{"gene":"PDGFD","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":2001,"finding":"PDGF-D is secreted as a disulphide-linked homodimer (PDGF-DD) and requires limited proteolysis for activation; upon proteolytic cleavage it becomes a specific agonistic ligand for PDGFR-β.","method":"Recombinant protein expression, biochemical characterization, receptor-binding and receptor activation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 — original discovery paper with reconstitution, receptor binding, and functional assays; independently confirmed by second concurrent paper (PMID:11331882)","pmids":["11331881","11331882"],"is_preprint":false},{"year":2001,"finding":"PDGF-D binds to and activates PDGFR-β; in cells expressing both receptors it can also activate PDGFR-α, likely through PDGFR-α/β heterodimerization.","method":"Receptor-specific cell lines, DNA synthesis assay, receptor phosphorylation assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 — functional assays with mutagenesis context; replicated across two independent labs in same year","pmids":["11331882","11331881"],"is_preprint":false},{"year":2001,"finding":"PDGFD gene maps to chromosome 11q22.3 and has a two-domain structure with an N-terminal CUB domain (encoded by exons 2–3) and a C-terminal PDGF cystine-knot growth factor homology domain (encoded by last 2 exons); proteolytic cleavage site is in exon 5.","method":"Fluorescence in situ hybridization, genomic DNA sequencing, exon structure determination","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1 — direct structural/genomic characterization with sequencing","pmids":["11342471"],"is_preprint":false},{"year":2003,"finding":"PDGF-D acts as a potent transforming growth factor for NIH/3T3 cells via PDGFR-β activation, inducing stress fibre reorganization, anchorage-independent growth, tumour formation in nude mice, and upregulation of VEGF.","method":"Stable transfection, soft agar assay, nude mouse tumour model, VEGF measurement","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in single study","pmids":["12629513"],"is_preprint":false},{"year":2003,"finding":"PDGF-D signals through PDGFR-β to activate ERK1/2, JNK, p38 MAPK, and PKB/Akt in hepatic stellate cells and myofibroblasts, exerting mitogenic and fibrogenic effects comparable to PDGF-B.","method":"PDGFRβ autophosphorylation assay, Western blot of downstream kinases, cell proliferation and collagen assays","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — multiple signaling readouts with functional consequence","pmids":["17397961"],"is_preprint":false},{"year":2004,"finding":"Full-length PDGF-D is activated in tissues and promotes macrophage recruitment, increased interstitial fluid pressure, and maturation/pericyte coating of blood vessels in vivo; combined expression with VEGF-E inhibits vascular leakiness.","method":"Transgenic mouse overexpression, adeno-associated virus vector delivery, histology, interstitial fluid pressure measurement, wound healing assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — multiple in vivo models with defined phenotypic readouts","pmids":["15271796"],"is_preprint":false},{"year":2004,"finding":"PDGF-D is a potent mesangial cell mitogen; adenoviral overexpression of PDGF-D in mice causes severe mesangial proliferative glomerulopathy via PDGFR-β engagement, whereas PDGF-C overexpression causes no measurable renal response.","method":"Adenoviral vector injection in mice, histology, in vitro mitogenicity assay","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — in vivo gain-of-function with specific phenotypic readout, confirmed in vitro","pmids":["14747375"],"is_preprint":false},{"year":2003,"finding":"Neutralizing PDGF-DD with fully human monoclonal antibody CR002 reduces glomerular mesangial cell proliferation, monocyte/macrophage infiltration, and fibronectin accumulation in rat mesangioproliferative nephritis.","method":"Neutralizing antibody treatment in rat anti-Thy1.1 nephritis model, immunostaining, BrdU incorporation","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — dose-dependent in vivo functional antagonism with multiple readouts","pmids":["12937299"],"is_preprint":false},{"year":2006,"finding":"PDGF-D antagonism by CR002 antibody in progressive glomerulonephritis reduces glomerulosclerosis, podocyte damage, tubulointerstitial fibrosis, collagen/fibronectin accumulation, and cortical macrophage infiltration, implicating PDGF-D in renal scarring.","method":"Long-term antibody treatment in uninephrectomised anti-Thy-1.1 rat model, histology, immunostaining","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with multiple orthogonal readouts over 8-week study","pmids":["16510766"],"is_preprint":false},{"year":2016,"finding":"Pdgfd knockout mice show significantly reduced renal interstitial fibrosis in unilateral ureteral obstruction and ischemia/reperfusion injury models, associated with reduced PDGFR-β and p38 phosphorylation; adenoviral PDGF-D overexpression increases renal collagen deposition.","method":"Pdgfd knockout mice, adenoviral overexpression, UUO and IRI models, histology, phosphoprotein analysis","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — genetic KO combined with gain-of-function, two independent disease models","pmids":["26924050"],"is_preprint":false},{"year":2015,"finding":"PDGF-D binds NRP1 via its C-terminal Arg residue; PDGF-D (but not PDGF-B) stimulation induces PDGFRβ–NRP1 complex formation in fibroblasts, translocates NRP1 to cell-cell junctions in endothelial cells (independently of PDGFRβ), and can signal in trans between endothelial cells and pericytes.","method":"Co-immunoprecipitation, direct binding assay, mutagenesis of C-terminal Arg, confocal microscopy, ex vivo sprouting assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding confirmed by mutagenesis, complex formation by Co-IP, functional consequence in sprouting assay","pmids":["28254885"],"is_preprint":false},{"year":2015,"finding":"Matriptase cleaves full-length PDGF-D dimer in a stepwise manner generating a hemidimer (HD) intermediate and then the active growth factor domain dimer (GFD-D); the cleavage site is R340R341GR343A within loop III of the GFD which is critical for PDGFRβ binding; the HD acts as a dominant-negative ligand; matriptase can further cleave and inactivate GFD-D; PDGF-D dimer species differentially deposit into the extracellular matrix.","method":"In vitro matriptase cleavage assay, mutagenesis of cleavage site, receptor activation assay, ECM binding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis and multiple functional readouts","pmids":["25678707"],"is_preprint":false},{"year":2022,"finding":"The PDGF-D CUB/prodomain inhibits PDGFR-β activation by sterically blocking D2/D3 receptor domains from recognizing the growth factor domain; the prodomain inhibits both PDGF-B and PDGF-D-mediated PDGFR-β transphosphorylation but inhibits NIH 3T3 cell proliferation induced by PDGF-D but not by PDGF-B, demonstrating differential inhibitory specificity.","method":"Structural modeling, in vitro PDGFR-β transphosphorylation assay, cell proliferation assay, prodomain inhibition experiments","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — structural modeling with mutagenesis-supported in vitro functional validation","pmids":["35777468"],"is_preprint":false},{"year":2014,"finding":"PDGFD is specifically expressed by radial glia in human but not mouse neocortex; pharmacological inhibition of PDGFD–PDGFRβ signalling in human cortical slice cultures prevents cell cycle progression of radial glia; ectopic PDGFD or constitutively active PDGFRβ in mouse neocortex increases radial glia proportion and subventricular dispersion.","method":"Transcriptional profiling, pharmacological inhibition in slice culture, in utero electroporation/injection in mouse","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — pharmacological and genetic gain-of-function experiments with defined cellular phenotypes; published in Nature","pmids":["25391964"],"is_preprint":false},{"year":2021,"finding":"HIF1α binds the PDGFD proximal promoter and PDGFRA intron enhancers in GBM cells under normoxia/mild-hypoxia to induce their expression; PDGF-D/PDGFRα constitutively activates AKT signaling which in turn increases HIF1α protein, forming a feedforward loop; severe hypoxia abrogates PDGFRα despite enhancing PDGF-D expression.","method":"ChIP analysis, sgRNA-Cas9 knockout, RNA-seq, loss/gain-of-function assays, intracranial xenograft model","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — ChIP for direct promoter binding, genetic KO with in vivo validation","pmids":["34470658"],"is_preprint":false},{"year":2021,"finding":"Macrophage-derived urokinase plasminogen activator (uPA) activates PDGF-D by cleaving full-length PDGF-D into the active PDGF-DD form, promoting cardiac remodeling in obese hypertensive mice; adipocyte-specific PDGF-D knockout attenuates this remodeling.","method":"Adipocyte-specific KO and transgenic mice, bone marrow-specific uPA knockdown, ELISA for active PDGF-DD, Western blot","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — genetic models (KO, KD, transgenic) with mechanistic identification of uPA as activating protease","pmids":["34236404"],"is_preprint":false},{"year":2023,"finding":"FOXC1/C2 transcription factor binding at the CAD-risk SNP rs2019090 promotes PDGFD transcription; Pdgfd promotes SMC expansion, migration, and transition to chondromyocyte phenotype in atherosclerosis; Pdgfd-expressing adventitial fibroblasts and pericytes express chemokines and leukocyte adhesion molecules linked to macrophage recruitment.","method":"Fine-mapping, ChIP, Pdgfd knockdown in SMC lineage-tracing atherosclerosis mouse model, single-cell transcriptomics","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches (genetic KO, lineage tracing, scRNA-seq, ChIP) in single study","pmids":["36792607"],"is_preprint":false},{"year":2015,"finding":"PDGF-D regulates proliferation and migration of adipose-derived stem cells (ASCs) through PI3K/Akt pathways and via mitochondrial reactive oxygen species generation and mitochondrial fission mediated by p66Shc phosphorylation; PDGF-D upregulates expression of multiple growth factors (VEGFA, FGF1, FGF5, etc.) through MAPK signalling.","method":"siRNA knockdown, pathway inhibitors, mitochondrial ROS measurement, RT-PCR, proliferation and migration assays","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling readouts but single lab","pmids":["25332166"],"is_preprint":false},{"year":2015,"finding":"In portal myofibroblasts and hepatic stellate cells, PDGF-D binds PDGFR-α as well as PDGFR-β, inducing receptor endocytosis, PDGFR-α-specific tyrosine phosphorylation (Y754 and Y1018), and CrkII adaptor protein recruitment; a recombinant PDGFR-α-Fc chimera blocks PDGF-D signaling.","method":"Receptor phosphorylation assay, receptor endocytosis assay, CrkII pulldown, PDGFR-α-Fc inhibition","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — biochemical assays with multiple signaling readouts; single lab","pmids":["25819339"],"is_preprint":false},{"year":2016,"finding":"ZIC5 transcriptionally upregulates PDGFD expression in melanoma; PDGF-D activates FAK and STAT3 to confer drug resistance; silencing ZIC5 or PDGFD enhances apoptosis under BRAF inhibition; FAK and STAT3 positively feedback to sustain ZIC5 expression.","method":"siRNA screening, microarray, Western blot, apoptosis assay, in vivo melanoma model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement by epistasis/knockdown with functional readouts; single lab","pmids":["27671679"],"is_preprint":false},{"year":2016,"finding":"PDGF-D (via PDGFR-β signalling) upregulates androgen receptor expression and nuclear AR translocation in PTEN-null prostate cells; AR contributes to radiation resistance; PDGF-D overexpression increases radioresistance reversed by enzalutamide.","method":"Immunoblot of nuclear/cytosolic AR fractions, RT-PCR of AR target genes, clonogenic survival assay, irradiation experiments","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — direct measurement of AR pathway, functional radioresistance readout; single lab","pmids":["26732854"],"is_preprint":false},{"year":2016,"finding":"PDGF-D–PDGFR-β signalling mediates post-ICH neuroinflammation; plasmin acts as an upstream activator of PDGF-D; PDGF-D promotes macrophage infiltration and TNF-α production; PDGFR-β inhibition reduces microglial activation and brain injury.","method":"Mouse ICH model with siRNA knockdown of PDGF-D, recombinant PDGF-D injection, PDGFR inhibitor (Gleevec), plasmin antagonist (EACA), immunostaining","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological and genetic interventions with defined phenotypic readouts; single lab","pmids":["27302678"],"is_preprint":false},{"year":2011,"finding":"PDGF-D overexpression promotes lymph node metastasis through induction of CXCR4 expression; blockade of CXCR4 abolishes PDGF-D-induced lymph node metastasis; PDGF-D increases perivascular cell coverage and normalises tumour vessels.","method":"Stable transfection of breast cancer cells, shRNAi, imatinib treatment, orthotopic mouse model, CXCR4 blockade","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological pathway placement with in vivo readouts","pmids":["21459800"],"is_preprint":false},{"year":2012,"finding":"PDGF-D released by adipose tissue-derived stem cells (ASCs) induces epithelial-mesenchymal transition (EMT) in breast cancer cells in a paracrine manner; neutralising PDGF-D antibody blocks this EMT and tumour growth.","method":"Conditioned medium experiments, neutralising antibody, Western blot for EMT markers, flow cytometry, mouse tumour model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — neutralising antibody confirms PDGF-D as the active paracrine factor; multiple readouts","pmids":["22038895"],"is_preprint":false},{"year":2017,"finding":"PDGF-D promotes EMT in colorectal cancer by upregulating Notch1 and Twist1; Notch1 overexpression rescues the effects of PDGF-D knockdown on Twist1 expression, placing PDGF-D upstream of Notch1/Twist1 axis.","method":"siRNA knockdown, plasmid overexpression, Western blot, migration assays, xenograft model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis rescue experiment placing PDGF-D upstream of Notch1/Twist1; single lab","pmids":["28035069"],"is_preprint":false},{"year":2023,"finding":"PDGFD promoter is reversibly demethylated in gemcitabine-resistant PDAC cells, increasing PDGFD expression; PDGF-D activates STAT3 in autocrine and paracrine manner to upregulate RRM1 expression, causing gemcitabine resistance.","method":"Reduced Representation Bisulfite Sequencing, demethylation experiments, STAT3 inhibition, RRM1 measurement, in vitro and in vivo resistance models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — epigenetic mechanism + downstream signaling identified with functional validation","pmids":["37321532"],"is_preprint":false},{"year":2015,"finding":"PDGF-D promotes fibroblast invasion in 3D collagen gels via PI3K, JNK, and ERK1/2 signalling pathways, inducing Snail expression which in turn upregulates MT1-MMP.","method":"3D type I collagen invasion assay, Snail siRNA knockdown, PI3K/JNK/ERK inhibitors, Western blot and RT-PCR","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — pathway dissected with multiple inhibitors and epistatic knockdown; single lab","pmids":["26234766"],"is_preprint":false},{"year":2022,"finding":"PDGFD drives endothelial commitment of embryonic stem cells via the MAPK/ERK pathway; PDGFD deletion or knockdown inhibits ESC differentiation into endothelial cells and reduces blood vessel density in embryonic, neonatal, and teratoma models.","method":"Loss- and gain-of-function assays, RNA sequencing, PDGFD knockout mice, embryonic and neonatal vascular analysis","journal":"Angiogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with multiple in vivo models and pathway identification","pmids":["35859222"],"is_preprint":false},{"year":2024,"finding":"Endothelial PDGF-D is transiently induced at ischemic stroke injury sites; increased PDGF-D bioavailability attenuates pericyte loss and fibrotic transition, promotes pericyte migration and endothelial coverage, and stimulates pro-angiogenic factor secretion, improving neurovascular recovery.","method":"Mouse ischemic stroke model, siRNA knockdown, recombinant PDGF-D administration, cell-based ischemia assays with human brain pericytes and endothelial cells","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss and gain of function with defined cellular and in vivo readouts; single lab","pmids":["38769116"],"is_preprint":false},{"year":2008,"finding":"PDGF-D induces MMP-9 mRNA expression and enhances secretion of MMP-2 and MMP-9 in monocytes/macrophages, and promotes monocyte migration in a concentration-dependent manner.","method":"Boyden chamber migration assay, RT-PCR for MMP-9, MMP-2/9 secretion assay","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 3 — direct functional assays but single lab; multiple readouts","pmids":["18573494"],"is_preprint":false},{"year":2018,"finding":"PVAT-derived PDGF-D promotes adventitial fibroblast proliferation, migration, and inflammatory factor expression; adipocyte-specific PDGF-D transgenic mice show exacerbated aortic aneurysm formation with AngII infusion; PDGF-D inhibition reduces AA incidence.","method":"Transcriptome analysis, adipocyte-specific transgenic mice, PDGF-D function inhibition, cultured adventitial fibroblast assays","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 — genetic transgenic and inhibition models with defined in vivo phenotype; single lab","pmids":["29794241"],"is_preprint":false},{"year":2023,"finding":"miR-145-5p directly targets PDGFD mRNA (validated by luciferase reporter assay); miR-145-5p inhibition promotes wound healing in diabetic foot ulcer models through upregulation of PDGFD, which increases fibroblast viability and migration.","method":"Luciferase reporter assay, miR-145-5p mimics/inhibitors, wound healing assay, DFU mouse model","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 3 — direct miRNA-target validation by luciferase assay with in vivo functional confirmation","pmids":["37950842"],"is_preprint":false},{"year":2026,"finding":"PDGF-D acts as a noncanonical ligand for NKp44 on human ILC3s; in mice (which lack NKp44), PDGF-D promotes IL-22 production and ILC3 proliferation through PDGFRβ; mice lacking PDGFRβ in ILC3s are susceptible to enteric infections; in NKp44-transgenic mice, PDGF-D engagement of NKp44 drives a type-1 effector programme (TNF-α and IFN-γ); fibroblasts and endothelial cells are the inflammation-responsive cellular source of PDGF-D.","method":"PDGFRβ conditional KO in ILC3s, NKp44 transgenic mice, PDGF-D reporter mice, enteric infection model, cytokine measurement","journal":"Science immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic models with defined functional readouts across species; multiple orthogonal approaches","pmids":["41758927"],"is_preprint":false},{"year":2025,"finding":"Pdgfd–Pdgfrb signalling in pancreatic cancer promotes perineural invasion by stimulating cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia; pharmacological blockade reduces perineural invasion in vivo.","method":"Spatial transcriptomics, in vitro invasion/neurite outgrowth assays, pharmacological inhibition, in vivo PNI model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple functional assays with in vivo validation; preprint, not yet peer-reviewed","pmids":["40909696"],"is_preprint":true}],"current_model":"PDGF-D is secreted as an inactive disulphide-linked homodimer requiring extracellular proteolytic cleavage (by proteases including plasmin, uPA, and matriptase) of its N-terminal CUB/prodomain to release the active growth factor domain dimer, which then signals primarily through PDGFR-β (and secondarily through PDGFR-α/β heterodimers or PDGFR-α), with NRP1 acting as a co-receptor, activating downstream PI3K/AKT, MAPK/ERK, JNK, p38, and STAT3 pathways to drive mesenchymal cell proliferation, migration, fibrosis, angiogenesis, EMT, and immune cell recruitment in development and disease."},"narrative":{"teleology":[{"year":2001,"claim":"Identification of PDGF-D as a new PDGFR-β ligand resolved a long-standing gap in the PDGF family by showing that PDGF-DD is secreted as an inactive homodimer requiring proteolytic processing to bind and activate PDGFR-β, and can also engage PDGFR-α/β heterodimers.","evidence":"Recombinant protein expression, receptor binding/activation assays, genomic mapping (two independent labs published concurrently)","pmids":["11331881","11331882","11342471"],"confidence":"High","gaps":["Identity of physiologically relevant activating proteases was unknown","No structural model of prodomain-mediated autoinhibition","Receptor specificity on cells co-expressing both PDGFRs not fully resolved"]},{"year":2003,"claim":"PDGF-D was established as a potent mitogen and fibrogenic factor, activating ERK1/2, JNK, p38, and AKT downstream of PDGFR-β in hepatic stellate cells and transforming NIH/3T3 cells, demonstrating oncogenic and pro-fibrotic potential.","evidence":"Stable transfection/nude mouse tumorigenesis, signaling pathway Western blots, mesangial cell proliferation assays, neutralizing antibody (CR002) in rat nephritis model","pmids":["12629513","17397961","12937299"],"confidence":"High","gaps":["In vivo activating proteases still unidentified","Relative contribution versus PDGF-B in fibrosis not delineated","Downstream transcriptional programs not mapped"]},{"year":2004,"claim":"In vivo gain-of-function studies demonstrated that PDGF-D recruits macrophages, promotes vessel maturation, and specifically causes mesangial proliferative glomerulopathy through PDGFR-β, distinguishing its biology from PDGF-C.","evidence":"Transgenic/adenoviral overexpression in mice, histology, interstitial fluid pressure measurement","pmids":["15271796","14747375"],"confidence":"High","gaps":["Loss-of-function genetic evidence still lacking","Mechanism of macrophage recruitment (direct vs. indirect) unclear"]},{"year":2006,"claim":"Long-term PDGF-D neutralization in progressive glomerulonephritis proved that PDGF-D drives renal scarring including glomerulosclerosis, tubulointerstitial fibrosis, and podocyte damage, establishing therapeutic relevance.","evidence":"8-week CR002 antibody treatment in uninephrectomized anti-Thy1.1 rat model with multiple histological readouts","pmids":["16510766"],"confidence":"High","gaps":["Whether PDGF-D inhibition reverses established fibrosis was not tested","Human translation not established"]},{"year":2014,"claim":"Discovery of species-specific PDGFD expression in human radial glia expanded PDGF-D's role beyond mesenchymal biology, showing it drives cortical progenitor proliferation and may have contributed to human neocortical expansion.","evidence":"Transcriptional profiling of sorted radial glia, pharmacological inhibition in human cortical slices, in utero electroporation in mouse","pmids":["25391964"],"confidence":"High","gaps":["Downstream transcriptional targets in radial glia not identified","Whether PDGF-D is sufficient for cortical expansion in non-human primates untested"]},{"year":2015,"claim":"The proteolytic activation mechanism was biochemically resolved: matriptase performs stepwise cleavage of PDGF-DD generating a dominant-negative hemidimer intermediate before releasing the active GFD dimer, with a critical R340R341 cleavage site overlapping the PDGFR-β binding interface; NRP1 was identified as a PDGF-D-specific co-receptor binding via the C-terminal arginine.","evidence":"In vitro matriptase reconstitution with mutagenesis, Co-IP of PDGFR-β–NRP1 complex, C-terminal Arg mutagenesis, ex vivo sprouting assay","pmids":["25678707","28254885"],"confidence":"High","gaps":["Crystal structure of PDGF-D GFD or CUB domain not determined","Whether NRP1 co-receptor function alters downstream signaling quality unknown","Hemidimer function in vivo not confirmed"]},{"year":2016,"claim":"Genetic knockout of Pdgfd confirmed its non-redundant role in renal fibrosis, showing reduced PDGFR-β/p38 signaling in two independent injury models and establishing PDGF-D as a bona fide fibrogenic driver in vivo.","evidence":"Pdgfd KO mice in UUO and IRI models, adenoviral gain-of-function, phosphoprotein analysis","pmids":["26924050"],"confidence":"High","gaps":["Combined Pdgfd/Pdgfb genetic studies not performed","Whether PDGF-D drives fibrosis in lung, liver, or heart by the same mechanism untested at KO level"]},{"year":2016,"claim":"PDGF-D was placed in multiple disease-relevant signaling circuits: activating STAT3/FAK to confer BRAF-inhibitor resistance in melanoma, upregulating androgen receptor for radioresistance in prostate cancer, and mediating neuroinflammation after intracerebral hemorrhage via plasmin-dependent activation.","evidence":"siRNA screening and epistasis in melanoma, nuclear AR fractionation in prostate cells, mouse ICH model with siRNA and Gleevec","pmids":["27671679","26732854","27302678"],"confidence":"Medium","gaps":["Each disease link from single lab","Direct PDGF-D–STAT3 connection versus indirect via PDGFR-β not fully resolved","Clinical relevance of PDGF-D in drug resistance untested"]},{"year":2021,"claim":"Macrophage-derived uPA was identified as a physiologically relevant activating protease for PDGF-D in cardiac remodeling, and HIF1α was shown to directly bind the PDGFD promoter to create a feedforward loop with PDGFR-α/AKT signaling in glioblastoma.","evidence":"Adipocyte-specific Pdgfd KO and uPA bone-marrow KD in obese mice; ChIP and CRISPR KO in GBM cells with intracranial xenograft","pmids":["34236404","34470658"],"confidence":"High","gaps":["Whether uPA is the dominant activating protease across tissues remains open","PDGFR-α versus PDGFR-β signaling quality downstream of PDGF-D in GBM not distinguished"]},{"year":2022,"claim":"The structural basis of prodomain autoinhibition was elucidated: the CUB domain sterically blocks PDGFR-β D2/D3 recognition of the growth factor domain, explaining why proteolytic removal is required, with differential inhibitory specificity for PDGF-D versus PDGF-B-induced proliferation.","evidence":"Structural modeling with mutagenesis-supported transphosphorylation and proliferation assays","pmids":["35777468"],"confidence":"High","gaps":["No experimental crystal/cryo-EM structure of full-length PDGF-DD","Prodomain interactions with ECM components not characterized"]},{"year":2023,"claim":"PDGFD was connected to coronary artery disease risk through FOXC1/C2-dependent transcription at the rs2019090 locus, with Pdgfd knockdown reducing SMC chondromyocyte transition and macrophage-recruiting chemokine expression in atherosclerosis.","evidence":"Fine-mapping, ChIP, Pdgfd KD in SMC lineage-tracing atherosclerosis mouse model, scRNA-seq","pmids":["36792607"],"confidence":"High","gaps":["Whether the CAD SNP effect is fully mediated through PDGFD or includes neighboring genes not excluded","Human vascular cell validation limited"]},{"year":2025,"claim":"PDGF-D was discovered to be a noncanonical ligand for NKp44 on human ILC3s and to signal through PDGFR-β on ILC3s in mice, promoting IL-22-dependent intestinal immunity; NKp44 engagement drives a distinct type-1 effector programme, revealing an unexpected immunological role.","evidence":"PDGFR-β conditional KO in ILC3s, NKp44 transgenic mice, PDGF-D reporter mice, enteric infection models","pmids":["41758927"],"confidence":"High","gaps":["Whether PDGF-D–NKp44 interaction is direct or requires co-receptor not fully resolved","Relevance to human IBD or intestinal infection not tested clinically","Signaling downstream of NKp44 upon PDGF-D engagement not mapped"]},{"year":null,"claim":"Key unresolved questions include the atomic structure of full-length PDGF-DD and its receptor complexes, the tissue-specific hierarchy of activating proteases, the functional distinction between PDGFR-α- and PDGFR-β-mediated signaling downstream of PDGF-D, and whether therapeutic PDGF-D modulation can translate to human fibrotic, cardiovascular, or immune diseases.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental high-resolution structure of PDGF-DD or CUB domain","Tissue-specific protease hierarchy unresolved","Clinical translation data absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,3,4,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,11]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,11,15]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,10,14,17]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[8,9,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,21,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,27]}],"complexes":["PDGF-DD homodimer"],"partners":["PDGFRB","PDGFRA","NRP1","PLAU","ST14","PLG"],"other_free_text":[]},"mechanistic_narrative":"PDGF-D is a secreted growth factor that functions as a major activator of PDGFR-β signaling to drive mesenchymal cell proliferation, migration, fibrosis, angiogenesis, and immune cell recruitment. It is produced as an inactive disulfide-linked homodimer (PDGF-DD) with an N-terminal CUB prodomain that sterically blocks receptor engagement at the D2/D3 domains of PDGFR-β; extracellular proteolytic cleavage by plasmin, uPA, or matriptase releases the active growth factor domain dimer, while matriptase can further generate a dominant-negative hemidimer intermediate [PMID:11331881, PMID:25678707, PMID:35777468, PMID:34236404]. Active PDGF-DD signals primarily through PDGFR-β and secondarily through PDGFR-α, engaging NRP1 as a co-receptor via its C-terminal arginine, and activating PI3K/AKT, ERK1/2, JNK, p38, and STAT3 cascades to promote fibroblast and smooth muscle cell expansion, extracellular matrix deposition, epithelial-mesenchymal transition, and vascular pericyte recruitment [PMID:11331882, PMID:17397961, PMID:28254885, PMID:36792607]. PDGF-D also serves as a noncanonical ligand for NKp44 on human ILC3s and signals through PDGFR-β on murine ILC3s to promote IL-22 production and intestinal immunity, and it is selectively expressed by human radial glia where it drives cortical progenitor proliferation [PMID:41758927, PMID:25391964]."},"prefetch_data":{"uniprot":{"accession":"Q9GZP0","full_name":"Platelet-derived growth factor D","aliases":["Iris-expressed growth factor","Spinal cord-derived growth factor B","SCDGF-B"],"length_aa":370,"mass_kda":42.8,"function":"Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen for cells of mesenchymal origin. Plays an important role in wound healing. Induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. 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domains.","date":"2021","source":"Platelets","url":"https://pubmed.ncbi.nlm.nih.gov/34275420","citation_count":4,"is_preprint":false},{"pmid":"40650643","id":"PMC_40650643","title":"EGR1 Promotes Craniofacial Bone Regeneration via Activation of ALPL⁺PDGFD⁺ Periosteal Stem Cells.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40650643","citation_count":3,"is_preprint":false},{"pmid":"40348059","id":"PMC_40348059","title":"Comprehensive Clinicopathological and Multiomics Characterization of Dermatofibrosarcoma Protuberans Revealed PDGFD Fusion as Distinct Molecular Subtype With Better Survival.","date":"2025","source":"Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc","url":"https://pubmed.ncbi.nlm.nih.gov/40348059","citation_count":3,"is_preprint":false},{"pmid":"38705811","id":"PMC_38705811","title":"The role of THBS1 and PDGFD in the immune microenvironment of Helicobacter pylori-associated gastric cancer.","date":"2024","source":"Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/38705811","citation_count":2,"is_preprint":false},{"pmid":"36747745","id":"PMC_36747745","title":"Molecular mechanisms of coronary artery disease risk at the PDGFD locus.","date":"2023","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/36747745","citation_count":1,"is_preprint":false},{"pmid":"26362023","id":"PMC_26362023","title":"A study on the association of rs7950273 polymorphism in the PDGFD with ischaemic stroke in the Chinese Han population.","date":"2015","source":"Annals of human biology","url":"https://pubmed.ncbi.nlm.nih.gov/26362023","citation_count":1,"is_preprint":false},{"pmid":"40152369","id":"PMC_40152369","title":"Effect of HepG2-Derived Exosome with PDGF-D Knockdown on Transformation of Normal Fibroblasts into Tumor-Associated Fibroblasts in Liver Cancer.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/40152369","citation_count":1,"is_preprint":false},{"pmid":"33762562","id":"PMC_33762562","title":"Retracted: Effects of 3-Tetrazolyl Methyl-3-Hydroxy-Oxindole Hybrid (THOH) on Cell Proliferation, Apoptosis, and G2/M Cell Cycle Arrest Occurs by Targeting Platelet-Derived Growth Factor D (PDGF-D) and the MEK/ERK Signaling Pathway in Human Lung Cell Lines SK-LU-1, A549, and A-427.","date":"2021","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/33762562","citation_count":1,"is_preprint":false},{"pmid":"40530904","id":"PMC_40530904","title":"PDGF-D Promotes Epithelial-Mesenchymal Transition of Glioma Cells Through the NF-κB/NOTCH1 Pathway.","date":"2025","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40530904","citation_count":0,"is_preprint":false},{"pmid":"39085670","id":"PMC_39085670","title":"CCL28 promotes progression of hepatocellular carcinoma through PDGFD-regulated MMP9 and VEGFA pathways.","date":"2024","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/39085670","citation_count":0,"is_preprint":false},{"pmid":"41899473","id":"PMC_41899473","title":"PDGFD: A Dual-Function Regulator That Maintains Myoblast Pool and Fuels Myogenic Differentiation.","date":"2026","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41899473","citation_count":0,"is_preprint":false},{"pmid":"40909696","id":"PMC_40909696","title":"The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/40909696","citation_count":0,"is_preprint":false},{"pmid":"38309427","id":"PMC_38309427","title":"PDGF-D Is Dispensable for the Development and Progression of Murine Alport Syndrome.","date":"2024","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38309427","citation_count":0,"is_preprint":false},{"pmid":"41711154","id":"PMC_41711154","title":"Novel FGL2::PDGFD and TGFBI::PDGFB Fusions Expand the Molecular Spectrum of Dermatofibrosarcoma Protuberans.","date":"2026","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/41711154","citation_count":0,"is_preprint":false},{"pmid":"41767679","id":"PMC_41767679","title":"PDGFD maintains ovine tail ADSCs in a proliferative state by suppressing CXCL8 and activating PI3K/MAPK signaling.","date":"2026","source":"Frontiers in veterinary science","url":"https://pubmed.ncbi.nlm.nih.gov/41767679","citation_count":0,"is_preprint":false},{"pmid":"41758927","id":"PMC_41758927","title":"Divergent ILC3 responses to PDGF-D control mucosal immunity.","date":"2026","source":"Science immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41758927","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47118,"output_tokens":7462,"usd":0.126642},"stage2":{"model":"claude-opus-4-6","input_tokens":11408,"output_tokens":6902,"usd":0.344385},"total_usd":0.471027,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-D is secreted as a disulphide-linked homodimer (PDGF-DD) and requires limited proteolysis for activation; upon proteolytic cleavage it becomes a specific agonistic ligand for PDGFR-β.\",\n      \"method\": \"Recombinant protein expression, biochemical characterization, receptor-binding and receptor activation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original discovery paper with reconstitution, receptor binding, and functional assays; independently confirmed by second concurrent paper (PMID:11331882)\",\n      \"pmids\": [\"11331881\", \"11331882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-D binds to and activates PDGFR-β; in cells expressing both receptors it can also activate PDGFR-α, likely through PDGFR-α/β heterodimerization.\",\n      \"method\": \"Receptor-specific cell lines, DNA synthesis assay, receptor phosphorylation assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional assays with mutagenesis context; replicated across two independent labs in same year\",\n      \"pmids\": [\"11331882\", \"11331881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGFD gene maps to chromosome 11q22.3 and has a two-domain structure with an N-terminal CUB domain (encoded by exons 2–3) and a C-terminal PDGF cystine-knot growth factor homology domain (encoded by last 2 exons); proteolytic cleavage site is in exon 5.\",\n      \"method\": \"Fluorescence in situ hybridization, genomic DNA sequencing, exon structure determination\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural/genomic characterization with sequencing\",\n      \"pmids\": [\"11342471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PDGF-D acts as a potent transforming growth factor for NIH/3T3 cells via PDGFR-β activation, inducing stress fibre reorganization, anchorage-independent growth, tumour formation in nude mice, and upregulation of VEGF.\",\n      \"method\": \"Stable transfection, soft agar assay, nude mouse tumour model, VEGF measurement\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in single study\",\n      \"pmids\": [\"12629513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PDGF-D signals through PDGFR-β to activate ERK1/2, JNK, p38 MAPK, and PKB/Akt in hepatic stellate cells and myofibroblasts, exerting mitogenic and fibrogenic effects comparable to PDGF-B.\",\n      \"method\": \"PDGFRβ autophosphorylation assay, Western blot of downstream kinases, cell proliferation and collagen assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts with functional consequence\",\n      \"pmids\": [\"17397961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Full-length PDGF-D is activated in tissues and promotes macrophage recruitment, increased interstitial fluid pressure, and maturation/pericyte coating of blood vessels in vivo; combined expression with VEGF-E inhibits vascular leakiness.\",\n      \"method\": \"Transgenic mouse overexpression, adeno-associated virus vector delivery, histology, interstitial fluid pressure measurement, wound healing assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vivo models with defined phenotypic readouts\",\n      \"pmids\": [\"15271796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"PDGF-D is a potent mesangial cell mitogen; adenoviral overexpression of PDGF-D in mice causes severe mesangial proliferative glomerulopathy via PDGFR-β engagement, whereas PDGF-C overexpression causes no measurable renal response.\",\n      \"method\": \"Adenoviral vector injection in mice, histology, in vitro mitogenicity assay\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gain-of-function with specific phenotypic readout, confirmed in vitro\",\n      \"pmids\": [\"14747375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Neutralizing PDGF-DD with fully human monoclonal antibody CR002 reduces glomerular mesangial cell proliferation, monocyte/macrophage infiltration, and fibronectin accumulation in rat mesangioproliferative nephritis.\",\n      \"method\": \"Neutralizing antibody treatment in rat anti-Thy1.1 nephritis model, immunostaining, BrdU incorporation\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dose-dependent in vivo functional antagonism with multiple readouts\",\n      \"pmids\": [\"12937299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PDGF-D antagonism by CR002 antibody in progressive glomerulonephritis reduces glomerulosclerosis, podocyte damage, tubulointerstitial fibrosis, collagen/fibronectin accumulation, and cortical macrophage infiltration, implicating PDGF-D in renal scarring.\",\n      \"method\": \"Long-term antibody treatment in uninephrectomised anti-Thy-1.1 rat model, histology, immunostaining\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with multiple orthogonal readouts over 8-week study\",\n      \"pmids\": [\"16510766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Pdgfd knockout mice show significantly reduced renal interstitial fibrosis in unilateral ureteral obstruction and ischemia/reperfusion injury models, associated with reduced PDGFR-β and p38 phosphorylation; adenoviral PDGF-D overexpression increases renal collagen deposition.\",\n      \"method\": \"Pdgfd knockout mice, adenoviral overexpression, UUO and IRI models, histology, phosphoprotein analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO combined with gain-of-function, two independent disease models\",\n      \"pmids\": [\"26924050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDGF-D binds NRP1 via its C-terminal Arg residue; PDGF-D (but not PDGF-B) stimulation induces PDGFRβ–NRP1 complex formation in fibroblasts, translocates NRP1 to cell-cell junctions in endothelial cells (independently of PDGFRβ), and can signal in trans between endothelial cells and pericytes.\",\n      \"method\": \"Co-immunoprecipitation, direct binding assay, mutagenesis of C-terminal Arg, confocal microscopy, ex vivo sprouting assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding confirmed by mutagenesis, complex formation by Co-IP, functional consequence in sprouting assay\",\n      \"pmids\": [\"28254885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Matriptase cleaves full-length PDGF-D dimer in a stepwise manner generating a hemidimer (HD) intermediate and then the active growth factor domain dimer (GFD-D); the cleavage site is R340R341GR343A within loop III of the GFD which is critical for PDGFRβ binding; the HD acts as a dominant-negative ligand; matriptase can further cleave and inactivate GFD-D; PDGF-D dimer species differentially deposit into the extracellular matrix.\",\n      \"method\": \"In vitro matriptase cleavage assay, mutagenesis of cleavage site, receptor activation assay, ECM binding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and multiple functional readouts\",\n      \"pmids\": [\"25678707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The PDGF-D CUB/prodomain inhibits PDGFR-β activation by sterically blocking D2/D3 receptor domains from recognizing the growth factor domain; the prodomain inhibits both PDGF-B and PDGF-D-mediated PDGFR-β transphosphorylation but inhibits NIH 3T3 cell proliferation induced by PDGF-D but not by PDGF-B, demonstrating differential inhibitory specificity.\",\n      \"method\": \"Structural modeling, in vitro PDGFR-β transphosphorylation assay, cell proliferation assay, prodomain inhibition experiments\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural modeling with mutagenesis-supported in vitro functional validation\",\n      \"pmids\": [\"35777468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDGFD is specifically expressed by radial glia in human but not mouse neocortex; pharmacological inhibition of PDGFD–PDGFRβ signalling in human cortical slice cultures prevents cell cycle progression of radial glia; ectopic PDGFD or constitutively active PDGFRβ in mouse neocortex increases radial glia proportion and subventricular dispersion.\",\n      \"method\": \"Transcriptional profiling, pharmacological inhibition in slice culture, in utero electroporation/injection in mouse\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic gain-of-function experiments with defined cellular phenotypes; published in Nature\",\n      \"pmids\": [\"25391964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HIF1α binds the PDGFD proximal promoter and PDGFRA intron enhancers in GBM cells under normoxia/mild-hypoxia to induce their expression; PDGF-D/PDGFRα constitutively activates AKT signaling which in turn increases HIF1α protein, forming a feedforward loop; severe hypoxia abrogates PDGFRα despite enhancing PDGF-D expression.\",\n      \"method\": \"ChIP analysis, sgRNA-Cas9 knockout, RNA-seq, loss/gain-of-function assays, intracranial xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for direct promoter binding, genetic KO with in vivo validation\",\n      \"pmids\": [\"34470658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Macrophage-derived urokinase plasminogen activator (uPA) activates PDGF-D by cleaving full-length PDGF-D into the active PDGF-DD form, promoting cardiac remodeling in obese hypertensive mice; adipocyte-specific PDGF-D knockout attenuates this remodeling.\",\n      \"method\": \"Adipocyte-specific KO and transgenic mice, bone marrow-specific uPA knockdown, ELISA for active PDGF-DD, Western blot\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic models (KO, KD, transgenic) with mechanistic identification of uPA as activating protease\",\n      \"pmids\": [\"34236404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXC1/C2 transcription factor binding at the CAD-risk SNP rs2019090 promotes PDGFD transcription; Pdgfd promotes SMC expansion, migration, and transition to chondromyocyte phenotype in atherosclerosis; Pdgfd-expressing adventitial fibroblasts and pericytes express chemokines and leukocyte adhesion molecules linked to macrophage recruitment.\",\n      \"method\": \"Fine-mapping, ChIP, Pdgfd knockdown in SMC lineage-tracing atherosclerosis mouse model, single-cell transcriptomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches (genetic KO, lineage tracing, scRNA-seq, ChIP) in single study\",\n      \"pmids\": [\"36792607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDGF-D regulates proliferation and migration of adipose-derived stem cells (ASCs) through PI3K/Akt pathways and via mitochondrial reactive oxygen species generation and mitochondrial fission mediated by p66Shc phosphorylation; PDGF-D upregulates expression of multiple growth factors (VEGFA, FGF1, FGF5, etc.) through MAPK signalling.\",\n      \"method\": \"siRNA knockdown, pathway inhibitors, mitochondrial ROS measurement, RT-PCR, proliferation and migration assays\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts but single lab\",\n      \"pmids\": [\"25332166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In portal myofibroblasts and hepatic stellate cells, PDGF-D binds PDGFR-α as well as PDGFR-β, inducing receptor endocytosis, PDGFR-α-specific tyrosine phosphorylation (Y754 and Y1018), and CrkII adaptor protein recruitment; a recombinant PDGFR-α-Fc chimera blocks PDGF-D signaling.\",\n      \"method\": \"Receptor phosphorylation assay, receptor endocytosis assay, CrkII pulldown, PDGFR-α-Fc inhibition\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — biochemical assays with multiple signaling readouts; single lab\",\n      \"pmids\": [\"25819339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ZIC5 transcriptionally upregulates PDGFD expression in melanoma; PDGF-D activates FAK and STAT3 to confer drug resistance; silencing ZIC5 or PDGFD enhances apoptosis under BRAF inhibition; FAK and STAT3 positively feedback to sustain ZIC5 expression.\",\n      \"method\": \"siRNA screening, microarray, Western blot, apoptosis assay, in vivo melanoma model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement by epistasis/knockdown with functional readouts; single lab\",\n      \"pmids\": [\"27671679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDGF-D (via PDGFR-β signalling) upregulates androgen receptor expression and nuclear AR translocation in PTEN-null prostate cells; AR contributes to radiation resistance; PDGF-D overexpression increases radioresistance reversed by enzalutamide.\",\n      \"method\": \"Immunoblot of nuclear/cytosolic AR fractions, RT-PCR of AR target genes, clonogenic survival assay, irradiation experiments\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct measurement of AR pathway, functional radioresistance readout; single lab\",\n      \"pmids\": [\"26732854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PDGF-D–PDGFR-β signalling mediates post-ICH neuroinflammation; plasmin acts as an upstream activator of PDGF-D; PDGF-D promotes macrophage infiltration and TNF-α production; PDGFR-β inhibition reduces microglial activation and brain injury.\",\n      \"method\": \"Mouse ICH model with siRNA knockdown of PDGF-D, recombinant PDGF-D injection, PDGFR inhibitor (Gleevec), plasmin antagonist (EACA), immunostaining\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic interventions with defined phenotypic readouts; single lab\",\n      \"pmids\": [\"27302678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PDGF-D overexpression promotes lymph node metastasis through induction of CXCR4 expression; blockade of CXCR4 abolishes PDGF-D-induced lymph node metastasis; PDGF-D increases perivascular cell coverage and normalises tumour vessels.\",\n      \"method\": \"Stable transfection of breast cancer cells, shRNAi, imatinib treatment, orthotopic mouse model, CXCR4 blockade\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological pathway placement with in vivo readouts\",\n      \"pmids\": [\"21459800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDGF-D released by adipose tissue-derived stem cells (ASCs) induces epithelial-mesenchymal transition (EMT) in breast cancer cells in a paracrine manner; neutralising PDGF-D antibody blocks this EMT and tumour growth.\",\n      \"method\": \"Conditioned medium experiments, neutralising antibody, Western blot for EMT markers, flow cytometry, mouse tumour model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — neutralising antibody confirms PDGF-D as the active paracrine factor; multiple readouts\",\n      \"pmids\": [\"22038895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PDGF-D promotes EMT in colorectal cancer by upregulating Notch1 and Twist1; Notch1 overexpression rescues the effects of PDGF-D knockdown on Twist1 expression, placing PDGF-D upstream of Notch1/Twist1 axis.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, Western blot, migration assays, xenograft model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis rescue experiment placing PDGF-D upstream of Notch1/Twist1; single lab\",\n      \"pmids\": [\"28035069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PDGFD promoter is reversibly demethylated in gemcitabine-resistant PDAC cells, increasing PDGFD expression; PDGF-D activates STAT3 in autocrine and paracrine manner to upregulate RRM1 expression, causing gemcitabine resistance.\",\n      \"method\": \"Reduced Representation Bisulfite Sequencing, demethylation experiments, STAT3 inhibition, RRM1 measurement, in vitro and in vivo resistance models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epigenetic mechanism + downstream signaling identified with functional validation\",\n      \"pmids\": [\"37321532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PDGF-D promotes fibroblast invasion in 3D collagen gels via PI3K, JNK, and ERK1/2 signalling pathways, inducing Snail expression which in turn upregulates MT1-MMP.\",\n      \"method\": \"3D type I collagen invasion assay, Snail siRNA knockdown, PI3K/JNK/ERK inhibitors, Western blot and RT-PCR\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway dissected with multiple inhibitors and epistatic knockdown; single lab\",\n      \"pmids\": [\"26234766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDGFD drives endothelial commitment of embryonic stem cells via the MAPK/ERK pathway; PDGFD deletion or knockdown inhibits ESC differentiation into endothelial cells and reduces blood vessel density in embryonic, neonatal, and teratoma models.\",\n      \"method\": \"Loss- and gain-of-function assays, RNA sequencing, PDGFD knockout mice, embryonic and neonatal vascular analysis\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple in vivo models and pathway identification\",\n      \"pmids\": [\"35859222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Endothelial PDGF-D is transiently induced at ischemic stroke injury sites; increased PDGF-D bioavailability attenuates pericyte loss and fibrotic transition, promotes pericyte migration and endothelial coverage, and stimulates pro-angiogenic factor secretion, improving neurovascular recovery.\",\n      \"method\": \"Mouse ischemic stroke model, siRNA knockdown, recombinant PDGF-D administration, cell-based ischemia assays with human brain pericytes and endothelial cells\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss and gain of function with defined cellular and in vivo readouts; single lab\",\n      \"pmids\": [\"38769116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDGF-D induces MMP-9 mRNA expression and enhances secretion of MMP-2 and MMP-9 in monocytes/macrophages, and promotes monocyte migration in a concentration-dependent manner.\",\n      \"method\": \"Boyden chamber migration assay, RT-PCR for MMP-9, MMP-2/9 secretion assay\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct functional assays but single lab; multiple readouts\",\n      \"pmids\": [\"18573494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PVAT-derived PDGF-D promotes adventitial fibroblast proliferation, migration, and inflammatory factor expression; adipocyte-specific PDGF-D transgenic mice show exacerbated aortic aneurysm formation with AngII infusion; PDGF-D inhibition reduces AA incidence.\",\n      \"method\": \"Transcriptome analysis, adipocyte-specific transgenic mice, PDGF-D function inhibition, cultured adventitial fibroblast assays\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic transgenic and inhibition models with defined in vivo phenotype; single lab\",\n      \"pmids\": [\"29794241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-145-5p directly targets PDGFD mRNA (validated by luciferase reporter assay); miR-145-5p inhibition promotes wound healing in diabetic foot ulcer models through upregulation of PDGFD, which increases fibroblast viability and migration.\",\n      \"method\": \"Luciferase reporter assay, miR-145-5p mimics/inhibitors, wound healing assay, DFU mouse model\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct miRNA-target validation by luciferase assay with in vivo functional confirmation\",\n      \"pmids\": [\"37950842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDGF-D acts as a noncanonical ligand for NKp44 on human ILC3s; in mice (which lack NKp44), PDGF-D promotes IL-22 production and ILC3 proliferation through PDGFRβ; mice lacking PDGFRβ in ILC3s are susceptible to enteric infections; in NKp44-transgenic mice, PDGF-D engagement of NKp44 drives a type-1 effector programme (TNF-α and IFN-γ); fibroblasts and endothelial cells are the inflammation-responsive cellular source of PDGF-D.\",\n      \"method\": \"PDGFRβ conditional KO in ILC3s, NKp44 transgenic mice, PDGF-D reporter mice, enteric infection model, cytokine measurement\",\n      \"journal\": \"Science immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic models with defined functional readouts across species; multiple orthogonal approaches\",\n      \"pmids\": [\"41758927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pdgfd–Pdgfrb signalling in pancreatic cancer promotes perineural invasion by stimulating cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia; pharmacological blockade reduces perineural invasion in vivo.\",\n      \"method\": \"Spatial transcriptomics, in vitro invasion/neurite outgrowth assays, pharmacological inhibition, in vivo PNI model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple functional assays with in vivo validation; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"40909696\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PDGF-D is secreted as an inactive disulphide-linked homodimer requiring extracellular proteolytic cleavage (by proteases including plasmin, uPA, and matriptase) of its N-terminal CUB/prodomain to release the active growth factor domain dimer, which then signals primarily through PDGFR-β (and secondarily through PDGFR-α/β heterodimers or PDGFR-α), with NRP1 acting as a co-receptor, activating downstream PI3K/AKT, MAPK/ERK, JNK, p38, and STAT3 pathways to drive mesenchymal cell proliferation, migration, fibrosis, angiogenesis, EMT, and immune cell recruitment in development and disease.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDGF-D is a secreted growth factor that functions as a major activator of PDGFR-β signaling to drive mesenchymal cell proliferation, migration, fibrosis, angiogenesis, and immune cell recruitment. It is produced as an inactive disulfide-linked homodimer (PDGF-DD) with an N-terminal CUB prodomain that sterically blocks receptor engagement at the D2/D3 domains of PDGFR-β; extracellular proteolytic cleavage by plasmin, uPA, or matriptase releases the active growth factor domain dimer, while matriptase can further generate a dominant-negative hemidimer intermediate [PMID:11331881, PMID:25678707, PMID:35777468, PMID:34236404]. Active PDGF-DD signals primarily through PDGFR-β and secondarily through PDGFR-α, engaging NRP1 as a co-receptor via its C-terminal arginine, and activating PI3K/AKT, ERK1/2, JNK, p38, and STAT3 cascades to promote fibroblast and smooth muscle cell expansion, extracellular matrix deposition, epithelial-mesenchymal transition, and vascular pericyte recruitment [PMID:11331882, PMID:17397961, PMID:28254885, PMID:36792607]. PDGF-D also serves as a noncanonical ligand for NKp44 on human ILC3s and signals through PDGFR-β on murine ILC3s to promote IL-22 production and intestinal immunity, and it is selectively expressed by human radial glia where it drives cortical progenitor proliferation [PMID:41758927, PMID:25391964].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of PDGF-D as a new PDGFR-β ligand resolved a long-standing gap in the PDGF family by showing that PDGF-DD is secreted as an inactive homodimer requiring proteolytic processing to bind and activate PDGFR-β, and can also engage PDGFR-α/β heterodimers.\",\n      \"evidence\": \"Recombinant protein expression, receptor binding/activation assays, genomic mapping (two independent labs published concurrently)\",\n      \"pmids\": [\"11331881\", \"11331882\", \"11342471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of physiologically relevant activating proteases was unknown\", \"No structural model of prodomain-mediated autoinhibition\", \"Receptor specificity on cells co-expressing both PDGFRs not fully resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"PDGF-D was established as a potent mitogen and fibrogenic factor, activating ERK1/2, JNK, p38, and AKT downstream of PDGFR-β in hepatic stellate cells and transforming NIH/3T3 cells, demonstrating oncogenic and pro-fibrotic potential.\",\n      \"evidence\": \"Stable transfection/nude mouse tumorigenesis, signaling pathway Western blots, mesangial cell proliferation assays, neutralizing antibody (CR002) in rat nephritis model\",\n      \"pmids\": [\"12629513\", \"17397961\", \"12937299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo activating proteases still unidentified\", \"Relative contribution versus PDGF-B in fibrosis not delineated\", \"Downstream transcriptional programs not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vivo gain-of-function studies demonstrated that PDGF-D recruits macrophages, promotes vessel maturation, and specifically causes mesangial proliferative glomerulopathy through PDGFR-β, distinguishing its biology from PDGF-C.\",\n      \"evidence\": \"Transgenic/adenoviral overexpression in mice, histology, interstitial fluid pressure measurement\",\n      \"pmids\": [\"15271796\", \"14747375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loss-of-function genetic evidence still lacking\", \"Mechanism of macrophage recruitment (direct vs. indirect) unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Long-term PDGF-D neutralization in progressive glomerulonephritis proved that PDGF-D drives renal scarring including glomerulosclerosis, tubulointerstitial fibrosis, and podocyte damage, establishing therapeutic relevance.\",\n      \"evidence\": \"8-week CR002 antibody treatment in uninephrectomized anti-Thy1.1 rat model with multiple histological readouts\",\n      \"pmids\": [\"16510766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDGF-D inhibition reverses established fibrosis was not tested\", \"Human translation not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of species-specific PDGFD expression in human radial glia expanded PDGF-D's role beyond mesenchymal biology, showing it drives cortical progenitor proliferation and may have contributed to human neocortical expansion.\",\n      \"evidence\": \"Transcriptional profiling of sorted radial glia, pharmacological inhibition in human cortical slices, in utero electroporation in mouse\",\n      \"pmids\": [\"25391964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets in radial glia not identified\", \"Whether PDGF-D is sufficient for cortical expansion in non-human primates untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The proteolytic activation mechanism was biochemically resolved: matriptase performs stepwise cleavage of PDGF-DD generating a dominant-negative hemidimer intermediate before releasing the active GFD dimer, with a critical R340R341 cleavage site overlapping the PDGFR-β binding interface; NRP1 was identified as a PDGF-D-specific co-receptor binding via the C-terminal arginine.\",\n      \"evidence\": \"In vitro matriptase reconstitution with mutagenesis, Co-IP of PDGFR-β–NRP1 complex, C-terminal Arg mutagenesis, ex vivo sprouting assay\",\n      \"pmids\": [\"25678707\", \"28254885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of PDGF-D GFD or CUB domain not determined\", \"Whether NRP1 co-receptor function alters downstream signaling quality unknown\", \"Hemidimer function in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic knockout of Pdgfd confirmed its non-redundant role in renal fibrosis, showing reduced PDGFR-β/p38 signaling in two independent injury models and establishing PDGF-D as a bona fide fibrogenic driver in vivo.\",\n      \"evidence\": \"Pdgfd KO mice in UUO and IRI models, adenoviral gain-of-function, phosphoprotein analysis\",\n      \"pmids\": [\"26924050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combined Pdgfd/Pdgfb genetic studies not performed\", \"Whether PDGF-D drives fibrosis in lung, liver, or heart by the same mechanism untested at KO level\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"PDGF-D was placed in multiple disease-relevant signaling circuits: activating STAT3/FAK to confer BRAF-inhibitor resistance in melanoma, upregulating androgen receptor for radioresistance in prostate cancer, and mediating neuroinflammation after intracerebral hemorrhage via plasmin-dependent activation.\",\n      \"evidence\": \"siRNA screening and epistasis in melanoma, nuclear AR fractionation in prostate cells, mouse ICH model with siRNA and Gleevec\",\n      \"pmids\": [\"27671679\", \"26732854\", \"27302678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each disease link from single lab\", \"Direct PDGF-D–STAT3 connection versus indirect via PDGFR-β not fully resolved\", \"Clinical relevance of PDGF-D in drug resistance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Macrophage-derived uPA was identified as a physiologically relevant activating protease for PDGF-D in cardiac remodeling, and HIF1α was shown to directly bind the PDGFD promoter to create a feedforward loop with PDGFR-α/AKT signaling in glioblastoma.\",\n      \"evidence\": \"Adipocyte-specific Pdgfd KO and uPA bone-marrow KD in obese mice; ChIP and CRISPR KO in GBM cells with intracranial xenograft\",\n      \"pmids\": [\"34236404\", \"34470658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether uPA is the dominant activating protease across tissues remains open\", \"PDGFR-α versus PDGFR-β signaling quality downstream of PDGF-D in GBM not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The structural basis of prodomain autoinhibition was elucidated: the CUB domain sterically blocks PDGFR-β D2/D3 recognition of the growth factor domain, explaining why proteolytic removal is required, with differential inhibitory specificity for PDGF-D versus PDGF-B-induced proliferation.\",\n      \"evidence\": \"Structural modeling with mutagenesis-supported transphosphorylation and proliferation assays\",\n      \"pmids\": [\"35777468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental crystal/cryo-EM structure of full-length PDGF-DD\", \"Prodomain interactions with ECM components not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PDGFD was connected to coronary artery disease risk through FOXC1/C2-dependent transcription at the rs2019090 locus, with Pdgfd knockdown reducing SMC chondromyocyte transition and macrophage-recruiting chemokine expression in atherosclerosis.\",\n      \"evidence\": \"Fine-mapping, ChIP, Pdgfd KD in SMC lineage-tracing atherosclerosis mouse model, scRNA-seq\",\n      \"pmids\": [\"36792607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CAD SNP effect is fully mediated through PDGFD or includes neighboring genes not excluded\", \"Human vascular cell validation limited\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PDGF-D was discovered to be a noncanonical ligand for NKp44 on human ILC3s and to signal through PDGFR-β on ILC3s in mice, promoting IL-22-dependent intestinal immunity; NKp44 engagement drives a distinct type-1 effector programme, revealing an unexpected immunological role.\",\n      \"evidence\": \"PDGFR-β conditional KO in ILC3s, NKp44 transgenic mice, PDGF-D reporter mice, enteric infection models\",\n      \"pmids\": [\"41758927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDGF-D–NKp44 interaction is direct or requires co-receptor not fully resolved\", \"Relevance to human IBD or intestinal infection not tested clinically\", \"Signaling downstream of NKp44 upon PDGF-D engagement not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of full-length PDGF-DD and its receptor complexes, the tissue-specific hierarchy of activating proteases, the functional distinction between PDGFR-α- and PDGFR-β-mediated signaling downstream of PDGF-D, and whether therapeutic PDGF-D modulation can translate to human fibrotic, cardiovascular, or immune diseases.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental high-resolution structure of PDGF-DD or CUB domain\", \"Tissue-specific protease hierarchy unresolved\", \"Clinical translation data absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 11, 15]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 1, 4, 10, 14, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 10, 14, 17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 9, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 21, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 27]}\n    ],\n    \"complexes\": [\n      \"PDGF-DD homodimer\"\n    ],\n    \"partners\": [\n      \"PDGFRB\",\n      \"PDGFRA\",\n      \"NRP1\",\n      \"PLAU\",\n      \"ST14\",\n      \"PLG\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway entries — I accidentally included a GO term. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"PDGF-D is a secreted growth factor that functions as a major activator of PDGFR-β signaling to drive mesenchymal cell proliferation, migration, fibrosis, angiogenesis, and immune cell recruitment. It is produced as an inactive disulfide-linked homodimer (PDGF-DD) with an N-terminal CUB prodomain that sterically blocks receptor engagement at the D2/D3 domains of PDGFR-β; extracellular proteolytic cleavage by plasmin, uPA, or matriptase releases the active growth factor domain dimer, while matriptase can further generate a dominant-negative hemidimer intermediate [PMID:11331881, PMID:25678707, PMID:35777468, PMID:34236404]. Active PDGF-DD signals primarily through PDGFR-β and secondarily through PDGFR-α, engaging NRP1 as a co-receptor via its C-terminal arginine, and activating PI3K/AKT, ERK1/2, JNK, p38, and STAT3 cascades to promote fibroblast and smooth muscle cell expansion, extracellular matrix deposition, epithelial-mesenchymal transition, and vascular pericyte recruitment [PMID:11331882, PMID:17397961, PMID:28254885, PMID:36792607]. PDGF-D also serves as a noncanonical ligand for NKp44 on human ILC3s and signals through PDGFR-β on murine ILC3s to promote IL-22 production and intestinal immunity, and it is selectively expressed by human radial glia where it drives cortical progenitor proliferation [PMID:41758927, PMID:25391964].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of PDGF-D as a new PDGFR-β ligand resolved a long-standing gap in the PDGF family by showing that PDGF-DD is secreted as an inactive homodimer requiring proteolytic processing to bind and activate PDGFR-β, and can also engage PDGFR-α/β heterodimers.\",\n      \"evidence\": \"Recombinant protein expression, receptor binding/activation assays, genomic mapping (two independent labs published concurrently)\",\n      \"pmids\": [\"11331881\", \"11331882\", \"11342471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of physiologically relevant activating proteases was unknown\", \"No structural model of prodomain-mediated autoinhibition\", \"Receptor specificity on cells co-expressing both PDGFRs not fully resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"PDGF-D was established as a potent mitogen and fibrogenic factor, activating ERK1/2, JNK, p38, and AKT downstream of PDGFR-β in hepatic stellate cells and transforming NIH/3T3 cells, while neutralizing antibody confirmed its role in mesangial proliferative nephritis.\",\n      \"evidence\": \"Stable transfection/nude mouse tumorigenesis, signaling pathway Western blots, CR002 neutralizing antibody in rat nephritis model\",\n      \"pmids\": [\"12629513\", \"17397961\", \"12937299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo activating proteases still unidentified\", \"Relative contribution versus PDGF-B in fibrosis not delineated\", \"Downstream transcriptional programs not mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"In vivo gain-of-function studies demonstrated that PDGF-D recruits macrophages, promotes vessel maturation, and specifically causes mesangial proliferative glomerulopathy through PDGFR-β, distinguishing its biology from PDGF-C.\",\n      \"evidence\": \"Transgenic/adenoviral overexpression in mice, histology, interstitial fluid pressure measurement\",\n      \"pmids\": [\"15271796\", \"14747375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loss-of-function genetic evidence still lacking\", \"Mechanism of macrophage recruitment (direct vs. indirect) unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Long-term PDGF-D neutralization in progressive glomerulonephritis proved that PDGF-D drives renal scarring including glomerulosclerosis, tubulointerstitial fibrosis, and podocyte damage, establishing therapeutic relevance.\",\n      \"evidence\": \"8-week CR002 antibody treatment in uninephrectomized anti-Thy1.1 rat model with multiple histological readouts\",\n      \"pmids\": [\"16510766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDGF-D inhibition reverses established fibrosis was not tested\", \"Human translation not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery of species-specific PDGFD expression in human radial glia expanded PDGF-D's role beyond mesenchymal biology, showing it drives cortical progenitor proliferation and may have contributed to human neocortical expansion.\",\n      \"evidence\": \"Transcriptional profiling of sorted radial glia, pharmacological inhibition in human cortical slices, in utero electroporation in mouse\",\n      \"pmids\": [\"25391964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional targets in radial glia not identified\", \"Whether PDGF-D is sufficient for cortical expansion in non-human primates untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The proteolytic activation mechanism was biochemically resolved: matriptase performs stepwise cleavage generating a dominant-negative hemidimer intermediate, and NRP1 was identified as a PDGF-D-specific co-receptor binding via the C-terminal arginine residue.\",\n      \"evidence\": \"In vitro matriptase reconstitution with mutagenesis, Co-IP of PDGFR-β–NRP1 complex, C-terminal Arg mutagenesis, ex vivo sprouting assay\",\n      \"pmids\": [\"25678707\", \"28254885\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of PDGF-D GFD or CUB domain not determined\", \"Whether NRP1 co-receptor function alters downstream signaling quality unknown\", \"Hemidimer function in vivo not confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Genetic knockout of Pdgfd confirmed its non-redundant role in renal fibrosis and placed PDGF-D in multiple disease-relevant signaling circuits including STAT3/FAK-mediated drug resistance in melanoma, AR upregulation in prostate cancer, and plasmin-dependent neuroinflammation.\",\n      \"evidence\": \"Pdgfd KO mice in UUO/IRI models; siRNA epistasis in melanoma and prostate cancer cells; mouse ICH model with PDGF-D siRNA and Gleevec\",\n      \"pmids\": [\"26924050\", \"27671679\", \"26732854\", \"27302678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Each cancer/disease link from single lab\", \"Combined Pdgfd/Pdgfb genetic studies not performed\", \"Clinical relevance of PDGF-D in drug resistance untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Macrophage-derived uPA was identified as a physiologically relevant activating protease for PDGF-D in cardiac remodeling, and HIF1α was shown to directly bind the PDGFD promoter to create a feedforward loop with PDGFR-α/AKT signaling in glioblastoma.\",\n      \"evidence\": \"Adipocyte-specific Pdgfd KO and uPA bone-marrow KD in obese mice; ChIP and CRISPR KO in GBM cells with intracranial xenograft\",\n      \"pmids\": [\"34236404\", \"34470658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether uPA is the dominant activating protease across tissues remains open\", \"PDGFR-α versus PDGFR-β signaling quality downstream of PDGF-D in GBM not distinguished\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The structural basis of prodomain autoinhibition was elucidated—the CUB domain sterically blocks PDGFR-β D2/D3 recognition—and PDGF-D was shown to drive endothelial commitment of embryonic stem cells via MAPK/ERK.\",\n      \"evidence\": \"Structural modeling with mutagenesis-supported transphosphorylation assays; Pdgfd KO mice with embryonic/neonatal vascular analysis\",\n      \"pmids\": [\"35777468\", \"35859222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental crystal/cryo-EM structure of full-length PDGF-DD\", \"Prodomain interactions with ECM components not characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"PDGFD was connected to coronary artery disease risk through FOXC1/C2-dependent transcription at the rs2019090 locus, with Pdgfd knockdown reducing SMC chondromyocyte transition and atherosclerotic inflammation, while PDGF-D–STAT3–RRM1 signaling was linked to gemcitabine resistance in pancreatic cancer.\",\n      \"evidence\": \"Fine-mapping, ChIP, Pdgfd KD in SMC lineage-tracing atherosclerosis model, scRNA-seq; bisulfite sequencing and STAT3 inhibition in PDAC resistance models\",\n      \"pmids\": [\"36792607\", \"37321532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the CAD SNP effect is fully mediated through PDGFD not excluded\", \"STAT3-RRM1 axis confirmed in single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"PDGF-D was discovered to be a noncanonical ligand for NKp44 on human ILC3s and to signal through PDGFR-β on ILC3s in mice, promoting IL-22-dependent intestinal immunity—revealing an unexpected innate immune function.\",\n      \"evidence\": \"PDGFR-β conditional KO in ILC3s, NKp44 transgenic mice, PDGF-D reporter mice, enteric infection models\",\n      \"pmids\": [\"41758927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PDGF-D–NKp44 interaction is direct or requires co-receptor not fully resolved\", \"Relevance to human IBD or intestinal infection not tested clinically\", \"Signaling downstream of NKp44 upon PDGF-D engagement not mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic structure of full-length PDGF-DD and its receptor complexes, the tissue-specific hierarchy of activating proteases, the functional distinction between PDGFR-α- and PDGFR-β-mediated signaling downstream of PDGF-D, and whether therapeutic PDGF-D modulation can translate to human fibrotic, cardiovascular, or immune diseases.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental high-resolution structure of PDGF-DD or CUB domain\", \"Tissue-specific protease hierarchy unresolved\", \"Clinical translation data absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 3, 4, 6, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 11, 15]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 10, 14, 17]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [8, 9, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 21, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 27]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 22, 25]}\n    ],\n    \"complexes\": [\n      \"PDGF-DD homodimer\"\n    ],\n    \"partners\": [\n      \"PDGFRB\",\n      \"PDGFRA\",\n      \"NRP1\",\n      \"PLAU\",\n      \"ST14\",\n      \"PLG\",\n      \"NCR2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}