{"gene":"PDPN","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":1999,"finding":"PA2.26 (PDPN) is a mucin-like transmembrane glycoprotein that colocalizes with ERM (ezrin, radixin, moesin) family proteins in actin-rich microvilli and plasma membrane projections; ezrin and moesin (but not radixin) can be co-immunoprecipitated with PA2.26. Ectopic expression of PA2.26 in nontumorigenic keratinocytes induces epithelial-fibroblastoid morphological conversion with increased plasma membrane extensions, major reorganization of the actin cytoskeleton, redistribution of ezrin to cell-surface projections, and enhanced motility.","method":"Co-immunoprecipitation, confocal/immunoelectron microscopy, ectopic expression in keratinocytes with functional readouts","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple orthogonal methods (Co-IP + microscopy + functional overexpression assay) in a single focused study","pmids":["10574709"],"is_preprint":false},{"year":2000,"finding":"Ectopic expression of PA2.26 (PDPN) in premalignant MCA3D keratinocytes leads to destabilization of adherens junctions (downregulation of E- and P-cadherin protein via proteolytic degradation), loss of cortical actin, vimentin/K8 upregulation, K14 downregulation, and acquisition of a fully transformed, metastatic phenotype including lymphatic invasion and regional lymph node metastases in nude mice.","method":"Stable transfection, Western blot, immunofluorescence, xenograft tumor transplantation","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Western blot, immunofluorescence, in vivo xenograft) in one focused study establishing functional mechanism","pmids":["11092535"],"is_preprint":false},{"year":2003,"finding":"Aggrus/PDPN (T1alpha) directly induces platelet aggregation without requiring plasma components. The platelet aggregation-stimulating (PLAG) domain bearing putative O-glycosylated threonine residues is the critical determinant; an 8F11 neutralizing monoclonal antibody targeting this domain suppresses tumor-induced platelet aggregation.","method":"Protein purification, platelet aggregation assay, monoclonal antibody neutralization, expression in CHO cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro platelet aggregation reconstitution, domain mapping with antibody neutralization, replicated by multiple subsequent studies","pmids":["14522983"],"is_preprint":false},{"year":2004,"finding":"Sialylated O-glycans (specifically sialylated core 1 structures: sialic acid plus Galβ1,3GalNAc-Ser/Thr) on Aggrus/PDPN are critical for its platelet aggregation-inducing activity. Expression in CMP-sialic acid transporter-deficient (Lec2) or UDP-galactose transporter-deficient (Lec8) CHO cells abolished platelet aggregation, while N-glycan-deficient (Lec1) cells retained activity.","method":"Stable expression in glycosylation-deficient CHO cell mutants, platelet aggregation assay, lectin blotting","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted function in defined glycosylation-deficient cell lines with multiple lectins confirming glycan structure; orthogonal methods","pmids":["15231832"],"is_preprint":false},{"year":2005,"finding":"Human PA2.26/PDPN colocalizes with ezrin at the cell surface in oral squamous cell carcinoma cells. 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 functional assays","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — colocalization plus functional overexpression, single lab but multiple orthogonal methods","pmids":["15515019"],"is_preprint":false},{"year":2006,"finding":"The PLAG domain of Aggrus/PDPN is conserved across mammalian homologues (rat, hamster, dog, bovine, human, mouse) and contains three tandem repeats. Point mutation shows that either the first or last (but not the middle) PLAG domain is critical for platelet aggregation-inducing activity. Bovine Aggrus with a sporadic deletion in the first PLAG domain lacks platelet aggregation activity.","method":"cDNA cloning, site-directed mutagenesis, platelet aggregation assay, sequence analysis","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis coupled with functional platelet aggregation assay, identifying specific residues required for activity","pmids":["16766141"],"is_preprint":false},{"year":2006,"finding":"E11/gp38 (PDPN) is the earliest osteocyte-selective protein expressed during osteoblast-to-osteocyte differentiation. Fluid flow shear stress increases E11 mRNA in osteocyte-like MLO-Y4 cells. siRNA knockdown of E11 blocks shear-stress-induced dendrite elongation in MLO-Y4 cells. Mechanical load in vivo increases E11 expression in osteocytes. These results establish E11/gp38 as functionally required for mechanically-stimulated osteocyte dendrite elongation.","method":"siRNA knockdown, fluid flow shear stress assay, in vivo mechanical loading, immunostaining, RT-PCR","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with specific cellular phenotype (dendrite elongation), confirmed in vitro and in vivo with multiple orthogonal methods","pmids":["16738320"],"is_preprint":false},{"year":2007,"finding":"Aggrus/podoplanin promotes pulmonary metastasis by inducing platelet aggregation. CHO cells expressing Aggrus show platelet coating and lung microvasculature arrest within 30 minutes of injection. Point mutations at Thr34 and Thr52 in the PLAG domain abolish both platelet aggregation and metastasis. Aspirin treatment reduces metastatic foci.","method":"In vivo experimental and spontaneous metastasis mouse models, point mutagenesis (Thr34/Thr52), platelet aggregation assay, drug treatment","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of specific residues with coupled in vivo metastasis and in vitro platelet aggregation assays; replicated across multiple models","pmids":["17392172"],"is_preprint":false},{"year":2008,"finding":"CD9 (tetraspanin) forms a complex with Aggrus/podoplanin via its transmembrane domains 1 and 2 (TM1 and TM2). CD9 and Aggrus colocalize in low-density membrane fractions. CD9 expression inhibits Aggrus-induced platelet aggregation and pulmonary metastasis; deletion of TM1 and TM2 abolishes this inhibition and also disrupts CD9 homophilic interaction and low-density membrane localization.","method":"Co-immunoprecipitation, domain deletion mutagenesis, platelet aggregation assay, in vivo metastasis assay, membrane fractionation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — reciprocal Co-IP with domain mapping, functional validation in vitro and in vivo, multiple orthogonal methods in single study","pmids":["18541721"],"is_preprint":false},{"year":2008,"finding":"Podoplanin/PA2.26 protein levels are regulated post-translationally by calpain-mediated proteolysis. Calpain-1 cleaves podoplanin in vitro; treatment with calpain inhibitor calpeptin (but not the proteasome inhibitor lactacystin) causes podoplanin accumulation in multiple tumor cell lines that transcribe PDPN but show little protein.","method":"In vitro calpain cleavage assay, pharmacological inhibition (calpeptin vs lactacystin), Western blot","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay showing calpain-1 cleaves PDPN, supported by pharmacological rescue experiments","pmids":["19146981"],"is_preprint":false},{"year":2012,"finding":"IMP-3 (IGF2BP3) stabilizes the PDPN mRNA via interaction with the 3'UTR, maintaining PDPN expression required for functional invadopodia formation and extracellular matrix degradation in oral squamous cell carcinoma cells. IMP-3 depletion reduces PDPN mRNA levels and abolishes ECM degradation activity despite intact invadopodia structure.","method":"siRNA knockdown, RNA in situ hybridization with 3'UTR probe, luciferase reporter assay with PDPN 3'UTR, xenograft model","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter assay and ISH establish mRNA stabilization mechanism, plus functional in vivo validation; single lab","pmids":["22859271"],"is_preprint":false},{"year":2013,"finding":"Aggrus/podoplanin directly binds to the platelet receptor CLEC-2, and this interaction mediates platelet aggregation, platelet-induced tumor cell proliferation, and pulmonary metastasis. Anti-Aggrus antibody MS-1 blocks Aggrus-CLEC-2 binding and suppresses both metastasis and tumor growth in vivo. Aggrus knockdown reduces platelet-induced proliferation in vitro.","method":"Binding assay (Aggrus-CLEC-2), anti-Aggrus neutralizing monoclonal antibody, siRNA knockdown, in vivo xenograft/metastasis models","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay identifying CLEC-2 as receptor, neutralizing antibody and siRNA knockdown with in vitro and in vivo functional readouts; replicated across studies","pmids":["23991201"],"is_preprint":false},{"year":2013,"finding":"The two conserved intracellular serine residues of PDPN can be phosphorylated by PKA (protein kinase A). Conversion of these serines to non-phosphorylatable alanine enhances cell migration, while conversion to phosphomimetic aspartate decreases cell migration. PDPN expression in fibroblasts facilitates motility and viability of co-cultured melanoma cells.","method":"Pdpn knockout mouse embryonic fibroblasts, site-directed mutagenesis (Ser→Ala and Ser→Asp), PKA phosphorylation assay, cell migration assays, co-culture","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis on null background, in vitro kinase assay, functional migration readouts; multiple orthogonal approaches in single study","pmids":["23530051"],"is_preprint":false},{"year":2014,"finding":"Podoplanin (gp38) in rheumatoid arthritis synovial fibroblasts interacts with the platelet receptor CLEC-2 in vivo. gp38 silencing in synovial fibroblasts reduces IL-6 and IL-8 gene expression induced by fibroblast-platelet interaction, but does not affect fibroblast migration or invasion.","method":"gp38 siRNA silencing in cultured synovial fibroblasts, platelet-fibroblast co-culture, gene expression analysis, immunohistochemistry","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with specific cytokine readout in co-culture, single lab; negative result for migration/invasion also noted","pmids":["24932813"],"is_preprint":false},{"year":2015,"finding":"Both PKA and CDK5 phosphorylate PDPN on its two conserved intracellular serine residues, and they cooperate to phosphorylate both residues to decrease cell motility. CDK5 was identified as a new PDPN kinase in addition to PKA.","method":"In vitro kinase assays with PKA and CDK5, site-directed mutagenesis of individual serine residues, cell motility assays","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro kinase assays with mutagenesis of specific residues, functional motility readout; extends prior mechanistic work","pmids":["25959509"],"is_preprint":false},{"year":2019,"finding":"PDPN promotes invasiveness in BcPAP papillary thyroid carcinoma cells by regulating ezrin/radixin/moesin (E/R/M) protein phosphorylation, MMP-2 and MMP-9 expression/activity, actin cytoskeleton remodeling, and cellular protrusion formation. PDPN expression is associated with the MAPK signaling pathway; MAPK inhibition decreases PDPN expression, increases E/R/M phosphorylation, and reduces cell migration.","method":"siRNA knockdown, scratch/Transwell invasion assays, zymography, Western blot, MAPK pathway inhibitors (U0126, PLX4720)","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with multiple orthogonal readouts (invasion, MMP activity, ERM phosphorylation), single lab","pmids":["30654768"],"is_preprint":false},{"year":2021,"finding":"CD177 (neutrophil protein) is a novel cell-surface binding partner of PDPN on cancer-associated fibroblasts, identified by high-throughput cell surface interactome screening. CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs. Quantitative phosphoproteomics of CAFs links PDPN to cell signaling, growth, and actomyosin contractility pathways.","method":"High-throughput cell surface protein interaction screen, quantitative phosphoproteomics, cellular functional assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased interactome screen plus phosphoproteomics and functional antagonist assays; single lab, novel receptor identification","pmids":["34879110"],"is_preprint":false},{"year":2024,"finding":"PDPN+ cancer-associated fibroblasts in colorectal cancer maintain CAF heterogeneity and promote angiogenesis via an autocrine PDPN/CCL2/STAT3 feedback loop. NF-κB p65 binds the CCL2 promoter to induce CCL2 secretion; paracrine CCL2 activates STAT3 in endothelial cells. CCL2 interacts with its non-classical receptor ACKR1 on endothelial cells to mediate pro-angiogenic effects. STAT3 inhibitor WP1066 blocks both the feedback loop in CAFs and STAT3 in endothelial cells.","method":"Single-cell analysis, ChIP/promoter binding assay (p65 on CCL2 promoter), CCL2 neutralizing antibody, AKT inhibitor, in vivo tumor growth assays","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding assay plus functional antibody/inhibitor experiments and in vivo validation; single lab","pmids":["39115624"],"is_preprint":false}],"current_model":"PDPN (podoplanin/Aggrus) is a mucin-type transmembrane sialoglycoprotein that promotes cell migration and tumor metastasis by: (1) interacting via its extracellular PLAG domain (bearing critical sialylated O-glycans on Thr34/Thr52) with the platelet receptor CLEC-2 to induce platelet aggregation and facilitate hematogenous metastasis; (2) engaging ERM proteins (ezrin/moesin) at the cell surface to remodel the actin cytoskeleton, destabilize adherens junctions, and drive cell motility; (3) having its intracellular serine residues phosphorylated by PKA and CDK5 to inhibit cell motility; (4) undergoing post-translational regulation by calpain-1-mediated proteolysis; (5) being negatively regulated by complex formation with CD9 (via TM1/TM2) and by CD177 (a functional antagonist); and (6) in osteocytes, being required for mechanically-stimulated dendrite elongation downstream of fluid flow shear stress."},"narrative":{"mechanistic_narrative":"PDPN (podoplanin/Aggrus/PA2.26/E11/gp38) is a mucin-type transmembrane sialoglycoprotein that drives cell migration, tumor invasion, and hematogenous metastasis while also serving differentiated tissue functions such as mechanically stimulated osteocyte dendrite formation [PMID:10574709, PMID:14522983, PMID:16738320]. At the cell surface, PDPN couples to the actin cytoskeleton by associating with ERM proteins ezrin and moesin, redistributing ezrin to membrane projections, remodeling cortical actin, destabilizing E-/P-cadherin adherens junctions, and converting epithelial cells to a motile, fibroblastoid, metastatic phenotype [PMID:10574709, PMID:11092535, PMID:15515019]; in carcinoma cells it regulates ERM phosphorylation together with MMP-2/MMP-9 activity to promote invadopodia-driven matrix degradation and invasion [PMID:30654768]. Its prometastatic activity depends on a conserved extracellular PLAG domain carrying sialylated core-1 O-glycans on Thr34/Thr52, which directly engages the platelet receptor CLEC-2 to trigger platelet aggregation, tumor cell coating, microvascular arrest, and platelet-induced tumor proliferation [PMID:14522983, PMID:15231832, PMID:16766141, PMID:17392172, PMID:23991201]. PDPN cytoplasmic function is controlled by phosphorylation of two conserved intracellular serines by PKA and CDK5, which cooperatively suppress motility [PMID:23530051, PMID:25959509]. PDPN abundance and signaling are further tuned post-transcriptionally and post-translationally by IMP-3 (IGF2BP3)-mediated mRNA stabilization, calpain-1 proteolysis, inhibitory complex formation with the tetraspanin CD9, and antagonism by CD177 [PMID:19146981, PMID:22859271, PMID:18541721, PMID:34879110]. In the tumor stroma, PDPN+ cancer-associated fibroblasts sustain a pro-angiogenic CCL2/STAT3 feedback program [PMID:39115624].","teleology":[{"year":1999,"claim":"Established that PDPN is not a passive surface marker but a cytoskeletal organizer, linking it physically to ERM proteins and to actin-based motility.","evidence":"Reciprocal Co-IP, confocal/immunoelectron microscopy, and ectopic expression in keratinocytes","pmids":["10574709"],"confidence":"High","gaps":["Did not define the ERM-binding motif on PDPN","Did not link ERM engagement to in vivo phenotypes"]},{"year":2000,"claim":"Showed that PDPN expression alone confers a transformed, lymphatically invasive, metastatic phenotype via adherens junction destabilization.","evidence":"Stable transfection, Western blot, immunofluorescence, and xenograft transplantation in nude mice","pmids":["11092535"],"confidence":"High","gaps":["Mechanism of cadherin proteolytic degradation not identified","Surface receptor mediating metastasis not yet known"]},{"year":2003,"claim":"Defined the platelet aggregation-stimulating (PLAG) domain as the functional determinant of PDPN-induced platelet aggregation, independent of plasma factors.","evidence":"Protein purification, platelet aggregation assay, neutralizing antibody (8F11), and CHO expression","pmids":["14522983"],"confidence":"High","gaps":["Platelet receptor not identified","Specific glycan requirement not yet resolved"]},{"year":2004,"claim":"Resolved the glycan code for activity, showing sialylated core-1 O-glycans (not N-glycans) are required for platelet aggregation.","evidence":"Expression in glycosylation-deficient CHO mutants (Lec1/Lec2/Lec8) with platelet aggregation and lectin blotting","pmids":["15231832"],"confidence":"High","gaps":["Did not map which threonines carry the critical glycans","Glycosyltransferases responsible not identified"]},{"year":2006,"claim":"Mapped PLAG-domain architecture, showing tandem repeats with the first or last (not middle) repeat critical for platelet aggregation.","evidence":"cDNA cloning across mammals, site-directed mutagenesis, and platelet aggregation assays","pmids":["16766141"],"confidence":"High","gaps":["Single critical threonine residues not yet pinpointed","Structural basis of repeat redundancy unknown"]},{"year":2006,"claim":"Extended PDPN function beyond cancer, establishing it as required for mechanically stimulated osteocyte dendrite elongation.","evidence":"siRNA knockdown in MLO-Y4 cells, fluid flow shear stress, and in vivo mechanical loading","pmids":["16738320"],"confidence":"High","gaps":["Signaling pathway downstream of shear stress to PDPN not defined","Whether ERM/CLEC-2 axes operate in osteocytes unknown"]},{"year":2007,"claim":"Tied platelet aggregation mechanistically to metastasis, identifying Thr34/Thr52 as the critical glycosylated residues and showing aspirin reduces metastasis.","evidence":"In vivo metastasis models, Thr34/Thr52 point mutagenesis, platelet aggregation assays, and drug treatment","pmids":["17392172"],"confidence":"High","gaps":["Platelet receptor still unidentified at this stage","Contribution of non-platelet mechanisms to metastasis not separated"]},{"year":2008,"claim":"Identified CD9 as a negative regulator forming a TM1/TM2-dependent complex that suppresses PDPN-driven platelet aggregation and metastasis.","evidence":"Co-IP with domain deletion mutagenesis, membrane fractionation, and in vitro/in vivo assays","pmids":["18541721"],"confidence":"High","gaps":["Mechanism by which CD9 sterically blocks CLEC-2 engagement not resolved","Physiological contexts of CD9-PDPN balance unclear"]},{"year":2008,"claim":"Established that PDPN protein levels are set post-translationally, with calpain-1 cleaving PDPN to limit surface abundance.","evidence":"In vitro calpain cleavage assay, calpeptin vs lactacystin pharmacology, and Western blot","pmids":["19146981"],"confidence":"High","gaps":["Cleavage site on PDPN not mapped","Physiological trigger for calpain processing unknown"]},{"year":2012,"claim":"Revealed post-transcriptional control of PDPN by IMP-3 (IGF2BP3), linking mRNA stability to invadopodia-mediated matrix degradation.","evidence":"siRNA knockdown, 3'UTR ISH and luciferase reporter, and xenograft model","pmids":["22859271"],"confidence":"Medium","gaps":["Direct IMP-3 binding site on the 3'UTR not finely mapped","Single-lab study"]},{"year":2013,"claim":"Closed the long-standing gap by identifying CLEC-2 as the direct platelet receptor for PDPN and connecting it to platelet-induced tumor proliferation.","evidence":"Direct binding assay, neutralizing antibody MS-1, siRNA knockdown, and in vivo xenograft/metastasis models","pmids":["23991201"],"confidence":"High","gaps":["Structural stoichiometry of PDPN-CLEC-2 not defined here","Relative weight of proliferation vs aggregation in vivo unclear"]},{"year":2013,"claim":"Defined intracellular regulation of PDPN motility function, showing PKA phosphorylation of two conserved serines suppresses migration.","evidence":"Pdpn-null MEFs, Ser→Ala/Asp mutagenesis, PKA kinase assay, and migration/co-culture assays","pmids":["23530051"],"confidence":"High","gaps":["How serine phosphorylation alters ERM coupling not resolved","Upstream signals activating PKA toward PDPN unknown"]},{"year":2014,"claim":"Generalized PDPN-CLEC-2 signaling to inflammatory stroma, showing synovial fibroblast PDPN drives platelet-induced IL-6/IL-8 without affecting migration.","evidence":"gp38 siRNA silencing in synovial fibroblasts, platelet co-culture, and gene expression analysis","pmids":["24932813"],"confidence":"Medium","gaps":["Signaling pathway from PDPN-platelet contact to cytokine induction not mapped","Negative migration result limits generalization"]},{"year":2015,"claim":"Refined the kinase control of PDPN by identifying CDK5 as a second kinase cooperating with PKA on both serines to suppress motility.","evidence":"In vitro PKA and CDK5 kinase assays with single-residue mutagenesis and motility assays","pmids":["25959509"],"confidence":"High","gaps":["Spatiotemporal coordination of the two kinases in cells not defined","Phosphatase counteracting these sites unknown"]},{"year":2019,"claim":"Linked PDPN to upstream MAPK signaling and downstream MMP activity in thyroid carcinoma invasion through ERM phosphorylation control.","evidence":"siRNA knockdown, invasion assays, zymography, and MAPK inhibitors (U0126, PLX4720)","pmids":["30654768"],"confidence":"Medium","gaps":["Direct mechanism connecting PDPN to MMP transcription unclear","Single-lab, single-cell-line study"]},{"year":2021,"claim":"Identified CD177 as a novel surface binding partner acting as a functional antagonist of PDPN on cancer-associated fibroblasts.","evidence":"High-throughput surface interactome screen, quantitative phosphoproteomics, and functional CAF assays","pmids":["34879110"],"confidence":"Medium","gaps":["Mechanism of CD177 antagonism not resolved","Interaction not validated by reciprocal structural/biochemical means"]},{"year":2024,"claim":"Showed PDPN+ CAFs drive tumor angiogenesis via an autocrine PDPN/CCL2/STAT3 feedback loop signaling to endothelial cells through ACKR1.","evidence":"Single-cell analysis, p65 ChIP on CCL2 promoter, CCL2 neutralization, and in vivo tumor assays","pmids":["39115624"],"confidence":"Medium","gaps":["How PDPN initiates the p65/CCL2 program mechanistically not defined","Single-lab study"]},{"year":null,"claim":"The structural basis of the PDPN-CLEC-2 interface, how intracellular serine phosphorylation reprograms ERM coupling, and how the competing regulators (CD9, CD177, calpain-1, IMP-3) are integrated in vivo remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No high-resolution structure of full-length PDPN or its receptor complexes","Integration of post-transcriptional, proteolytic, and phosphorylation controls into a single regulatory model is undefined","Tissue-specific roles (osteocyte vs tumor vs synovial) not mechanistically unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,4,15]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[11,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,15]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[2,7,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,7,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,14,17]}],"complexes":[],"partners":["CLEC-2","EZR","MSN","CD9","CD177","IGF2BP3","CAPN1","CDK5"],"other_free_text":[]}},"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; PROCR","url":"https://www.omim.org/entry/600646"},{"mim_id":"177075","title":"MAF bZIP TRANSCRIPTION FACTOR; MAF","url":"https://www.omim.org/entry/177075"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"placenta","ntpm":127.2}],"url":"https://www.proteinatlas.org/search/PDPN"},"hgnc":{"alias_symbol":["T1A-2","Gp38","aggrus","GP40","PA2.26","D2-40"],"prev_symbol":[]},"alphafold":{"accession":"Q86YL7","domains":[{"cath_id":"1.20.5","chopping":"131-158","consensus_level":"medium","plddt":86.0368,"start":131,"end":158}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YL7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YL7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q86YL7-F1-predicted_aligned_error_v6.png","plddt_mean":57.97},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDPN","jax_strain_url":"https://www.jax.org/strain/search?query=PDPN"},"sequence":{"accession":"Q86YL7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q86YL7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q86YL7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q86YL7"}},"corpus_meta":[{"pmid":"1596899","id":"PMC_1596899","title":"Distribution 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therapy","url":"https://pubmed.ncbi.nlm.nih.gov/36434176","citation_count":16,"is_preprint":false},{"pmid":"32380790","id":"PMC_32380790","title":"PDPN Is Expressed in Various Types of Canine Tumors and Its Silencing Induces Apoptosis and Cell Cycle Arrest in Canine Malignant Melanoma.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32380790","citation_count":16,"is_preprint":false},{"pmid":"24673328","id":"PMC_24673328","title":"Expression of Prox1, D2-40, and WT1 in spindle cell hemangioma.","date":"2014","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24673328","citation_count":16,"is_preprint":false},{"pmid":"39764562","id":"PMC_39764562","title":"PDPN+ cancer-associated fibroblasts enhance gastric cancer angiogenesis via AKT/NF-κB activation and the CCL2-ACKR1 axis.","date":"2025","source":"MedComm","url":"https://pubmed.ncbi.nlm.nih.gov/39764562","citation_count":15,"is_preprint":false},{"pmid":"21497368","id":"PMC_21497368","title":"D2-40 immunoreactivity in penile squamous cell carcinoma: a marker of aggressiveness.","date":"2011","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21497368","citation_count":15,"is_preprint":false},{"pmid":"38167452","id":"PMC_38167452","title":"A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/β-catenin and modulates the immune cells.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38167452","citation_count":15,"is_preprint":false},{"pmid":"25083424","id":"PMC_25083424","title":"Expressions of D2-40, CK19, galectin-3, VEGF and EGFR in papillary thyroid carcinoma.","date":"2012","source":"Gland surgery","url":"https://pubmed.ncbi.nlm.nih.gov/25083424","citation_count":15,"is_preprint":false},{"pmid":"32390409","id":"PMC_32390409","title":"CD31 and D2-40 Contribute to Peritoneal Metastasis of Colorectal Cancer by Promoting Epithelial-Mesenchymal Transition.","date":"2021","source":"Gut and liver","url":"https://pubmed.ncbi.nlm.nih.gov/32390409","citation_count":14,"is_preprint":false},{"pmid":"24606466","id":"PMC_24606466","title":"Clinical significance of detecting lymphatic and blood vessel invasion in stage II colon cancer using markers D2-40 and CD34 in combination.","date":"2014","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/24606466","citation_count":14,"is_preprint":false},{"pmid":"34879110","id":"PMC_34879110","title":"The neutrophil protein CD177 is a novel PDPN receptor that regulates human cancer-associated fibroblast physiology.","date":"2021","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/34879110","citation_count":13,"is_preprint":false},{"pmid":"21326813","id":"PMC_21326813","title":"D2-40: an additional marker for myoepithelial cells of breast and the precaution in interpreting tumor lymphovascular invasion.","date":"2011","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21326813","citation_count":13,"is_preprint":false},{"pmid":"39002130","id":"PMC_39002130","title":"Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39002130","citation_count":12,"is_preprint":false},{"pmid":"39970234","id":"PMC_39970234","title":"Antibodies targeting Crimean-Congo hemorrhagic fever virus GP38 limit vascular leak and viral spread.","date":"2025","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39970234","citation_count":12,"is_preprint":false},{"pmid":"24969973","id":"PMC_24969973","title":"Expression of p53, D2-40 and α-smooth muscle actin in different histological subtypes of facial basal cell carcinoma.","date":"2014","source":"Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie","url":"https://pubmed.ncbi.nlm.nih.gov/24969973","citation_count":12,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54735,"output_tokens":4920,"usd":0.119002,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13078,"output_tokens":4791,"usd":0.092582,"stage2_stop_reason":"end_turn"},"total_usd":0.211584,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"PA2.26 (PDPN) is a mucin-like transmembrane glycoprotein that colocalizes with ERM (ezrin, radixin, moesin) family proteins in actin-rich microvilli and plasma membrane projections; ezrin and moesin (but not radixin) can be co-immunoprecipitated with PA2.26. Ectopic expression of PA2.26 in nontumorigenic keratinocytes induces epithelial-fibroblastoid morphological conversion with increased plasma membrane extensions, major reorganization of the actin cytoskeleton, redistribution of ezrin to cell-surface projections, and enhanced motility.\",\n      \"method\": \"Co-immunoprecipitation, confocal/immunoelectron microscopy, ectopic expression in keratinocytes with functional readouts\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple orthogonal methods (Co-IP + microscopy + functional overexpression assay) in a single focused study\",\n      \"pmids\": [\"10574709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ectopic expression of PA2.26 (PDPN) in premalignant MCA3D keratinocytes leads to destabilization of adherens junctions (downregulation of E- and P-cadherin protein via proteolytic degradation), loss of cortical actin, vimentin/K8 upregulation, K14 downregulation, and acquisition of a fully transformed, metastatic phenotype including lymphatic invasion and regional lymph node metastases in nude mice.\",\n      \"method\": \"Stable transfection, Western blot, immunofluorescence, xenograft tumor transplantation\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Western blot, immunofluorescence, in vivo xenograft) in one focused study establishing functional mechanism\",\n      \"pmids\": [\"11092535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Aggrus/PDPN (T1alpha) directly induces platelet aggregation without requiring plasma components. The platelet aggregation-stimulating (PLAG) domain bearing putative O-glycosylated threonine residues is the critical determinant; an 8F11 neutralizing monoclonal antibody targeting this domain suppresses tumor-induced platelet aggregation.\",\n      \"method\": \"Protein purification, platelet aggregation assay, monoclonal antibody neutralization, expression in CHO cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro platelet aggregation reconstitution, domain mapping with antibody neutralization, replicated by multiple 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 Galβ1,3GalNAc-Ser/Thr) on Aggrus/PDPN are critical for its platelet aggregation-inducing activity. Expression in CMP-sialic acid transporter-deficient (Lec2) or 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 assay, lectin blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted function in defined glycosylation-deficient cell lines with multiple lectins confirming glycan structure; orthogonal methods\",\n      \"pmids\": [\"15231832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Human PA2.26/PDPN colocalizes with ezrin at the cell surface in oral squamous cell carcinoma cells. 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 functional assays\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — colocalization plus functional overexpression, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15515019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The PLAG domain of Aggrus/PDPN is conserved across mammalian homologues (rat, hamster, dog, bovine, human, mouse) and contains three tandem repeats. Point mutation shows that either the first or last (but not the middle) PLAG domain is critical for platelet aggregation-inducing activity. Bovine Aggrus with a sporadic deletion in the first PLAG domain lacks platelet aggregation activity.\",\n      \"method\": \"cDNA cloning, site-directed mutagenesis, platelet aggregation assay, sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis coupled with functional platelet aggregation assay, identifying specific residues required for activity\",\n      \"pmids\": [\"16766141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"E11/gp38 (PDPN) is the earliest osteocyte-selective protein expressed during osteoblast-to-osteocyte differentiation. Fluid flow shear stress increases E11 mRNA in osteocyte-like MLO-Y4 cells. siRNA knockdown of E11 blocks shear-stress-induced dendrite elongation in MLO-Y4 cells. Mechanical load in vivo increases E11 expression in osteocytes. These results establish E11/gp38 as functionally required for mechanically-stimulated osteocyte dendrite elongation.\",\n      \"method\": \"siRNA knockdown, fluid flow shear stress assay, in vivo mechanical loading, immunostaining, RT-PCR\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with specific cellular phenotype (dendrite elongation), confirmed in vitro and in vivo with multiple orthogonal methods\",\n      \"pmids\": [\"16738320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Aggrus/podoplanin promotes pulmonary metastasis by inducing platelet aggregation. CHO cells expressing Aggrus show platelet coating and lung microvasculature arrest within 30 minutes of injection. Point mutations at Thr34 and Thr52 in the PLAG domain abolish both platelet aggregation and metastasis. Aspirin treatment reduces metastatic foci.\",\n      \"method\": \"In vivo experimental and spontaneous metastasis mouse models, point mutagenesis (Thr34/Thr52), platelet aggregation assay, drug treatment\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of specific residues with coupled in vivo metastasis and in vitro platelet aggregation assays; replicated across multiple models\",\n      \"pmids\": [\"17392172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CD9 (tetraspanin) forms a complex with Aggrus/podoplanin via its transmembrane domains 1 and 2 (TM1 and TM2). CD9 and Aggrus colocalize in low-density membrane fractions. CD9 expression inhibits Aggrus-induced platelet aggregation and pulmonary metastasis; deletion of TM1 and TM2 abolishes this inhibition and also disrupts CD9 homophilic interaction and low-density membrane localization.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion mutagenesis, platelet aggregation assay, in vivo metastasis assay, membrane fractionation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reciprocal Co-IP with domain mapping, functional validation in vitro and in vivo, multiple orthogonal methods in single study\",\n      \"pmids\": [\"18541721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Podoplanin/PA2.26 protein levels are regulated post-translationally by calpain-mediated proteolysis. Calpain-1 cleaves podoplanin in vitro; treatment with calpain inhibitor calpeptin (but not the proteasome inhibitor lactacystin) causes podoplanin accumulation in multiple tumor cell lines that transcribe PDPN but show little protein.\",\n      \"method\": \"In vitro calpain cleavage assay, pharmacological inhibition (calpeptin vs lactacystin), Western blot\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay showing calpain-1 cleaves PDPN, supported by pharmacological rescue experiments\",\n      \"pmids\": [\"19146981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IMP-3 (IGF2BP3) stabilizes the PDPN mRNA via interaction with the 3'UTR, maintaining PDPN expression required for functional invadopodia formation and extracellular matrix degradation in oral squamous cell carcinoma cells. IMP-3 depletion reduces PDPN mRNA levels and abolishes ECM degradation activity despite intact invadopodia structure.\",\n      \"method\": \"siRNA knockdown, RNA in situ hybridization with 3'UTR probe, luciferase reporter assay with PDPN 3'UTR, xenograft model\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter assay and ISH establish mRNA stabilization mechanism, plus functional in vivo validation; single lab\",\n      \"pmids\": [\"22859271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aggrus/podoplanin directly binds to the platelet receptor CLEC-2, and this interaction mediates platelet aggregation, platelet-induced tumor cell proliferation, and pulmonary metastasis. Anti-Aggrus antibody MS-1 blocks Aggrus-CLEC-2 binding and suppresses both metastasis and tumor growth in vivo. Aggrus knockdown reduces platelet-induced proliferation in vitro.\",\n      \"method\": \"Binding assay (Aggrus-CLEC-2), anti-Aggrus neutralizing monoclonal antibody, siRNA knockdown, in vivo xenograft/metastasis models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay identifying CLEC-2 as receptor, neutralizing antibody and siRNA knockdown with in vitro and in vivo functional readouts; replicated across studies\",\n      \"pmids\": [\"23991201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The two conserved intracellular serine residues of PDPN can be phosphorylated by PKA (protein kinase A). Conversion of these serines to non-phosphorylatable alanine enhances cell migration, while conversion to phosphomimetic aspartate decreases cell migration. PDPN expression in fibroblasts facilitates motility and viability of co-cultured melanoma cells.\",\n      \"method\": \"Pdpn knockout mouse embryonic fibroblasts, site-directed mutagenesis (Ser→Ala and Ser→Asp), PKA phosphorylation assay, cell migration assays, co-culture\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis on null background, in vitro kinase assay, functional migration readouts; multiple orthogonal approaches in single study\",\n      \"pmids\": [\"23530051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Podoplanin (gp38) in rheumatoid arthritis synovial fibroblasts interacts with the platelet receptor CLEC-2 in vivo. gp38 silencing in synovial fibroblasts reduces IL-6 and IL-8 gene expression induced by fibroblast-platelet interaction, but does not affect fibroblast migration or invasion.\",\n      \"method\": \"gp38 siRNA silencing in cultured synovial fibroblasts, platelet-fibroblast co-culture, gene expression analysis, immunohistochemistry\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with specific cytokine readout in co-culture, single lab; negative result for migration/invasion also noted\",\n      \"pmids\": [\"24932813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Both PKA and CDK5 phosphorylate PDPN on its two conserved intracellular serine residues, and they cooperate to phosphorylate both residues to decrease cell motility. CDK5 was identified as a new PDPN kinase in addition to PKA.\",\n      \"method\": \"In vitro kinase assays with PKA and CDK5, site-directed mutagenesis of individual serine residues, cell motility assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro kinase assays with mutagenesis of specific residues, functional motility readout; extends prior mechanistic work\",\n      \"pmids\": [\"25959509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDPN promotes invasiveness in BcPAP papillary thyroid carcinoma cells by regulating ezrin/radixin/moesin (E/R/M) protein phosphorylation, MMP-2 and MMP-9 expression/activity, actin cytoskeleton remodeling, and cellular protrusion formation. PDPN expression is associated with the MAPK signaling pathway; MAPK inhibition decreases PDPN expression, increases E/R/M phosphorylation, and reduces cell migration.\",\n      \"method\": \"siRNA knockdown, scratch/Transwell invasion assays, zymography, Western blot, MAPK pathway inhibitors (U0126, PLX4720)\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with multiple orthogonal readouts (invasion, MMP activity, ERM phosphorylation), single lab\",\n      \"pmids\": [\"30654768\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD177 (neutrophil protein) is a novel cell-surface binding partner of PDPN on cancer-associated fibroblasts, identified by high-throughput cell surface interactome screening. CD177 acts as a functional antagonist of PDPN, recapitulating the phenotype of PDPN-deficient CAFs. Quantitative phosphoproteomics of CAFs links PDPN to cell signaling, growth, and actomyosin contractility pathways.\",\n      \"method\": \"High-throughput cell surface protein interaction screen, quantitative phosphoproteomics, cellular functional assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased interactome screen plus phosphoproteomics and functional antagonist assays; single lab, novel receptor identification\",\n      \"pmids\": [\"34879110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDPN+ cancer-associated fibroblasts in colorectal cancer maintain CAF heterogeneity and promote angiogenesis via an autocrine PDPN/CCL2/STAT3 feedback loop. NF-κB p65 binds the CCL2 promoter to induce CCL2 secretion; paracrine CCL2 activates STAT3 in endothelial cells. CCL2 interacts with its non-classical receptor ACKR1 on endothelial cells to mediate pro-angiogenic effects. STAT3 inhibitor WP1066 blocks both the feedback loop in CAFs and STAT3 in endothelial cells.\",\n      \"method\": \"Single-cell analysis, ChIP/promoter binding assay (p65 on CCL2 promoter), CCL2 neutralizing antibody, AKT inhibitor, in vivo tumor growth assays\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding assay plus functional antibody/inhibitor experiments and in vivo validation; single lab\",\n      \"pmids\": [\"39115624\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDPN (podoplanin/Aggrus) is a mucin-type transmembrane sialoglycoprotein that promotes cell migration and tumor metastasis by: (1) interacting via its extracellular PLAG domain (bearing critical sialylated O-glycans on Thr34/Thr52) with the platelet receptor CLEC-2 to induce platelet aggregation and facilitate hematogenous metastasis; (2) engaging ERM proteins (ezrin/moesin) at the cell surface to remodel the actin cytoskeleton, destabilize adherens junctions, and drive cell motility; (3) having its intracellular serine residues phosphorylated by PKA and CDK5 to inhibit cell motility; (4) undergoing post-translational regulation by calpain-1-mediated proteolysis; (5) being negatively regulated by complex formation with CD9 (via TM1/TM2) and by CD177 (a functional antagonist); and (6) in osteocytes, being required for mechanically-stimulated dendrite elongation downstream of fluid flow shear stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDPN (podoplanin/Aggrus/PA2.26/E11/gp38) is a mucin-type transmembrane sialoglycoprotein that drives cell migration, tumor invasion, and hematogenous metastasis while also serving differentiated tissue functions such as mechanically stimulated osteocyte dendrite formation [#0, #2, #6]. At the cell surface, PDPN couples to the actin cytoskeleton by associating with ERM proteins ezrin and moesin, redistributing ezrin to membrane projections, remodeling cortical actin, destabilizing E-/P-cadherin adherens junctions, and converting epithelial cells to a motile, fibroblastoid, metastatic phenotype [#0, #1, #4]; in carcinoma cells it regulates ERM phosphorylation together with MMP-2/MMP-9 activity to promote invadopodia-driven matrix degradation and invasion [#15]. Its prometastatic activity depends on a conserved extracellular PLAG domain carrying sialylated core-1 O-glycans on Thr34/Thr52, which directly engages the platelet receptor CLEC-2 to trigger platelet aggregation, tumor cell coating, microvascular arrest, and platelet-induced tumor proliferation [#2, #3, #5, #7, #11]. PDPN cytoplasmic function is controlled by phosphorylation of two conserved intracellular serines by PKA and CDK5, which cooperatively suppress motility [#12, #14]. PDPN abundance and signaling are further tuned post-transcriptionally and post-translationally by IMP-3 (IGF2BP3)-mediated mRNA stabilization, calpain-1 proteolysis, inhibitory complex formation with the tetraspanin CD9, and antagonism by CD177 [#9, #10, #8, #16]. In the tumor stroma, PDPN+ cancer-associated fibroblasts sustain a pro-angiogenic CCL2/STAT3 feedback program [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that PDPN is not a passive surface marker but a cytoskeletal organizer, linking it physically to ERM proteins and to actin-based motility.\",\n      \"evidence\": \"Reciprocal Co-IP, confocal/immunoelectron microscopy, and ectopic expression in keratinocytes\",\n      \"pmids\": [\"10574709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the ERM-binding motif on PDPN\", \"Did not link ERM engagement to in vivo phenotypes\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that PDPN expression alone confers a transformed, lymphatically invasive, metastatic phenotype via adherens junction destabilization.\",\n      \"evidence\": \"Stable transfection, Western blot, immunofluorescence, and xenograft transplantation in nude mice\",\n      \"pmids\": [\"11092535\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cadherin proteolytic degradation not identified\", \"Surface receptor mediating metastasis not yet known\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the platelet aggregation-stimulating (PLAG) domain as the functional determinant of PDPN-induced platelet aggregation, independent of plasma factors.\",\n      \"evidence\": \"Protein purification, platelet aggregation assay, neutralizing antibody (8F11), and CHO expression\",\n      \"pmids\": [\"14522983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Platelet receptor not identified\", \"Specific glycan requirement not yet resolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the glycan code for activity, showing sialylated core-1 O-glycans (not N-glycans) are required for platelet aggregation.\",\n      \"evidence\": \"Expression in glycosylation-deficient CHO mutants (Lec1/Lec2/Lec8) with platelet aggregation and lectin blotting\",\n      \"pmids\": [\"15231832\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which threonines carry the critical glycans\", \"Glycosyltransferases responsible not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Mapped PLAG-domain architecture, showing tandem repeats with the first or last (not middle) repeat critical for platelet aggregation.\",\n      \"evidence\": \"cDNA cloning across mammals, site-directed mutagenesis, and platelet aggregation assays\",\n      \"pmids\": [\"16766141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single critical threonine residues not yet pinpointed\", \"Structural basis of repeat redundancy unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended PDPN function beyond cancer, establishing it as required for mechanically stimulated osteocyte dendrite elongation.\",\n      \"evidence\": \"siRNA knockdown in MLO-Y4 cells, fluid flow shear stress, and in vivo mechanical loading\",\n      \"pmids\": [\"16738320\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway downstream of shear stress to PDPN not defined\", \"Whether ERM/CLEC-2 axes operate in osteocytes unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Tied platelet aggregation mechanistically to metastasis, identifying Thr34/Thr52 as the critical glycosylated residues and showing aspirin reduces metastasis.\",\n      \"evidence\": \"In vivo metastasis models, Thr34/Thr52 point mutagenesis, platelet aggregation assays, and drug treatment\",\n      \"pmids\": [\"17392172\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Platelet receptor still unidentified at this stage\", \"Contribution of non-platelet mechanisms to metastasis not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified CD9 as a negative regulator forming a TM1/TM2-dependent complex that suppresses PDPN-driven platelet aggregation and metastasis.\",\n      \"evidence\": \"Co-IP with domain deletion mutagenesis, membrane fractionation, and in vitro/in vivo assays\",\n      \"pmids\": [\"18541721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which CD9 sterically blocks CLEC-2 engagement not resolved\", \"Physiological contexts of CD9-PDPN balance unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that PDPN protein levels are set post-translationally, with calpain-1 cleaving PDPN to limit surface abundance.\",\n      \"evidence\": \"In vitro calpain cleavage assay, calpeptin vs lactacystin pharmacology, and Western blot\",\n      \"pmids\": [\"19146981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage site on PDPN not mapped\", \"Physiological trigger for calpain processing unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed post-transcriptional control of PDPN by IMP-3 (IGF2BP3), linking mRNA stability to invadopodia-mediated matrix degradation.\",\n      \"evidence\": \"siRNA knockdown, 3'UTR ISH and luciferase reporter, and xenograft model\",\n      \"pmids\": [\"22859271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IMP-3 binding site on the 3'UTR not finely mapped\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Closed the long-standing gap by identifying CLEC-2 as the direct platelet receptor for PDPN and connecting it to platelet-induced tumor proliferation.\",\n      \"evidence\": \"Direct binding assay, neutralizing antibody MS-1, siRNA knockdown, and in vivo xenograft/metastasis models\",\n      \"pmids\": [\"23991201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural stoichiometry of PDPN-CLEC-2 not defined here\", \"Relative weight of proliferation vs aggregation in vivo unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined intracellular regulation of PDPN motility function, showing PKA phosphorylation of two conserved serines suppresses migration.\",\n      \"evidence\": \"Pdpn-null MEFs, Ser\\u2192Ala/Asp mutagenesis, PKA kinase assay, and migration/co-culture assays\",\n      \"pmids\": [\"23530051\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How serine phosphorylation alters ERM coupling not resolved\", \"Upstream signals activating PKA toward PDPN unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Generalized PDPN-CLEC-2 signaling to inflammatory stroma, showing synovial fibroblast PDPN drives platelet-induced IL-6/IL-8 without affecting migration.\",\n      \"evidence\": \"gp38 siRNA silencing in synovial fibroblasts, platelet co-culture, and gene expression analysis\",\n      \"pmids\": [\"24932813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling pathway from PDPN-platelet contact to cytokine induction not mapped\", \"Negative migration result limits generalization\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Refined the kinase control of PDPN by identifying CDK5 as a second kinase cooperating with PKA on both serines to suppress motility.\",\n      \"evidence\": \"In vitro PKA and CDK5 kinase assays with single-residue mutagenesis and motility assays\",\n      \"pmids\": [\"25959509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatiotemporal coordination of the two kinases in cells not defined\", \"Phosphatase counteracting these sites unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked PDPN to upstream MAPK signaling and downstream MMP activity in thyroid carcinoma invasion through ERM phosphorylation control.\",\n      \"evidence\": \"siRNA knockdown, invasion assays, zymography, and MAPK inhibitors (U0126, PLX4720)\",\n      \"pmids\": [\"30654768\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism connecting PDPN to MMP transcription unclear\", \"Single-lab, single-cell-line study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified CD177 as a novel surface binding partner acting as a functional antagonist of PDPN on cancer-associated fibroblasts.\",\n      \"evidence\": \"High-throughput surface interactome screen, quantitative phosphoproteomics, and functional CAF assays\",\n      \"pmids\": [\"34879110\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CD177 antagonism not resolved\", \"Interaction not validated by reciprocal structural/biochemical means\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PDPN+ CAFs drive tumor angiogenesis via an autocrine PDPN/CCL2/STAT3 feedback loop signaling to endothelial cells through ACKR1.\",\n      \"evidence\": \"Single-cell analysis, p65 ChIP on CCL2 promoter, CCL2 neutralization, and in vivo tumor assays\",\n      \"pmids\": [\"39115624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PDPN initiates the p65/CCL2 program mechanistically not defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of the PDPN-CLEC-2 interface, how intracellular serine phosphorylation reprograms ERM coupling, and how the competing regulators (CD9, CD177, calpain-1, IMP-3) are integrated in vivo remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structure of full-length PDPN or its receptor complexes\", \"Integration of post-transcriptional, proteolytic, and phosphorylation controls into a single regulatory model is undefined\", \"Tissue-specific roles (osteocyte vs tumor vs synovial) not mechanistically unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 4, 15]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [11, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [2, 7, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 7, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 14, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CLEC-2\", \"EZR\", \"MSN\", \"CD9\", \"CD177\", \"IGF2BP3\", \"CAPN1\", \"CDK5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}