"CAPN1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}