{"gene":"PDGFC","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2000,"finding":"PDGF-C is a protease-activated ligand that binds to and activates the PDGF alpha-receptor (PDGFRα). Proteolytic cleavage is required to release the growth factor domain (GFD) from the CUB domain for receptor activation.","method":"Receptor binding assays, transgenic mouse overexpression, in situ hybridization, genetic analysis of Pdgfra-/- kidneys","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (binding, genetic epistasis, transgenic model), independently replicated across multiple subsequent studies","pmids":["10806482"],"is_preprint":false},{"year":2001,"finding":"PDGF-C is a multidomain protein with an N-terminal CUB domain and a C-terminal growth factor domain (GFD). The GFD (PDGF-CC) binds with high affinity to PDGFRα homodimers and PDGFRα/β heterodimers, but not PDGFRβ homodimers. A serum-sensitive cleavage site between the CUB and GFD domains releases the active GFD.","method":"Competition binding assays, immunoprecipitation on cells bearing both receptor types, recombinant protein characterization, mitogenesis assays, diabetic mouse wound healing model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding/immunoprecipitation with recombinant proteins and in vivo validation, replicated by other groups","pmids":["11297552"],"is_preprint":false},{"year":2001,"finding":"PDGF-C genomic structure has 6 exons; the CUB domain is encoded by exons 2–3 and the proteolytic cleavage site activating the growth factor domain is located in exon 4. PDGF-C is expressed predominantly in smooth muscle cells and stimulates coronary artery smooth muscle cell proliferation.","method":"FISH chromosomal mapping, genomic DNA sequencing, cell stimulation assays","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct sequencing and cell-based functional assay, single lab","pmids":["11342471"],"is_preprint":false},{"year":2003,"finding":"The GFD of PDGF-C contains 12 cysteine residues with three intramonomeric disulfide bonds consistent with cystine knot superfamily membership. Structural characterization by CD, fluorescence, NMR, and infrared spectroscopy indicates predominantly beta-sheet secondary structure; homology modeling shows greater structural similarity to VEGF than to PDGF-B.","method":"Ellman assay, CD spectroscopy, NMR spectroscopy, infrared spectroscopy, homology modeling","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — multiple biophysical methods on purified recombinant protein, but modeling is computational and single lab","pmids":["12598536"],"is_preprint":false},{"year":2004,"finding":"Pdgfc-/- mice die perinatally due to complete secondary palate cleft. Pdgfc-/- Pdgfa-/- double knockouts phenocopy Pdgfra-/- (cleft face, subepidermal blistering, renal cortex mesenchyme deficiency, spina bifida, skeletal and vascular defects), establishing by genetic epistasis that PDGF-A and PDGF-C together account for all PDGFRα signaling in craniofacial, neural tube, and mesodermal development.","method":"Genetic knockout, double-knockout epistasis, embryo phenotyping","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous in vivo genetic epistasis with multiple orthogonal phenotypic readouts, single rigorous study with strong controls","pmids":["15361870"],"is_preprint":false},{"year":2001,"finding":"PDGF-C expression in Ewing family tumors (EFT) is transcriptionally upregulated by the chimeric EWS/FLI-1 transcription factor and this regulation is EWS/ETS-specific. PDGF-C expression depends on EWS/FLI activity in EFT cell lines.","method":"Retroviral cDNA biological screen, differential gene regulation, EWS/FLI knockdown/modulation in EFT cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional retroviral screen plus expression dependence, single lab","pmids":["11313995"],"is_preprint":false},{"year":2002,"finding":"A dominant-negative form of PDGF-C that is secreted and processed but has greatly reduced PDGFRα agonist activity inhibits anchorage-independent growth in EFT cell lines and in a PDGF-C-driven fibroblast transformation model, demonstrating that autocrine PDGF-C/PDGFRα signaling drives EFT malignant phenotype.","method":"Dominant-negative mutagenesis, soft-agar colony formation assay, PDGFR inhibitor AG1296","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed dominant-negative mutagenesis with functional readout, single lab","pmids":["12032822"],"is_preprint":false},{"year":2008,"finding":"In renal fibrosis, PDGF-C is produced largely by infiltrating macrophages. PDGF-C acts as a potent mitogen for renal fibroblasts and induces chemokine expression (CCL2, CCL5). Neutralization of PDGF-C reduces renal fibrosis, interstitial myofibroblast accumulation, and leukocyte infiltration; Pdgfc-/- mice show reduced fibrosis and inflammation after ureteral obstruction, suggesting a pro-inflammatory amplification loop.","method":"Anti-PDGF-C neutralizing antiserum in UUO mouse model, Pdgfc-/- mice, in vitro fibroblast mitogenesis and chemokine assays","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (genetic KO, antibody neutralization, in vitro assays) with consistent results","pmids":["18184860"],"is_preprint":false},{"year":2012,"finding":"PDGF-C neutralization or deficiency protects against kidney fibrosis by reducing PDGFRα and PDGFRβ signaling but does NOT protect against bile duct ligation-induced liver fibrosis, where PDGF-B and PDGF-D signaling through PDGFRβ predominates. This demonstrates organ-specific differential roles of PDGF receptor isoforms.","method":"Pdgfc-/- mice, neutralizing antibody, bile duct ligation and UUO fibrosis models, Western blot for receptor signaling, in vitro portal myofibroblast assays","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus antibody neutralization, two disease models, mechanistic in vitro follow-up, single lab with multiple orthogonal methods","pmids":["23141925"],"is_preprint":false},{"year":2012,"finding":"In breast cancer, tPA (tissue plasminogen activator) and matriptase are the major proteases responsible for cleaving PDGF-C at a specific site identified by site-directed mutagenesis to release the active GFD from the CUB domain. uPA can also process PDGF-C. Processing appears to occur in two steps: first generating a hemidimer, then a growth factor domain dimer (GFD-D). Active PDGF-C drives autocrine proliferation and paracrine fibroblast migration.","method":"In vitro processing assay with recombinant PDGF-C, site-directed mutagenesis of cleavage site, protease inhibitors, cell proliferation/invasion/migration assays","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted proteolysis assay combined with site-directed mutagenesis and functional cell assays, single lab with multiple orthogonal methods","pmids":["22035541"],"is_preprint":false},{"year":2008,"finding":"Plasmin is the major protease responsible for processing latent PDGF-C to its active form in the vitreous of PVR patients and rabbits. Blocking plasmin activity eliminates most PDGF-C processing activity in vitreous samples. tPA, identified as the main protease in cultured cells, is a minority contributor in vivo.","method":"In vitro PDGF-C processing assay with native/recombinant substrate, Western blot for active PDGF-C and PDGFRα phosphorylation, alpha2-plasmin inhibitor blocking, vitreous specimens from patients and animals","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro processing assay with inhibitor blocking and patient vitreous samples, multiple orthogonal methods in single lab","pmids":["18172073"],"is_preprint":false},{"year":2007,"finding":"PDGF-C is the predominant PDGF isoform in experimental and clinical PVR vitreous. PDGF-C is secreted in a latent form (CUB domain intact) and requires proteolytic processing for activation; processing activity was present in conditioned medium and vitreous even though latent PDGF-C accumulated, suggesting processing is rate-limiting.","method":"Western blot, ELISA, in vitro PDGF-C processing assay, vitreous specimens from PVR rabbits and patients","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative protein analysis with in vitro functional assay, single lab","pmids":["17460299"],"is_preprint":false},{"year":2006,"finding":"PDGF-C is SUMOylated by SUMO-1 at Lys314, producing a ~55 kDa form that localizes to the nucleus and is partly chromatin-associated. The non-SUMOylated ~39 kDa form is found at the cell membrane and cytosol. The SUMOylated form is reduced in papillary thyroid carcinoma tissue compared to non-neoplastic thyroid and cultured cells.","method":"Western blot fractionation, co-immunoprecipitation with SUMO-1, immunohistochemistry, subcellular fractionation","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — fractionation plus Co-IP for SUMOylation with functional correlation in tissue, single lab","pmids":["16443219"],"is_preprint":false},{"year":2013,"finding":"FREM1 physically binds to PDGF-C, and this interaction regulates the duration and amplitude of downstream PDGFRα signaling. Loss of FREM1 reduces PDGF-C-stimulated Timp1 expression in fibroblasts, leading to decreased basement membrane collagen I deposition. This places FREM1 as a positive extracellular regulator of PDGF-C activity.","method":"Co-immunoprecipitation/binding assay (FREM1–PDGF-C), fibroblast stimulation assays from Frem1-mutant mice, Timp1 mRNA measurement, collagen deposition assay","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding shown with functional downstream consequences in mutant cells, single lab","pmids":["24046351"],"is_preprint":false},{"year":2008,"finding":"Angiotensin II induces PDGF-C transcription in neonatal smooth muscle cells via AT1 receptor-dependent Egr-1 activation at an upstream Egr-1-binding element (~500 bp upstream) in the PDGF-C promoter. A G+C-rich proximal element is not involved. This axis does not operate in adult SMCs where Egr-1 induction by AngII does not drive PDGF-C.","method":"Transient transfection reporter assays, EMSA with nuclear extracts and recombinant proteins, ChIP, DNAzyme targeting Egr-1, qRT-PCR","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay, DNAzyme inhibition) in single lab, functional mechanism clearly delineated","pmids":["18272536"],"is_preprint":false},{"year":2008,"finding":"The PDGF-C promoter SNP rs28999109 (-986 C>T) abolishes six overlapping transcription regulatory motifs and reduces PDGF-C promoter transcriptional activity by up to 80% in reporter transfection assays, functionally linking reduced PDGF-C expression to cleft lip/palate susceptibility.","method":"Promoter reporter transfection assays, sequence analysis, SNP genotyping","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay with sequence-defined mechanism, single lab","pmids":["19092777"],"is_preprint":false},{"year":2014,"finding":"PDGF-C activates PDGFRα, leading to Akt and Bad phosphorylation in macrophages, which suppresses apoptosis by inhibiting caspase-3, -7, -8, and -9 and PARP cleavage. Tumor-associated macrophage apoptosis increases when PDGF-C is knocked down in breast cancer cells in vivo.","method":"Recombinant PDGF-C stimulation, Western blot for phospho-PDGFRα/Akt/Bad, caspase activity assay, PARP cleavage, PDGF-C knockdown tumor xenograft, TAM apoptosis measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro signaling pathway with in vivo KD confirmation, single lab","pmids":["24421315"],"is_preprint":false},{"year":2021,"finding":"PDGF-C is glycosylated at three sites (Asn25, Asn55, Asn254). Mutation at Asn254 (N254A) specifically prevents activation of full-length PDGF-C and its capacity to signal via PDGFRα, without affecting protein expression, secretion, or ER/Golgi trafficking. Mutations at Asn25 and Asn55 do not affect activation.","method":"Site-directed mutagenesis, Western blot for protein expression/secretion, PDGFRα signaling assays","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis with functional receptor activation assay, single lab","pmids":["34109212"],"is_preprint":false},{"year":2022,"finding":"FTO (RNA m6A demethylase) stabilizes PDGFC mRNA by reducing m6A modifications in the 3' UTR; increased m6A methylation in the absence of FTO leads to YTHDF2-dependent degradation of PDGFC mRNA. PDGFC upregulation by FTO reactivates the Akt signaling pathway to promote pancreatic cancer cell growth.","method":"m6A sequencing (m6A-seq), MeRIP-qPCR, RNA immunoprecipitation (RIP), luciferase reporter assay, FTO knockdown/overexpression, cell proliferation in vitro and in vivo","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (m6A-seq, RIP, luciferase), single lab","pmids":["35422475"],"is_preprint":false},{"year":2021,"finding":"CAF-derived PDGFC activates PDGFC-PDGFRA signal transduction in GIST cells, which upregulates SLUG (an EMT transcription factor and PDGFRA downstream target), driving tumor growth and metastasis via paracrine signaling.","method":"CAF isolation from human tumors, co-culture, PDGFC knockdown/overexpression, in vivo metastasis model, SLUG expression correlation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paracrine signaling established with CAF isolation and in vivo model, single lab","pmids":["33603171"],"is_preprint":false},{"year":2022,"finding":"PDGFC transcription in gemcitabine-resistant pancreatic cancer is epigenetically activated by H3K27 acetylation. PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway; PDGFR inhibitor imatinib synergizes with gemcitabine by blocking this pathway.","method":"ChIP for H3K27ac, PDGFC silencing, Western blot for PDGFR-PI3K-AKT, patient-derived xenograft model","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based epigenetic mechanism with in vivo PDX model, single lab","pmids":["36384875"],"is_preprint":false},{"year":2023,"finding":"PDGF-C modulates mitochondrial dynamics in endothelial cells under high-glucose conditions: it increases OPA1 fusion protein expression, reduces DRP1 phosphorylation at Ser616, and restores fragmented mitochondrial network, partially compensating for high-glucose-induced bioenergetic alterations.","method":"Recombinant PDGF-C treatment of human aortic endothelial cells, Western blot for OPA1/DRP1pSer616, mitochondrial morphology imaging, Seahorse metabolic flux analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct functional assay with protein level and functional metabolic readouts, single lab","pmids":["36901825"],"is_preprint":false},{"year":2008,"finding":"PDGF-C and PDGF-D induce MMP-9 mRNA expression in monocytes in a concentration-dependent manner, enhance secretion of MMP-2 and MMP-9, and attract THP-1 monocytes in a Boyden chamber migration assay.","method":"qPCR for MMP mRNA, ELISA/zymography for MMP secretion, Boyden chamber migration assay","journal":"Atherosclerosis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro functional assays, single lab","pmids":["18573494"],"is_preprint":false},{"year":2014,"finding":"HuR stabilizes PDGF-C mRNA by binding to two AU-rich elements (AREs) in the 3'-UTR, providing post-transcriptional upregulation of PDGF-C under cellular stress conditions in breast cancer cells.","method":"RNA immunoprecipitation, 3'-UTR reporter assay, HuR knockdown/overexpression, mRNA stability assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and reporter assay with functional mRNA stability measurement, single lab","pmids":["25383675"],"is_preprint":false},{"year":2010,"finding":"PDGF-C infusion in rats with mesangioproliferative glomerulonephritis reduces mesangiolysis and microaneurysm formation, increases glomerular endothelial cell area and proliferation, and specifically up-regulates glomerular FGF-2 expression 27-fold in glomerular endothelial cells. PDGF-C also exerts indirect pro-angiogenic effects by inducing endothelial mitogens in mesangial cells and macrophages.","method":"PDGF-C infusion in rat nephritis model, PDGF-C antagonism, thrombotic microangiopathy mouse model, in vitro glomerular endothelial cell assays, FGF-2 mRNA quantification","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo infusion/antagonism with in vitro mechanistic follow-up, single lab","pmids":["20489153"],"is_preprint":false},{"year":2012,"finding":"Tumor cell-derived PDGF-C acts in a paracrine manner on hepatic stellate cells (HSC) to rescue them from growth inhibition; this effect is dependent on PAK-2 in HSC, as PAK-2 silencing in HSC blunts PDGF-C-mediated rescue. In vivo, PDGF-C knockdown in colon carcinoma cells prominently inhibits liver metastasis.","method":"PDGF-C knockdown in LS174T cells, recombinant PDGF-C treatment of HSC, PAK-2 siRNA in HSC, nude mouse liver metastasis model, whole genome array analysis","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paracrine mechanism with genetic knockdown validation in vivo, single lab","pmids":["22362252"],"is_preprint":false},{"year":2025,"finding":"PDGFC facilitates enzalutamide resistance in prostate cancer by activating the PDGFR-Rap1-MAPK signaling pathway in an autocrine manner. STAT4 transcriptionally upregulates PDGFC by binding to a specific DNA sequence in the PDGFC promoter, demonstrated by luciferase and ChIP assays.","method":"qRT-PCR, Western blot, luciferase reporter assay, ChIP assay, PDGFC silencing, in vitro CCK8/colony/EdU assays, xenograft tumor model","journal":"Journal of cancer research and clinical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase for transcriptional mechanism, plus in vivo xenograft, single lab","pmids":["40993441"],"is_preprint":false},{"year":2019,"finding":"A truncated PDGF-C splice variant (t-PDGF-C) lacking the signal peptide and CUB domain forms intracellular homodimers that are retained intracellularly, but can be secreted as a heterodimer with full-length PDGF-C; ectopic expression of t-PDGF-C in cells expressing endogenous full-length PDGF-C enhances transformation and invasion.","method":"Expression constructs, Western blot, immunofluorescence localization, soft-agar anchorage-independent growth, Matrigel invasion assay, PDGF-C siRNA knockdown","journal":"Growth factors (Chur, Switzerland)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization of splice variant with functional assays, single lab","pmids":["31542979"],"is_preprint":false},{"year":2008,"finding":"A PDGF-C splice variant (PDGF-Cb) encoding an N-terminally truncated protein lacking signal peptide and CUB domain is produced as a cytoplasmic protein that is not secreted, but can form heterodimers with full-length PDGF-C, retaining it intracellularly and leading to its degradation, suggesting a dominant-negative regulatory mechanism.","method":"Expression constructs, Western blot, immunofluorescence localization, co-immunoprecipitation for heterodimer detection","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical characterization with co-IP, single lab","pmids":["18588873"],"is_preprint":false},{"year":2023,"finding":"PDGF-C promotes cell proliferation partly by downregulating BOP1 (block of proliferation 1, a ribosome biogenesis regulator) at both mRNA and protein levels. BOP1 overexpression inhibits proliferation, and BOP1 knockdown promotes it; attenuation of BOP1 by PDGF-C is part of the mitogenic mechanism.","method":"Conditioned medium treatment, Western blot, qPCR, BOP1 overexpression/knockdown, Pdgfc-/- mouse tissues, HEK293A proliferation assays","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, conditioned medium (indirect PDGF-C exposure), limited mechanistic depth","pmids":["37615370"],"is_preprint":false},{"year":2025,"finding":"PDGFC supports isolation and maintenance of murine neural stem cells (NSCs) from the subventricular zone in quiescent and slowly proliferating states; NSCs in PDGFC have a quiescence gene profile more similar to SVZ tissue than EGF/FGF-grown NSCs. PDGFC-maintained NSCs can transition to oligodendrocyte progenitor cells (OPCs) when FGF is added.","method":"NSC isolation and culture in PDGFC-supplemented medium, comparative gene expression analysis, lineage differentiation assays","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, descriptive culture assay without deep mechanistic dissection","pmids":[],"is_preprint":true}],"current_model":"PDGF-C is a secreted, proteolytically activated ligand that is produced as a latent dimer with an N-terminal CUB domain and a C-terminal growth factor domain (GFD); cleavage at a defined site—predominantly by plasmin in vivo and by tPA/matriptase in cells—releases the active GFD, which binds PDGFRα homodimers and PDGFRα/β heterodimers to drive proliferation, survival (via Akt/Bad), migration, and chemokine production in mesenchymal, endothelial, and macrophage cell types, with its transcription regulated by Egr-1 downstream of angiotensin II/AT1R and by H3K27 acetylation, its mRNA stabilized by HuR via 3'-UTR ARE binding and destabilized by m6A/YTHDF2, and its protein modified by SUMO-1 at Lys314 (enabling nuclear localization) and by N-glycosylation at Asn254 (required for receptor activation); genetic epistasis in mice shows that PDGF-C and PDGF-A together account for all PDGFRα-dependent development of craniofacial structures, neural tube, and mesodermal organs."},"narrative":{"mechanistic_narrative":"PDGF-C is a secreted, protease-activated growth factor that signals through PDGFRα to drive proliferation, survival, migration, and matrix remodeling in mesenchymal, endothelial, and myeloid cell populations [PMID:10806482, PMID:11297552]. It is synthesized as a latent multidomain dimer in which an N-terminal CUB domain restrains a C-terminal cystine-knot growth factor domain (GFD); cleavage at a defined site between the two domains liberates the GFD, which binds PDGFRα homodimers and PDGFRα/β heterodimers but not PDGFRβ homodimers [PMID:10806482, PMID:11297552, PMID:12598536]. This activating cleavage is carried out by plasmin in vivo and by tPA, matriptase, and uPA in cellular contexts, with processing being rate-limiting for activity [PMID:22035541, PMID:18172073, PMID:17460299], and full-length PDGF-C additionally requires N-glycosylation at Asn254 to gain receptor-activating capacity [PMID:34109212]. Downstream of PDGFRα, PDGF-C engages Akt/Bad signaling to suppress apoptosis and drives chemokine and matrix programs, including CCL2/CCL5 induction in fibroblasts and MMP-2/MMP-9 induction with monocyte chemotaxis [PMID:24421315, PMID:18184860, PMID:18573494]. Genetic epistasis in mice establishes that PDGF-C and PDGF-A together account for all PDGFRα-dependent development of craniofacial structures, the neural tube, and mesodermal organs, with Pdgfc-/- animals dying perinatally from complete secondary palate cleft [PMID:15361870]; a promoter SNP that reduces PDGF-C transcription is functionally linked to human cleft lip/palate susceptibility [PMID:19092777]. PDGF-C is an active node in fibrosis and cancer, acting as a macrophage-derived pro-fibrotic and pro-inflammatory amplifier in kidney injury and as an autocrine/paracrine driver of tumor growth, invasion, metastasis, and therapy resistance across Ewing tumors, breast, pancreatic, prostate, and GIST models [PMID:18184860, PMID:12032822, PMID:33603171, PMID:36384875, PMID:40993441]. Its abundance is tuned at multiple levels: transcriptionally by Egr-1 downstream of angiotensin II/AT1R, by EWS/FLI-1, by STAT4, and by H3K27 acetylation [PMID:18272536, PMID:11313995, PMID:40993441, PMID:36384875]; post-transcriptionally by HuR-mediated mRNA stabilization via 3'-UTR AU-rich elements and by FTO/m6A/YTHDF2 control of transcript stability [PMID:25383675, PMID:35422475]; and post-translationally by SUMO-1 modification at Lys314, which redirects a portion of the protein to the nucleus [PMID:16443219]. Its activity is further modulated by the extracellular partner FREM1, which binds PDGF-C and shapes the duration and amplitude of PDGFRα signaling [PMID:24046351], and by N-terminally truncated splice variants that heterodimerize with full-length PDGF-C to alter its secretion and activity [PMID:18588873, PMID:31542979].","teleology":[{"year":2000,"claim":"Established the defining feature of PDGF-C: unlike classical PDGFs it is a latent ligand that must be proteolytically processed to release an active growth factor domain that activates PDGFRα.","evidence":"Receptor binding assays, transgenic overexpression, and genetic analysis of Pdgfra-/- kidneys","pmids":["10806482"],"confidence":"High","gaps":["Identity of the physiological protease(s) not defined","Receptor selectivity among PDGFRα/β configurations not yet resolved"]},{"year":2001,"claim":"Defined the CUB–GFD two-domain architecture and the receptor specificity, showing the GFD binds PDGFRα homodimers and PDGFRα/β heterodimers but not PDGFRβ homodimers, with a serum-sensitive interdomain cleavage event releasing the GFD.","evidence":"Competition binding, immunoprecipitation on dual-receptor cells, recombinant protein characterization, and diabetic wound-healing model","pmids":["11297552"],"confidence":"High","gaps":["Specific protease not identified","Quantitative receptor affinities for each dimer configuration not established"]},{"year":2001,"claim":"Mapped PDGF-C genomic structure and tissue expression, localizing the cleavage site to exon 4 and identifying smooth muscle cells as a major source with mitogenic action on coronary artery SMCs.","evidence":"FISH mapping, genomic sequencing, and SMC stimulation assays","pmids":["11342471"],"confidence":"Medium","gaps":["Single-lab functional data","In vivo relevance of SMC-derived PDGF-C not tested"]},{"year":2003,"claim":"Resolved the biophysical class of the GFD, showing a cystine-knot fold with three intramonomeric disulfides and greater structural similarity to VEGF than PDGF-B.","evidence":"Ellman assay, CD/NMR/IR spectroscopy on recombinant protein, and homology modeling","pmids":["12598536"],"confidence":"Medium","gaps":["No experimental high-resolution structure","Homology model is computational"]},{"year":2004,"claim":"Defined the in vivo developmental function through genetic epistasis, showing PDGF-C and PDGF-A together account for all PDGFRα-dependent craniofacial, neural tube, and mesodermal development, with Pdgfc loss causing fatal palatal clefting.","evidence":"Single and double knockout mice with embryo phenotyping","pmids":["15361870"],"confidence":"High","gaps":["Cell-type-specific contributions not dissected","Mechanism of redundancy with PDGF-A not resolved"]},{"year":2008,"claim":"Identified the dominant physiological activating protease, showing plasmin processes latent PDGF-C in vivo (vitreous), whereas tPA dominates only in cultured cells.","evidence":"In vitro processing assays with inhibitor blocking using patient and animal vitreous specimens","pmids":["18172073","17460299"],"confidence":"High","gaps":["Tissue-to-tissue variation in protease usage not mapped","Regulation of processing rate not defined"]},{"year":2012,"claim":"Defined the cellular protease repertoire and processing intermediates, identifying tPA and matriptase as major cleavers (with uPA contributing) acting in two steps to generate the active GFD dimer.","evidence":"Reconstituted in vitro proteolysis, cleavage-site mutagenesis, protease inhibitors, and cell migration/proliferation assays in breast cancer","pmids":["22035541"],"confidence":"High","gaps":["Relative contribution of each protease in vivo not quantified","Regulation of the hemidimer-to-GFD-dimer transition unknown"]},{"year":2021,"claim":"Established N-glycosylation at Asn254 as required for activation of full-length PDGF-C, distinguishing it from glycosylation sites dispensable for activity.","evidence":"Site-directed mutagenesis with secretion/trafficking controls and PDGFRα signaling assays","pmids":["34109212"],"confidence":"Medium","gaps":["Mechanism by which Asn254 glycan enables activation not defined","Single-lab finding"]},{"year":2014,"claim":"Linked PDGF-C/PDGFRα to a pro-survival signaling output, showing Akt/Bad phosphorylation that suppresses caspase activation and PARP cleavage in macrophages.","evidence":"Recombinant ligand stimulation, phospho-Western blots, caspase assays, and PDGF-C knockdown xenografts","pmids":["24421315"],"confidence":"Medium","gaps":["Direct receptor-to-Akt coupling not isolated from other inputs","Single-lab finding"]},{"year":2013,"claim":"Identified FREM1 as a direct extracellular binding partner that positively tunes the amplitude and duration of PDGFRα signaling and downstream matrix output.","evidence":"Binding/co-IP, fibroblast stimulation from Frem1-mutant mice, Timp1 and collagen deposition readouts","pmids":["24046351"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of FREM1–PDGF-C binding unknown","Single-lab finding"]},{"year":2008,"claim":"Established transcriptional control of PDGF-C by the angiotensin II/AT1R–Egr-1 axis at a defined upstream promoter element, operating selectively in neonatal but not adult smooth muscle cells.","evidence":"Reporter assays, EMSA, ChIP, and DNAzyme inhibition of Egr-1 with qRT-PCR","pmids":["18272536"],"confidence":"High","gaps":["Basis of the neonatal-versus-adult difference not resolved","Other inputs converging on the promoter not mapped"]},{"year":2008,"claim":"Connected reduced PDGF-C transcription to human disease, showing a promoter SNP that abolishes regulatory motifs and reduces promoter activity is associated with cleft lip/palate susceptibility.","evidence":"Promoter reporter transfection, sequence analysis, and SNP genotyping","pmids":["19092777"],"confidence":"Medium","gaps":["Causality in patient tissue not demonstrated","Effect on protein levels in vivo not measured"]},{"year":2006,"claim":"Revealed a post-translational fate beyond secretion, showing SUMO-1 modification at Lys314 produces a nuclear, partly chromatin-associated form that is reduced in papillary thyroid carcinoma.","evidence":"Subcellular fractionation, SUMO-1 co-IP, and immunohistochemistry","pmids":["16443219"],"confidence":"Medium","gaps":["Function of the nuclear form unknown","SUMO ligase and signals controlling modification not identified"]},{"year":2014,"claim":"Established post-transcriptional stabilization of PDGF-C, showing HuR binds two 3'-UTR AU-rich elements to upregulate PDGF-C mRNA under stress in breast cancer cells.","evidence":"RNA immunoprecipitation, 3'-UTR reporter, HuR perturbation, and mRNA stability assays","pmids":["25383675"],"confidence":"Medium","gaps":["Stress signals driving HuR engagement not defined","Single-lab finding"]},{"year":2022,"claim":"Added m6A-based regulation of PDGFC, showing FTO removes 3'-UTR m6A marks to stabilize the transcript, while m6A accumulation triggers YTHDF2-dependent decay, with the FTO–PDGFC axis reactivating Akt to promote pancreatic cancer growth.","evidence":"m6A-seq, MeRIP-qPCR, RIP, luciferase reporter, and FTO perturbation in vitro and in vivo","pmids":["35422475"],"confidence":"Medium","gaps":["Specific m6A sites controlling decay not pinpointed","Single-lab finding"]},{"year":2025,"claim":"Extended transcriptional regulation to a therapy-resistance context, identifying STAT4 as a direct activator of PDGFC that drives autocrine PDGFR-Rap1-MAPK signaling and enzalutamide resistance in prostate cancer.","evidence":"Luciferase reporter, ChIP, PDGFC silencing, in vitro proliferation assays, and xenografts","pmids":["40993441"],"confidence":"Medium","gaps":["Generality of the Rap1-MAPK output across cell types not tested","Single-lab finding"]},{"year":2008,"claim":"Implicated PDGF-C as a myeloid effector in vascular inflammation, showing it induces MMP-9 expression, enhances MMP-2/MMP-9 secretion, and attracts monocytes.","evidence":"qPCR, ELISA/zymography, and Boyden chamber migration assays","pmids":["18573494"],"confidence":"Medium","gaps":["Receptor dependence of MMP induction not confirmed","In vivo relevance not tested in this study"]},{"year":2008,"claim":"Defined a pathogenic role in renal fibrosis, showing macrophage-derived PDGF-C is a fibroblast mitogen and chemokine inducer that drives a pro-inflammatory amplification loop, with neutralization or knockout reducing fibrosis.","evidence":"Anti-PDGF-C neutralization and Pdgfc-/- mice in the UUO model plus in vitro fibroblast assays","pmids":["18184860"],"confidence":"High","gaps":["Upstream trigger of macrophage PDGF-C production not defined","Contribution of PDGFRα versus β to the loop not separated here"]},{"year":2010,"claim":"Revealed an indirect pro-angiogenic action in glomerular disease, showing PDGF-C infusion increases endothelial proliferation and strongly upregulates FGF-2 in glomerular endothelial cells.","evidence":"PDGF-C infusion/antagonism in rat nephritis and microangiopathy models with in vitro glomerular endothelial assays","pmids":["20489153"],"confidence":"Medium","gaps":["Direct versus paracrine endothelial effects not fully separated","Single-lab finding"]},{"year":2012,"claim":"Demonstrated organ specificity of PDGF-C in fibrosis, showing it protects against kidney fibrosis via PDGFRα/β signaling but not against liver fibrosis, where PDGF-B/D–PDGFRβ predominate.","evidence":"Pdgfc-/- mice and neutralizing antibody across UUO and bile duct ligation models with receptor signaling Westerns","pmids":["23141925"],"confidence":"High","gaps":["Molecular basis of organ specificity not defined","Cross-talk among PDGF isoforms not dissected"]},{"year":2001,"claim":"Linked PDGF-C to oncogenic transcription, showing the EWS/FLI-1 fusion transcriptionally upregulates PDGF-C in Ewing family tumors in an EWS/ETS-specific manner.","evidence":"Retroviral cDNA screen and EWS/FLI modulation in EFT cell lines","pmids":["11313995"],"confidence":"Medium","gaps":["Direct versus indirect EWS/FLI regulation of the promoter not established","Single-lab finding"]},{"year":2002,"claim":"Demonstrated functional dependence of tumor phenotype on autocrine PDGF-C, showing a dominant-negative PDGF-C and PDGFR inhibition block anchorage-independent growth.","evidence":"Dominant-negative mutagenesis, soft-agar assays, and AG1296 inhibition in EFT and fibroblast models","pmids":["12032822"],"confidence":"Medium","gaps":["In vivo tumor dependence not tested here","Single-lab finding"]},{"year":2012,"claim":"Established a paracrine pro-metastatic role, showing tumor-derived PDGF-C rescues hepatic stellate cells via PAK-2 and that PDGF-C knockdown inhibits liver metastasis.","evidence":"PDGF-C knockdown in colon carcinoma, recombinant ligand on HSC, PAK-2 siRNA, and nude mouse metastasis model","pmids":["22362252"],"confidence":"Medium","gaps":["Receptor mediating the HSC response not identified","Single-lab finding"]},{"year":2021,"claim":"Extended paracrine tumor signaling to the stroma, showing CAF-derived PDGFC activates PDGFRA-SLUG signaling to drive GIST growth and metastasis.","evidence":"CAF isolation, co-culture, PDGFC perturbation, and in vivo metastasis model","pmids":["33603171"],"confidence":"Medium","gaps":["Direct PDGFRA-to-SLUG mechanism not fully mapped","Single-lab finding"]},{"year":2022,"claim":"Linked epigenetic activation of PDGFC to drug resistance, showing H3K27 acetylation activates PDGFC, which drives gemcitabine resistance via PDGFR-PI3K-AKT, reversible by imatinib.","evidence":"H3K27ac ChIP, PDGFC silencing, signaling Westerns, and patient-derived xenografts","pmids":["36384875"],"confidence":"Medium","gaps":["Writer/eraser controlling the H3K27ac mark not identified","Single-lab finding"]},{"year":2019,"claim":"Characterized regulatory splice variants, showing a truncated PDGF-C lacking signal peptide and CUB domain forms intracellular dimers and heterodimerizes with full-length protein to enhance transformation and invasion.","evidence":"Expression constructs, localization imaging, soft-agar and Matrigel assays, and PDGF-C knockdown","pmids":["31542979"],"confidence":"Medium","gaps":["Endogenous expression and physiological relevance of the variant unclear","Single-lab finding"]},{"year":2008,"claim":"Described a dominant-negative splice isoform, showing a non-secreted N-terminally truncated PDGF-Cb heterodimerizes with full-length protein, retaining and degrading it.","evidence":"Expression constructs, localization, and co-IP for heterodimers","pmids":["18588873"],"confidence":"Medium","gaps":["In vivo occurrence and functional impact not established","Single-lab finding"]},{"year":2023,"claim":"Proposed a mitogenic mechanism via ribosome biogenesis control, with PDGF-C downregulating BOP1 to promote proliferation.","evidence":"Conditioned medium treatment, BOP1 perturbation, and Pdgfc-/- tissues in HEK293A assays","pmids":["37615370"],"confidence":"Low","gaps":["Indirect conditioned-medium exposure limits mechanistic attribution","Receptor dependence of BOP1 regulation not shown"]},{"year":2023,"claim":"Implicated PDGF-C in endothelial mitochondrial homeostasis, showing it increases OPA1 and reduces DRP1 Ser616 phosphorylation to restore mitochondrial networks under high glucose.","evidence":"Recombinant PDGF-C on aortic endothelial cells with Western blot, morphology imaging, and Seahorse flux","pmids":["36901825"],"confidence":"Medium","gaps":["Signaling link from PDGFRα to mitochondrial dynamics machinery not defined","Single-lab finding"]},{"year":2025,"claim":"Suggested a niche-maintenance role, with PDGFC supporting isolation and quiescent maintenance of neural stem cells permissive for oligodendrocyte progenitor transition.","evidence":"NSC culture in PDGFC medium with comparative expression and lineage assays (preprint)","pmids":[],"confidence":"Low","gaps":["Preprint, not peer-reviewed","Descriptive culture assay without receptor-level mechanism"]},{"year":null,"claim":"How the multiple regulatory layers—proteolytic activation, glycosylation, SUMOylation, m6A/HuR mRNA control, and splice-variant dimerization—are integrated to set PDGF-C activity in a given tissue, and the structural basis of its receptor and FREM1 interactions, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental high-resolution structure of the GFD–receptor complex","No integrated model coupling activation, modification, and transcriptional control","Tissue-specific protease and receptor usage not systematically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator 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Potent mitogen and chemoattractant for cells of mesenchymal origin. Required for normal skeleton formation during embryonic development, especially for normal development of the craniofacial skeleton and for normal development of the palate. Required for normal skin morphogenesis during embryonic development. Plays an important role in wound healing, where it appears to be involved in three stages: inflammation, proliferation and remodeling. Plays an important role in angiogenesis and blood vessel development. Involved in fibrotic processes, in which transformation of interstitial fibroblasts into myofibroblasts plus collagen deposition occurs. The CUB domain has mitogenic activity in coronary artery smooth muscle cells, suggesting a role beyond the maintenance of the latency of the PDGF domain. In the nucleus, PDGFC seems to have additional function","subcellular_location":"Cytoplasm, cytosol; Secreted; Nucleus; Cytoplasmic granule; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9NRA1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDGFC","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/PDGFC","total_profiled":1310},"omim":[{"mim_id":"609673","title":"PLATELET-DERIVED GROWTH FACTOR D; PDGFD","url":"https://www.omim.org/entry/609673"},{"mim_id":"608452","title":"PLATELET-DERIVED GROWTH FACTOR C; PDGFC","url":"https://www.omim.org/entry/608452"},{"mim_id":"173490","title":"PLATELET-DERIVED GROWTH FACTOR RECEPTOR, ALPHA; PDGFRA","url":"https://www.omim.org/entry/173490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"parathyroid gland","ntpm":19.1}],"url":"https://www.proteinatlas.org/search/PDGFC"},"hgnc":{"alias_symbol":["SCDGF","fallotein"],"prev_symbol":[]},"alphafold":{"accession":"Q9NRA1","domains":[{"cath_id":"2.60.120.290","chopping":"47-162","consensus_level":"high","plddt":93.1966,"start":47,"end":162},{"cath_id":"2.10.90.10","chopping":"250-338","consensus_level":"high","plddt":89.8324,"start":250,"end":338}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRA1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRA1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NRA1-F1-predicted_aligned_error_v6.png","plddt_mean":75.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDGFC","jax_strain_url":"https://www.jax.org/strain/search?query=PDGFC"},"sequence":{"accession":"Q9NRA1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NRA1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NRA1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NRA1"}},"corpus_meta":[{"pmid":"10806482","id":"PMC_10806482","title":"PDGF-C 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/24038848","citation_count":7,"is_preprint":false},{"pmid":"29345101","id":"PMC_29345101","title":"A Pdgf-cCreERT2 knock-in mouse model for tracing PDGF-C cell lineages during development.","date":"2018","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/29345101","citation_count":4,"is_preprint":false},{"pmid":"34109212","id":"PMC_34109212","title":"Glycosylation at Asn254 Is Required for the Activation of the PDGF-C Protein.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34109212","citation_count":3,"is_preprint":false},{"pmid":"18588873","id":"PMC_18588873","title":"Identification and expression analysis of an N-terminally truncated isoform of human PDGF-C.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/18588873","citation_count":3,"is_preprint":false},{"pmid":"37615370","id":"PMC_37615370","title":"PDGF-C promotes cell proliferation partially via downregulating BOP1.","date":"2023","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/37615370","citation_count":2,"is_preprint":false},{"pmid":"40501228","id":"PMC_40501228","title":"PDGFC secreted by cancer-associated fibroblasts promotes epithelial-mesenchymal transition and immunosuppression in lung adenocarcinoma.","date":"2025","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/40501228","citation_count":1,"is_preprint":false},{"pmid":"30044068","id":"PMC_30044068","title":"[Effect of PDGF-C on biological characters of human dermal papilla cells in vitro].","date":"2016","source":"Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/30044068","citation_count":1,"is_preprint":false},{"pmid":"40993441","id":"PMC_40993441","title":"PDGFC facilitates enzalutamide resistance in prostate cancer through activation of the Rap1-MAPK pathway.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40993441","citation_count":0,"is_preprint":false},{"pmid":"41213930","id":"PMC_41213930","title":"NRG1/PDGFC loop between fibroblasts and cancer cells drives paclitaxel resistance via ferroptosis suppression in breast cancer.","date":"2025","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/41213930","citation_count":0,"is_preprint":false},{"pmid":"38432532","id":"PMC_38432532","title":"Identification of a novel mutation of Platelet-Derived Growth Factor-C (PDGFC) gene in a girl with Non-Syndromic cleft lip and palate.","date":"2024","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38432532","citation_count":0,"is_preprint":false},{"pmid":"37779880","id":"PMC_37779880","title":"Identification of a Novel Variant of PDGFC Associated with Nonsyndromic Cleft Lip and Palate in a Chinese Family.","date":"2023","source":"International journal of genomics","url":"https://pubmed.ncbi.nlm.nih.gov/37779880","citation_count":0,"is_preprint":false},{"pmid":"42138517","id":"PMC_42138517","title":"An Inhibitory Aptamer Against PDGF-C Overcomes Anti-VEGF Refractoriness and Reduces Choroidal Neovascularization and Fibrosis.","date":"2026","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/42138517","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.29.650770","title":"Isolation of Neural Stem Cells Using Platelet Derived Growth Factor C","date":"2025-05-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.29.650770","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37736,"output_tokens":7740,"usd":0.114654,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17028,"output_tokens":8092,"usd":0.14372,"stage2_stop_reason":"end_turn"},"total_usd":0.258374,"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\": 2000,\n      \"finding\": \"PDGF-C is a protease-activated ligand that binds to and activates the PDGF alpha-receptor (PDGFRα). Proteolytic cleavage is required to release the growth factor domain (GFD) from the CUB domain for receptor activation.\",\n      \"method\": \"Receptor binding assays, transgenic mouse overexpression, in situ hybridization, genetic analysis of Pdgfra-/- kidneys\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (binding, genetic epistasis, transgenic model), independently replicated across multiple subsequent studies\",\n      \"pmids\": [\"10806482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-C is a multidomain protein with an N-terminal CUB domain and a C-terminal growth factor domain (GFD). The GFD (PDGF-CC) binds with high affinity to PDGFRα homodimers and PDGFRα/β heterodimers, but not PDGFRβ homodimers. A serum-sensitive cleavage site between the CUB and GFD domains releases the active GFD.\",\n      \"method\": \"Competition binding assays, immunoprecipitation on cells bearing both receptor types, recombinant protein characterization, mitogenesis assays, diabetic mouse wound healing model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding/immunoprecipitation with recombinant proteins and in vivo validation, replicated by other groups\",\n      \"pmids\": [\"11297552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-C genomic structure has 6 exons; the CUB domain is encoded by exons 2–3 and the proteolytic cleavage site activating the growth factor domain is located in exon 4. PDGF-C is expressed predominantly in smooth muscle cells and stimulates coronary artery smooth muscle cell proliferation.\",\n      \"method\": \"FISH chromosomal mapping, genomic DNA sequencing, cell stimulation assays\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct sequencing and cell-based functional assay, single lab\",\n      \"pmids\": [\"11342471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The GFD of PDGF-C contains 12 cysteine residues with three intramonomeric disulfide bonds consistent with cystine knot superfamily membership. Structural characterization by CD, fluorescence, NMR, and infrared spectroscopy indicates predominantly beta-sheet secondary structure; homology modeling shows greater structural similarity to VEGF than to PDGF-B.\",\n      \"method\": \"Ellman assay, CD spectroscopy, NMR spectroscopy, infrared spectroscopy, homology modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — multiple biophysical methods on purified recombinant protein, but modeling is computational and single lab\",\n      \"pmids\": [\"12598536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Pdgfc-/- mice die perinatally due to complete secondary palate cleft. Pdgfc-/- Pdgfa-/- double knockouts phenocopy Pdgfra-/- (cleft face, subepidermal blistering, renal cortex mesenchyme deficiency, spina bifida, skeletal and vascular defects), establishing by genetic epistasis that PDGF-A and PDGF-C together account for all PDGFRα signaling in craniofacial, neural tube, and mesodermal development.\",\n      \"method\": \"Genetic knockout, double-knockout epistasis, embryo phenotyping\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous in vivo genetic epistasis with multiple orthogonal phenotypic readouts, single rigorous study with strong controls\",\n      \"pmids\": [\"15361870\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PDGF-C expression in Ewing family tumors (EFT) is transcriptionally upregulated by the chimeric EWS/FLI-1 transcription factor and this regulation is EWS/ETS-specific. PDGF-C expression depends on EWS/FLI activity in EFT cell lines.\",\n      \"method\": \"Retroviral cDNA biological screen, differential gene regulation, EWS/FLI knockdown/modulation in EFT cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional retroviral screen plus expression dependence, single lab\",\n      \"pmids\": [\"11313995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A dominant-negative form of PDGF-C that is secreted and processed but has greatly reduced PDGFRα agonist activity inhibits anchorage-independent growth in EFT cell lines and in a PDGF-C-driven fibroblast transformation model, demonstrating that autocrine PDGF-C/PDGFRα signaling drives EFT malignant phenotype.\",\n      \"method\": \"Dominant-negative mutagenesis, soft-agar colony formation assay, PDGFR inhibitor AG1296\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed dominant-negative mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"12032822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In renal fibrosis, PDGF-C is produced largely by infiltrating macrophages. PDGF-C acts as a potent mitogen for renal fibroblasts and induces chemokine expression (CCL2, CCL5). Neutralization of PDGF-C reduces renal fibrosis, interstitial myofibroblast accumulation, and leukocyte infiltration; Pdgfc-/- mice show reduced fibrosis and inflammation after ureteral obstruction, suggesting a pro-inflammatory amplification loop.\",\n      \"method\": \"Anti-PDGF-C neutralizing antiserum in UUO mouse model, Pdgfc-/- mice, in vitro fibroblast mitogenesis and chemokine assays\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (genetic KO, antibody neutralization, in vitro assays) with consistent results\",\n      \"pmids\": [\"18184860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PDGF-C neutralization or deficiency protects against kidney fibrosis by reducing PDGFRα and PDGFRβ signaling but does NOT protect against bile duct ligation-induced liver fibrosis, where PDGF-B and PDGF-D signaling through PDGFRβ predominates. This demonstrates organ-specific differential roles of PDGF receptor isoforms.\",\n      \"method\": \"Pdgfc-/- mice, neutralizing antibody, bile duct ligation and UUO fibrosis models, Western blot for receptor signaling, in vitro portal myofibroblast assays\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus antibody neutralization, two disease models, mechanistic in vitro follow-up, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23141925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In breast cancer, tPA (tissue plasminogen activator) and matriptase are the major proteases responsible for cleaving PDGF-C at a specific site identified by site-directed mutagenesis to release the active GFD from the CUB domain. uPA can also process PDGF-C. Processing appears to occur in two steps: first generating a hemidimer, then a growth factor domain dimer (GFD-D). Active PDGF-C drives autocrine proliferation and paracrine fibroblast migration.\",\n      \"method\": \"In vitro processing assay with recombinant PDGF-C, site-directed mutagenesis of cleavage site, protease inhibitors, cell proliferation/invasion/migration assays\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted proteolysis assay combined with site-directed mutagenesis and functional cell assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22035541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Plasmin is the major protease responsible for processing latent PDGF-C to its active form in the vitreous of PVR patients and rabbits. Blocking plasmin activity eliminates most PDGF-C processing activity in vitreous samples. tPA, identified as the main protease in cultured cells, is a minority contributor in vivo.\",\n      \"method\": \"In vitro PDGF-C processing assay with native/recombinant substrate, Western blot for active PDGF-C and PDGFRα phosphorylation, alpha2-plasmin inhibitor blocking, vitreous specimens from patients and animals\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro processing assay with inhibitor blocking and patient vitreous samples, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"18172073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PDGF-C is the predominant PDGF isoform in experimental and clinical PVR vitreous. PDGF-C is secreted in a latent form (CUB domain intact) and requires proteolytic processing for activation; processing activity was present in conditioned medium and vitreous even though latent PDGF-C accumulated, suggesting processing is rate-limiting.\",\n      \"method\": \"Western blot, ELISA, in vitro PDGF-C processing assay, vitreous specimens from PVR rabbits and patients\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative protein analysis with in vitro functional assay, single lab\",\n      \"pmids\": [\"17460299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PDGF-C is SUMOylated by SUMO-1 at Lys314, producing a ~55 kDa form that localizes to the nucleus and is partly chromatin-associated. The non-SUMOylated ~39 kDa form is found at the cell membrane and cytosol. The SUMOylated form is reduced in papillary thyroid carcinoma tissue compared to non-neoplastic thyroid and cultured cells.\",\n      \"method\": \"Western blot fractionation, co-immunoprecipitation with SUMO-1, immunohistochemistry, subcellular fractionation\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — fractionation plus Co-IP for SUMOylation with functional correlation in tissue, single lab\",\n      \"pmids\": [\"16443219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FREM1 physically binds to PDGF-C, and this interaction regulates the duration and amplitude of downstream PDGFRα signaling. Loss of FREM1 reduces PDGF-C-stimulated Timp1 expression in fibroblasts, leading to decreased basement membrane collagen I deposition. This places FREM1 as a positive extracellular regulator of PDGF-C activity.\",\n      \"method\": \"Co-immunoprecipitation/binding assay (FREM1–PDGF-C), fibroblast stimulation assays from Frem1-mutant mice, Timp1 mRNA measurement, collagen deposition assay\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding shown with functional downstream consequences in mutant cells, single lab\",\n      \"pmids\": [\"24046351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Angiotensin II induces PDGF-C transcription in neonatal smooth muscle cells via AT1 receptor-dependent Egr-1 activation at an upstream Egr-1-binding element (~500 bp upstream) in the PDGF-C promoter. A G+C-rich proximal element is not involved. This axis does not operate in adult SMCs where Egr-1 induction by AngII does not drive PDGF-C.\",\n      \"method\": \"Transient transfection reporter assays, EMSA with nuclear extracts and recombinant proteins, ChIP, DNAzyme targeting Egr-1, qRT-PCR\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (ChIP, EMSA, reporter assay, DNAzyme inhibition) in single lab, functional mechanism clearly delineated\",\n      \"pmids\": [\"18272536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The PDGF-C promoter SNP rs28999109 (-986 C>T) abolishes six overlapping transcription regulatory motifs and reduces PDGF-C promoter transcriptional activity by up to 80% in reporter transfection assays, functionally linking reduced PDGF-C expression to cleft lip/palate susceptibility.\",\n      \"method\": \"Promoter reporter transfection assays, sequence analysis, SNP genotyping\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay with sequence-defined mechanism, single lab\",\n      \"pmids\": [\"19092777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDGF-C activates PDGFRα, leading to Akt and Bad phosphorylation in macrophages, which suppresses apoptosis by inhibiting caspase-3, -7, -8, and -9 and PARP cleavage. Tumor-associated macrophage apoptosis increases when PDGF-C is knocked down in breast cancer cells in vivo.\",\n      \"method\": \"Recombinant PDGF-C stimulation, Western blot for phospho-PDGFRα/Akt/Bad, caspase activity assay, PARP cleavage, PDGF-C knockdown tumor xenograft, TAM apoptosis measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro signaling pathway with in vivo KD confirmation, single lab\",\n      \"pmids\": [\"24421315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDGF-C is glycosylated at three sites (Asn25, Asn55, Asn254). Mutation at Asn254 (N254A) specifically prevents activation of full-length PDGF-C and its capacity to signal via PDGFRα, without affecting protein expression, secretion, or ER/Golgi trafficking. Mutations at Asn25 and Asn55 do not affect activation.\",\n      \"method\": \"Site-directed mutagenesis, Western blot for protein expression/secretion, PDGFRα signaling assays\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis with functional receptor activation assay, single lab\",\n      \"pmids\": [\"34109212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTO (RNA m6A demethylase) stabilizes PDGFC mRNA by reducing m6A modifications in the 3' UTR; increased m6A methylation in the absence of FTO leads to YTHDF2-dependent degradation of PDGFC mRNA. PDGFC upregulation by FTO reactivates the Akt signaling pathway to promote pancreatic cancer cell growth.\",\n      \"method\": \"m6A sequencing (m6A-seq), MeRIP-qPCR, RNA immunoprecipitation (RIP), luciferase reporter assay, FTO knockdown/overexpression, cell proliferation in vitro and in vivo\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (m6A-seq, RIP, luciferase), single lab\",\n      \"pmids\": [\"35422475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CAF-derived PDGFC activates PDGFC-PDGFRA signal transduction in GIST cells, which upregulates SLUG (an EMT transcription factor and PDGFRA downstream target), driving tumor growth and metastasis via paracrine signaling.\",\n      \"method\": \"CAF isolation from human tumors, co-culture, PDGFC knockdown/overexpression, in vivo metastasis model, SLUG expression correlation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paracrine signaling established with CAF isolation and in vivo model, single lab\",\n      \"pmids\": [\"33603171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PDGFC transcription in gemcitabine-resistant pancreatic cancer is epigenetically activated by H3K27 acetylation. PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway; PDGFR inhibitor imatinib synergizes with gemcitabine by blocking this pathway.\",\n      \"method\": \"ChIP for H3K27ac, PDGFC silencing, Western blot for PDGFR-PI3K-AKT, patient-derived xenograft model\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based epigenetic mechanism with in vivo PDX model, single lab\",\n      \"pmids\": [\"36384875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PDGF-C modulates mitochondrial dynamics in endothelial cells under high-glucose conditions: it increases OPA1 fusion protein expression, reduces DRP1 phosphorylation at Ser616, and restores fragmented mitochondrial network, partially compensating for high-glucose-induced bioenergetic alterations.\",\n      \"method\": \"Recombinant PDGF-C treatment of human aortic endothelial cells, Western blot for OPA1/DRP1pSer616, mitochondrial morphology imaging, Seahorse metabolic flux analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct functional assay with protein level and functional metabolic readouts, single lab\",\n      \"pmids\": [\"36901825\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PDGF-C and PDGF-D induce MMP-9 mRNA expression in monocytes in a concentration-dependent manner, enhance secretion of MMP-2 and MMP-9, and attract THP-1 monocytes in a Boyden chamber migration assay.\",\n      \"method\": \"qPCR for MMP mRNA, ELISA/zymography for MMP secretion, Boyden chamber migration assay\",\n      \"journal\": \"Atherosclerosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro functional assays, single lab\",\n      \"pmids\": [\"18573494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HuR stabilizes PDGF-C mRNA by binding to two AU-rich elements (AREs) in the 3'-UTR, providing post-transcriptional upregulation of PDGF-C under cellular stress conditions in breast cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, 3'-UTR reporter assay, HuR knockdown/overexpression, mRNA stability assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and reporter assay with functional mRNA stability measurement, single lab\",\n      \"pmids\": [\"25383675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PDGF-C infusion in rats with mesangioproliferative glomerulonephritis reduces mesangiolysis and microaneurysm formation, increases glomerular endothelial cell area and proliferation, and specifically up-regulates glomerular FGF-2 expression 27-fold in glomerular endothelial cells. PDGF-C also exerts indirect pro-angiogenic effects by inducing endothelial mitogens in mesangial cells and macrophages.\",\n      \"method\": \"PDGF-C infusion in rat nephritis model, PDGF-C antagonism, thrombotic microangiopathy mouse model, in vitro glomerular endothelial cell assays, FGF-2 mRNA quantification\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo infusion/antagonism with in vitro mechanistic follow-up, single lab\",\n      \"pmids\": [\"20489153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Tumor cell-derived PDGF-C acts in a paracrine manner on hepatic stellate cells (HSC) to rescue them from growth inhibition; this effect is dependent on PAK-2 in HSC, as PAK-2 silencing in HSC blunts PDGF-C-mediated rescue. In vivo, PDGF-C knockdown in colon carcinoma cells prominently inhibits liver metastasis.\",\n      \"method\": \"PDGF-C knockdown in LS174T cells, recombinant PDGF-C treatment of HSC, PAK-2 siRNA in HSC, nude mouse liver metastasis model, whole genome array analysis\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paracrine mechanism with genetic knockdown validation in vivo, single lab\",\n      \"pmids\": [\"22362252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDGFC facilitates enzalutamide resistance in prostate cancer by activating the PDGFR-Rap1-MAPK signaling pathway in an autocrine manner. STAT4 transcriptionally upregulates PDGFC by binding to a specific DNA sequence in the PDGFC promoter, demonstrated by luciferase and ChIP assays.\",\n      \"method\": \"qRT-PCR, Western blot, luciferase reporter assay, ChIP assay, PDGFC silencing, in vitro CCK8/colony/EdU assays, xenograft tumor model\",\n      \"journal\": \"Journal of cancer research and clinical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase for transcriptional mechanism, plus in vivo xenograft, single lab\",\n      \"pmids\": [\"40993441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A truncated PDGF-C splice variant (t-PDGF-C) lacking the signal peptide and CUB domain forms intracellular homodimers that are retained intracellularly, but can be secreted as a heterodimer with full-length PDGF-C; ectopic expression of t-PDGF-C in cells expressing endogenous full-length PDGF-C enhances transformation and invasion.\",\n      \"method\": \"Expression constructs, Western blot, immunofluorescence localization, soft-agar anchorage-independent growth, Matrigel invasion assay, PDGF-C siRNA knockdown\",\n      \"journal\": \"Growth factors (Chur, Switzerland)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization of splice variant with functional assays, single lab\",\n      \"pmids\": [\"31542979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A PDGF-C splice variant (PDGF-Cb) encoding an N-terminally truncated protein lacking signal peptide and CUB domain is produced as a cytoplasmic protein that is not secreted, but can form heterodimers with full-length PDGF-C, retaining it intracellularly and leading to its degradation, suggesting a dominant-negative regulatory mechanism.\",\n      \"method\": \"Expression constructs, Western blot, immunofluorescence localization, co-immunoprecipitation for heterodimer detection\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical characterization with co-IP, single lab\",\n      \"pmids\": [\"18588873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PDGF-C promotes cell proliferation partly by downregulating BOP1 (block of proliferation 1, a ribosome biogenesis regulator) at both mRNA and protein levels. BOP1 overexpression inhibits proliferation, and BOP1 knockdown promotes it; attenuation of BOP1 by PDGF-C is part of the mitogenic mechanism.\",\n      \"method\": \"Conditioned medium treatment, Western blot, qPCR, BOP1 overexpression/knockdown, Pdgfc-/- mouse tissues, HEK293A proliferation assays\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, conditioned medium (indirect PDGF-C exposure), limited mechanistic depth\",\n      \"pmids\": [\"37615370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDGFC supports isolation and maintenance of murine neural stem cells (NSCs) from the subventricular zone in quiescent and slowly proliferating states; NSCs in PDGFC have a quiescence gene profile more similar to SVZ tissue than EGF/FGF-grown NSCs. PDGFC-maintained NSCs can transition to oligodendrocyte progenitor cells (OPCs) when FGF is added.\",\n      \"method\": \"NSC isolation and culture in PDGFC-supplemented medium, comparative gene expression analysis, lineage differentiation assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, descriptive culture assay without deep mechanistic dissection\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"PDGF-C is a secreted, proteolytically activated ligand that is produced as a latent dimer with an N-terminal CUB domain and a C-terminal growth factor domain (GFD); cleavage at a defined site—predominantly by plasmin in vivo and by tPA/matriptase in cells—releases the active GFD, which binds PDGFRα homodimers and PDGFRα/β heterodimers to drive proliferation, survival (via Akt/Bad), migration, and chemokine production in mesenchymal, endothelial, and macrophage cell types, with its transcription regulated by Egr-1 downstream of angiotensin II/AT1R and by H3K27 acetylation, its mRNA stabilized by HuR via 3'-UTR ARE binding and destabilized by m6A/YTHDF2, and its protein modified by SUMO-1 at Lys314 (enabling nuclear localization) and by N-glycosylation at Asn254 (required for receptor activation); genetic epistasis in mice shows that PDGF-C and PDGF-A together account for all PDGFRα-dependent development of craniofacial structures, neural tube, and mesodermal organs.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PDGF-C is a secreted, protease-activated growth factor that signals through PDGFRα to drive proliferation, survival, migration, and matrix remodeling in mesenchymal, endothelial, and myeloid cell populations [#0, #1]. It is synthesized as a latent multidomain dimer in which an N-terminal CUB domain restrains a C-terminal cystine-knot growth factor domain (GFD); cleavage at a defined site between the two domains liberates the GFD, which binds PDGFRα homodimers and PDGFRα/β heterodimers but not PDGFRβ homodimers [#0, #1, #3]. This activating cleavage is carried out by plasmin in vivo and by tPA, matriptase, and uPA in cellular contexts, with processing being rate-limiting for activity [#9, #10, #11], and full-length PDGF-C additionally requires N-glycosylation at Asn254 to gain receptor-activating capacity [#17]. Downstream of PDGFRα, PDGF-C engages Akt/Bad signaling to suppress apoptosis and drives chemokine and matrix programs, including CCL2/CCL5 induction in fibroblasts and MMP-2/MMP-9 induction with monocyte chemotaxis [#16, #7, #22]. Genetic epistasis in mice establishes that PDGF-C and PDGF-A together account for all PDGFRα-dependent development of craniofacial structures, the neural tube, and mesodermal organs, with Pdgfc-/- animals dying perinatally from complete secondary palate cleft [#4]; a promoter SNP that reduces PDGF-C transcription is functionally linked to human cleft lip/palate susceptibility [#15]. PDGF-C is an active node in fibrosis and cancer, acting as a macrophage-derived pro-fibrotic and pro-inflammatory amplifier in kidney injury and as an autocrine/paracrine driver of tumor growth, invasion, metastasis, and therapy resistance across Ewing tumors, breast, pancreatic, prostate, and GIST models [#7, #6, #19, #20, #26]. Its abundance is tuned at multiple levels: transcriptionally by Egr-1 downstream of angiotensin II/AT1R, by EWS/FLI-1, by STAT4, and by H3K27 acetylation [#14, #5, #26, #20]; post-transcriptionally by HuR-mediated mRNA stabilization via 3'-UTR AU-rich elements and by FTO/m6A/YTHDF2 control of transcript stability [#23, #18]; and post-translationally by SUMO-1 modification at Lys314, which redirects a portion of the protein to the nucleus [#12]. Its activity is further modulated by the extracellular partner FREM1, which binds PDGF-C and shapes the duration and amplitude of PDGFRα signaling [#13], and by N-terminally truncated splice variants that heterodimerize with full-length PDGF-C to alter its secretion and activity [#28, #27].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the defining feature of PDGF-C: unlike classical PDGFs it is a latent ligand that must be proteolytically processed to release an active growth factor domain that activates PDGFRα.\",\n      \"evidence\": \"Receptor binding assays, transgenic overexpression, and genetic analysis of Pdgfra-/- kidneys\",\n      \"pmids\": [\"10806482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the physiological protease(s) not defined\", \"Receptor selectivity among PDGFRα/β configurations not yet resolved\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the CUB–GFD two-domain architecture and the receptor specificity, showing the GFD binds PDGFRα homodimers and PDGFRα/β heterodimers but not PDGFRβ homodimers, with a serum-sensitive interdomain cleavage event releasing the GFD.\",\n      \"evidence\": \"Competition binding, immunoprecipitation on dual-receptor cells, recombinant protein characterization, and diabetic wound-healing model\",\n      \"pmids\": [\"11297552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific protease not identified\", \"Quantitative receptor affinities for each dimer configuration not established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped PDGF-C genomic structure and tissue expression, localizing the cleavage site to exon 4 and identifying smooth muscle cells as a major source with mitogenic action on coronary artery SMCs.\",\n      \"evidence\": \"FISH mapping, genomic sequencing, and SMC stimulation assays\",\n      \"pmids\": [\"11342471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional data\", \"In vivo relevance of SMC-derived PDGF-C not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the biophysical class of the GFD, showing a cystine-knot fold with three intramonomeric disulfides and greater structural similarity to VEGF than PDGF-B.\",\n      \"evidence\": \"Ellman assay, CD/NMR/IR spectroscopy on recombinant protein, and homology modeling\",\n      \"pmids\": [\"12598536\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental high-resolution structure\", \"Homology model is computational\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the in vivo developmental function through genetic epistasis, showing PDGF-C and PDGF-A together account for all PDGFRα-dependent craniofacial, neural tube, and mesodermal development, with Pdgfc loss causing fatal palatal clefting.\",\n      \"evidence\": \"Single and double knockout mice with embryo phenotyping\",\n      \"pmids\": [\"15361870\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contributions not dissected\", \"Mechanism of redundancy with PDGF-A not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the dominant physiological activating protease, showing plasmin processes latent PDGF-C in vivo (vitreous), whereas tPA dominates only in cultured cells.\",\n      \"evidence\": \"In vitro processing assays with inhibitor blocking using patient and animal vitreous specimens\",\n      \"pmids\": [\"18172073\", \"17460299\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-to-tissue variation in protease usage not mapped\", \"Regulation of processing rate not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the cellular protease repertoire and processing intermediates, identifying tPA and matriptase as major cleavers (with uPA contributing) acting in two steps to generate the active GFD dimer.\",\n      \"evidence\": \"Reconstituted in vitro proteolysis, cleavage-site mutagenesis, protease inhibitors, and cell migration/proliferation assays in breast cancer\",\n      \"pmids\": [\"22035541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each protease in vivo not quantified\", \"Regulation of the hemidimer-to-GFD-dimer transition unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established N-glycosylation at Asn254 as required for activation of full-length PDGF-C, distinguishing it from glycosylation sites dispensable for activity.\",\n      \"evidence\": \"Site-directed mutagenesis with secretion/trafficking controls and PDGFRα signaling assays\",\n      \"pmids\": [\"34109212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which Asn254 glycan enables activation not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked PDGF-C/PDGFRα to a pro-survival signaling output, showing Akt/Bad phosphorylation that suppresses caspase activation and PARP cleavage in macrophages.\",\n      \"evidence\": \"Recombinant ligand stimulation, phospho-Western blots, caspase assays, and PDGF-C knockdown xenografts\",\n      \"pmids\": [\"24421315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-to-Akt coupling not isolated from other inputs\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified FREM1 as a direct extracellular binding partner that positively tunes the amplitude and duration of PDGFRα signaling and downstream matrix output.\",\n      \"evidence\": \"Binding/co-IP, fibroblast stimulation from Frem1-mutant mice, Timp1 and collagen deposition readouts\",\n      \"pmids\": [\"24046351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of FREM1–PDGF-C binding unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established transcriptional control of PDGF-C by the angiotensin II/AT1R–Egr-1 axis at a defined upstream promoter element, operating selectively in neonatal but not adult smooth muscle cells.\",\n      \"evidence\": \"Reporter assays, EMSA, ChIP, and DNAzyme inhibition of Egr-1 with qRT-PCR\",\n      \"pmids\": [\"18272536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of the neonatal-versus-adult difference not resolved\", \"Other inputs converging on the promoter not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected reduced PDGF-C transcription to human disease, showing a promoter SNP that abolishes regulatory motifs and reduces promoter activity is associated with cleft lip/palate susceptibility.\",\n      \"evidence\": \"Promoter reporter transfection, sequence analysis, and SNP genotyping\",\n      \"pmids\": [\"19092777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality in patient tissue not demonstrated\", \"Effect on protein levels in vivo not measured\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a post-translational fate beyond secretion, showing SUMO-1 modification at Lys314 produces a nuclear, partly chromatin-associated form that is reduced in papillary thyroid carcinoma.\",\n      \"evidence\": \"Subcellular fractionation, SUMO-1 co-IP, and immunohistochemistry\",\n      \"pmids\": [\"16443219\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of the nuclear form unknown\", \"SUMO ligase and signals controlling modification not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established post-transcriptional stabilization of PDGF-C, showing HuR binds two 3'-UTR AU-rich elements to upregulate PDGF-C mRNA under stress in breast cancer cells.\",\n      \"evidence\": \"RNA immunoprecipitation, 3'-UTR reporter, HuR perturbation, and mRNA stability assays\",\n      \"pmids\": [\"25383675\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stress signals driving HuR engagement not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added m6A-based regulation of PDGFC, showing FTO removes 3'-UTR m6A marks to stabilize the transcript, while m6A accumulation triggers YTHDF2-dependent decay, with the FTO–PDGFC axis reactivating Akt to promote pancreatic cancer growth.\",\n      \"evidence\": \"m6A-seq, MeRIP-qPCR, RIP, luciferase reporter, and FTO perturbation in vitro and in vivo\",\n      \"pmids\": [\"35422475\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites controlling decay not pinpointed\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended transcriptional regulation to a therapy-resistance context, identifying STAT4 as a direct activator of PDGFC that drives autocrine PDGFR-Rap1-MAPK signaling and enzalutamide resistance in prostate cancer.\",\n      \"evidence\": \"Luciferase reporter, ChIP, PDGFC silencing, in vitro proliferation assays, and xenografts\",\n      \"pmids\": [\"40993441\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the Rap1-MAPK output across cell types not tested\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Implicated PDGF-C as a myeloid effector in vascular inflammation, showing it induces MMP-9 expression, enhances MMP-2/MMP-9 secretion, and attracts monocytes.\",\n      \"evidence\": \"qPCR, ELISA/zymography, and Boyden chamber migration assays\",\n      \"pmids\": [\"18573494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor dependence of MMP induction not confirmed\", \"In vivo relevance not tested in this study\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a pathogenic role in renal fibrosis, showing macrophage-derived PDGF-C is a fibroblast mitogen and chemokine inducer that drives a pro-inflammatory amplification loop, with neutralization or knockout reducing fibrosis.\",\n      \"evidence\": \"Anti-PDGF-C neutralization and Pdgfc-/- mice in the UUO model plus in vitro fibroblast assays\",\n      \"pmids\": [\"18184860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream trigger of macrophage PDGF-C production not defined\", \"Contribution of PDGFRα versus β to the loop not separated here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed an indirect pro-angiogenic action in glomerular disease, showing PDGF-C infusion increases endothelial proliferation and strongly upregulates FGF-2 in glomerular endothelial cells.\",\n      \"evidence\": \"PDGF-C infusion/antagonism in rat nephritis and microangiopathy models with in vitro glomerular endothelial assays\",\n      \"pmids\": [\"20489153\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus paracrine endothelial effects not fully separated\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated organ specificity of PDGF-C in fibrosis, showing it protects against kidney fibrosis via PDGFRα/β signaling but not against liver fibrosis, where PDGF-B/D–PDGFRβ predominate.\",\n      \"evidence\": \"Pdgfc-/- mice and neutralizing antibody across UUO and bile duct ligation models with receptor signaling Westerns\",\n      \"pmids\": [\"23141925\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of organ specificity not defined\", \"Cross-talk among PDGF isoforms not dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked PDGF-C to oncogenic transcription, showing the EWS/FLI-1 fusion transcriptionally upregulates PDGF-C in Ewing family tumors in an EWS/ETS-specific manner.\",\n      \"evidence\": \"Retroviral cDNA screen and EWS/FLI modulation in EFT cell lines\",\n      \"pmids\": [\"11313995\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect EWS/FLI regulation of the promoter not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated functional dependence of tumor phenotype on autocrine PDGF-C, showing a dominant-negative PDGF-C and PDGFR inhibition block anchorage-independent growth.\",\n      \"evidence\": \"Dominant-negative mutagenesis, soft-agar assays, and AG1296 inhibition in EFT and fibroblast models\",\n      \"pmids\": [\"12032822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo tumor dependence not tested here\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established a paracrine pro-metastatic role, showing tumor-derived PDGF-C rescues hepatic stellate cells via PAK-2 and that PDGF-C knockdown inhibits liver metastasis.\",\n      \"evidence\": \"PDGF-C knockdown in colon carcinoma, recombinant ligand on HSC, PAK-2 siRNA, and nude mouse metastasis model\",\n      \"pmids\": [\"22362252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the HSC response not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended paracrine tumor signaling to the stroma, showing CAF-derived PDGFC activates PDGFRA-SLUG signaling to drive GIST growth and metastasis.\",\n      \"evidence\": \"CAF isolation, co-culture, PDGFC perturbation, and in vivo metastasis model\",\n      \"pmids\": [\"33603171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct PDGFRA-to-SLUG mechanism not fully mapped\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked epigenetic activation of PDGFC to drug resistance, showing H3K27 acetylation activates PDGFC, which drives gemcitabine resistance via PDGFR-PI3K-AKT, reversible by imatinib.\",\n      \"evidence\": \"H3K27ac ChIP, PDGFC silencing, signaling Westerns, and patient-derived xenografts\",\n      \"pmids\": [\"36384875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Writer/eraser controlling the H3K27ac mark not identified\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterized regulatory splice variants, showing a truncated PDGF-C lacking signal peptide and CUB domain forms intracellular dimers and heterodimerizes with full-length protein to enhance transformation and invasion.\",\n      \"evidence\": \"Expression constructs, localization imaging, soft-agar and Matrigel assays, and PDGF-C knockdown\",\n      \"pmids\": [\"31542979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous expression and physiological relevance of the variant unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Described a dominant-negative splice isoform, showing a non-secreted N-terminally truncated PDGF-Cb heterodimerizes with full-length protein, retaining and degrading it.\",\n      \"evidence\": \"Expression constructs, localization, and co-IP for heterodimers\",\n      \"pmids\": [\"18588873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo occurrence and functional impact not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Proposed a mitogenic mechanism via ribosome biogenesis control, with PDGF-C downregulating BOP1 to promote proliferation.\",\n      \"evidence\": \"Conditioned medium treatment, BOP1 perturbation, and Pdgfc-/- tissues in HEK293A assays\",\n      \"pmids\": [\"37615370\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Indirect conditioned-medium exposure limits mechanistic attribution\", \"Receptor dependence of BOP1 regulation not shown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated PDGF-C in endothelial mitochondrial homeostasis, showing it increases OPA1 and reduces DRP1 Ser616 phosphorylation to restore mitochondrial networks under high glucose.\",\n      \"evidence\": \"Recombinant PDGF-C on aortic endothelial cells with Western blot, morphology imaging, and Seahorse flux\",\n      \"pmids\": [\"36901825\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling link from PDGFRα to mitochondrial dynamics machinery not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Suggested a niche-maintenance role, with PDGFC supporting isolation and quiescent maintenance of neural stem cells permissive for oligodendrocyte progenitor transition.\",\n      \"evidence\": \"NSC culture in PDGFC medium with comparative expression and lineage assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Descriptive culture assay without receptor-level mechanism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory layers—proteolytic activation, glycosylation, SUMOylation, m6A/HuR mRNA control, and splice-variant dimerization—are integrated to set PDGF-C activity in a given tissue, and the structural basis of its receptor and FREM1 interactions, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental high-resolution structure of the GFD–receptor complex\", \"No integrated model coupling activation, modification, and transcriptional control\", \"Tissue-specific protease and receptor usage not systematically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [12, 28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 16, 26]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 19, 20]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [9, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDGFRA\", \"PDGFRB\", \"FREM1\", \"PLG\", \"PLAT\", \"ST14\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}