{"gene":"HSPG2","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1994,"finding":"Perlecan induces high-affinity binding of bFGF (FGF-2) to cells deficient in heparan sulfate and to soluble FGF receptors, functioning as a major accessory/co-receptor for bFGF; monoclonal antibodies to perlecan block this receptor-binding-promoting activity; perlecan potently induces bFGF-mediated neovascularization in vivo.","method":"Affinity-purified HSPG binding assays, monoclonal antibody inhibition, in vivo rabbit ear angiogenesis model","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (cell-based binding, antibody inhibition, in vivo rescue), replicated by subsequent antisense studies","pmids":["7528102"],"is_preprint":false},{"year":1997,"finding":"Stable antisense suppression of perlecan in NIH 3T3 fibroblasts and melanoma cells dramatically reduces high-affinity bFGF receptor binding and mitogenic response, which can be rescued by exogenous heparin or perlecan, confirming perlecan as a major bFGF accessory receptor in vivo.","method":"Antisense cDNA stable transfection, Northern blot, immunoblot, 125I-bFGF receptor binding/affinity labeling, thymidine incorporation proliferation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — genetic loss-of-function with multiple orthogonal readouts and rescue experiment","pmids":["9121441"],"is_preprint":false},{"year":1999,"finding":"Homozygous perlecan (Hspg2) null mice develop normally formed basement membranes initially, but BMs deteriorate under mechanical stress (contracting myocardium, expanding brain vesicles), causing cardiac blood leakage, exencephaly, and severe chondrodysplasia with disorganized fibrillar collagen network, demonstrating perlecan is essential for BM integrity and cartilage ECM maintenance.","method":"Gene knockout mouse, electron microscopy, histology, immunohistochemistry, collagen ECM gene expression analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific phenotypic readouts, replicated independently in two labs same year","pmids":["10579729"],"is_preprint":false},{"year":1999,"finding":"Hspg2-/- mice exhibit severe skeletal dysplasia with disorganized chondrocyte columnar structures, reduced collagen fibrils and glycosaminoglycans in cartilage matrix, reduced chondrocyte proliferation, and diminished prehypertrophic zone, phenotypically similar to thanatophoric dysplasia caused by activating FGFR3 mutations, placing perlecan in the FGF/FGFR3 signaling axis regulating chondrogenesis.","method":"Hspg2 gene disruption in mice, histology, immunostaining, comparison with Fgfr3 gain-of-function mouse phenotype (genetic epistasis inference)","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — independent knockout with multiple phenotypic readouts, replicates findings of Costell et al. 1999","pmids":["10545953"],"is_preprint":false},{"year":2000,"finding":"The protein core of perlecan binds FGF-7 (KGF) specifically to the N-terminal half of domain III and to domain V, with affinity constants ~60 nM, independent of heparan sulfate chains; this interaction is demonstrated by overlay protein assays, radioligand binding, and yeast two-hybrid.","method":"Overlay protein assays, radioligand binding experiments, yeast two-hybrid system","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — three orthogonal binding methods, domain-mapped interaction","pmids":["10702276"],"is_preprint":false},{"year":2000,"finding":"Perlecan mediates internalization and lysosomal delivery of atherogenic lipoproteins enriched in lipoprotein lipase via a kinetically and biochemically distinct pathway from coated pits or syndecan-mediated endocytosis; binding is blocked by heparitinase, degradation by chloroquine, and internalization is inhibited by genistein but not cytochalasin D; beta1 integrins serve as cell-surface attachment sites for perlecan.","method":"Cell-based binding, internalization and degradation assays using cells expressing perlecan but no other proteoglycans; pharmacological inhibitors; antibody blockade","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal approaches in a defined cell system, mechanistic pathway dissection","pmids":["10818109"],"is_preprint":false},{"year":2001,"finding":"Perlecan domain III interacts with FGF-binding protein (FGF-BP) at the second EGF repeat; this interaction was identified by yeast two-hybrid, confirmed by co-immunoprecipitation and solid-phase binding to recombinant domain III-alkaline phosphatase fusion protein, and they co-localize in tumor stroma in vivo.","method":"Yeast two-hybrid, co-immunoprecipitation, solid-phase binding, immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — three orthogonal binding methods, domain-mapped interaction with in vivo co-localization","pmids":["11148217"],"is_preprint":false},{"year":2001,"finding":"In perlecan-null ES cells, complex laminin-1 matrix structures fail to form, and laminin and perlecan reciprocally modulate each other's organization on the cell surface; beta1 integrin function is required downstream of dystroglycan for laminin matrix assembly.","method":"Null-mutant ES cell lines (perlecan-deficient, beta1 integrin-deficient, dystroglycan-deficient), laminin clustering assays, fluorescence microscopy","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — genetic null cells with specific phenotypic readouts, mechanistic ordering of pathway components","pmids":["11228157"],"is_preprint":false},{"year":2001,"finding":"Perlecan protein core (not heparan sulfate chains) is required for functional activation of the KGF receptor (FGFR2-IIIb) and downstream signaling in colon carcinoma cells; perlecan-deficient cells (via targeted homologous recombination) do not respond to FGF7, and heparin cannot substitute for perlecan in this signaling context.","method":"Targeted homologous recombination to disrupt HSPG2, KGF receptor signaling assays, growth assays, FGF7 surface binding","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — genetic disruption with rescue experiments, first genetic evidence for protein core role in FGF7 signaling","pmids":["11563979"],"is_preprint":false},{"year":2003,"finding":"Perlecan (encoded by trol) regulates neuroblast division in Drosophila by modulating both FGF and Hedgehog signaling; human FGF-2 rescues trol mutant proliferation phenotype; Trol co-immunoprecipitates with Hh and mammalian perlecan with Shh (not competed by heparan sulfate); trol affects Hh movement through tissue, placing perlecan upstream of both FGF/MAPK and Hh pathways.","method":"Drosophila trol mutant genetic analysis, FGF-2 rescue in culture, co-immunoprecipitation, MAPK inhibitor assays, genetic epistasis (trol, hh, ttv mutations)","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis + biochemical (Co-IP) + functional rescue, ortholog in model organism","pmids":["12645928"],"is_preprint":false},{"year":2003,"finding":"Perlecan co-immunoprecipitates with CTGF/Hcs24 from chondrocytes; CTGF stimulates perlecan gene expression; CTGF effects on chondrocyte aggrecan expression and DNA/proteoglycan synthesis are abolished by heparinase pretreatment, demonstrating that CTGF signals through heparan sulfate proteoglycans including perlecan to regulate chondrocyte proliferation and differentiation.","method":"Immunofluorescence co-localization, Northern blot, in vitro co-immunoprecipitation, 125I-rCTGF binding, heparinase inhibition of CTGF-stimulated gene expression","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP confirmed with functional heparinase experiment, single lab","pmids":["12811819"],"is_preprint":false},{"year":2003,"finding":"Heparanase (HPSE-1) specifically degrades heparan sulfate chains of purified perlecan (as well as syndecan-1); cell-surface syndecan-1 inhibits HPSE-1-mediated invasion of melanoma cells in a manner requiring its HS chains, revealing perlecan as a degradative substrate of heparanase with implications for tumor invasion.","method":"In vitro enzymatic digestion of purified HSPGs, in vitro chemoinvasion assays, pharmacological/HS-chain-dependent inhibition experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro enzymatic assay on purified substrate, functional validation","pmids":["14630925"],"is_preprint":false},{"year":2003,"finding":"Progranulin binds specifically to perlecan domain V (first two laminin- and EGF-like repeats interacting with granulins F and B) with KD ~1 µM; both progranulin and domain V individually stimulate adrenal carcinoma cell growth, but equimolar combination antagonizes each other's activity.","method":"Yeast two-hybrid, co-immunoprecipitation (cell-free transcription/translation and transient transfection), surface plasmon resonance","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — yeast two-hybrid confirmed by Co-IP and quantitative SPR, domain mapping, functional consequence demonstrated","pmids":["12900424"],"is_preprint":false},{"year":2003,"finding":"Perlecan-null cartilage shows reduced collagen fibril density not attributable to increased gelatinase (MMP-2/MMP-9) activity; crossing perlecan null onto MMP-9 null background fails to rescue cartilage ultrastructural abnormalities, ruling out MMP-9 as the primary effector of collagen loss.","method":"Genetic cross of perlecan-null and MMP-9-null mice, immunohistochemistry, in situ and SDS-PAGE zymography","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis by double-null crosses with enzymatic activity confirmation","pmids":["12814946"],"is_preprint":false},{"year":2003,"finding":"Perlecan heparan sulfate chains of exon 3 (domain I) are indispensable for lens capsule integrity but not required for kidney glomerular filtration under normal conditions; deletion of HS attachment sites causes lens apoptosis, cellular membrane leakage, and lens degeneration; glomerular HS charge density is maintained by chondroitin sulfate compensation in mutant mice.","method":"Hspg2 exon 3 deletion mouse (HS-deficient perlecan), electron microscopy, apoptosis assay, urinalysis, immunostaining","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — clean domain-specific knock-in mouse with multiple phenotypic and biochemical readouts","pmids":["12514129"],"is_preprint":false},{"year":2004,"finding":"Perlecan heparan sulfate (HS) side chains of smooth muscle cell perlecan suppress SMC proliferation; HS-deficient perlecan transgenic mice show increased SMC proliferation and enhanced intimal hyperplasia after carotid artery flow cessation; HS-deficient perlecan shows defective ECM-binding capacity for FGF-2.","method":"Transgenic mice with HS-deficient perlecan (Hspg2Δ3/Δ3), flow cessation carotid artery model, SMC culture proliferation assays, FGF-2 ECM-binding assay","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro results concordant, specific molecular mechanism (FGF-2 sequestration via HS) identified","pmids":["14739157"],"is_preprint":false},{"year":2005,"finding":"Heparan sulfate chains of perlecan in domain I contribute to glomerular filtration of protein; Hspg2Δ3/Δ3 mice exhibit remarkable proteinuria when protein-loaded, despite no baseline structural abnormality; mutant perlecan is partially substituted with chondroitin sulfate instead, maintaining charge density under basal conditions.","method":"Hspg2Δ3/Δ3 mouse, BSA challenge intraperitoneal injection, urinary protein measurement, polyethyleneimine charge staining, immunostaining, transcript analysis","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — domain-specific knockout with functional challenge, concordant biochemical and physiological data","pmids":["15872080"],"is_preprint":false},{"year":2005,"finding":"Epidermally derived perlecan (not dermal) is essential for keratinocyte survival and stratification during epidermal formation; perlecan-deficient keratinocytes show premature apoptosis and fail stratification; exogenous perlecan restores epidermal formation; FGF-7 partially rescues perlecan-deficient keratinocytes from cell death, suggesting perlecan regulates FGF-7 bioavailability.","method":"Perlecan siRNA knockdown in engineered human skin (organotypic coculture), rescue with exogenous perlecan or FGF-7, apoptosis assays, immunostaining","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with specific cellular phenotype, rescue experiments, tissue-specific dissection","pmids":["16269412"],"is_preprint":false},{"year":2006,"finding":"Cartilage perlecan bearing chondroitin sulfate chains (specifically 4,6-disulfated chondroitin sulfate E) binds collagen and accelerates collagen type II fibril formation in vitro, producing more defined fibril morphology and increased fibril diameters; this enhancement is glycosaminoglycan- (not core protein-) dependent and is mimicked by chondroitin sulfate E but not chondroitin sulfate D.","method":"In vitro collagen fibril formation assay with purified perlecan, chondroitinase treatment, GAG disaccharide compositional analysis, electron microscopy of fibrils","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro collagen fibril formation with defined GAG variants, mechanistic specificity demonstrated","pmids":["16956876"],"is_preprint":false},{"year":2007,"finding":"The perlecan core protein (not HS or CS chains) binds FGF-18 via cysteine-rich regions of domain III with KD ~27.8–145 nM; perlecan reverses FGF-18-stimulated chondrocyte proliferation, acting as an antagonist of FGF-18 mitogenic activity in growth plate chondrocytes.","method":"Cationic filtration and immunoprecipitation binding assays, chondroitinase/heparitinase treatment, reduction/alkylation of core protein, recombinant domain expression, 3H-thymidine incorporation","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1-2 — quantitative binding with domain mapping, orthogonal functional assay","pmids":["17971291"],"is_preprint":false},{"year":2008,"finding":"Perlecan depletion in zebrafish causes severe myopathy with abnormal actin filament orientation and disorganized sarcomeres, and failure of primary intersegmental vessel sprouts to extend; phenotype is partially rescued by injection of human perlecan or its C-terminal domain V/endorepellin, demonstrating endorepellin mediates most biological activities of perlecan in muscle and angiogenesis.","method":"Morpholino-based protein depletion in zebrafish, protein rescue microinjection, live videomicroscopy, fluorescence imaging of actin and vasculature","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function with domain-specific rescue, multiple orthogonal phenotypic readouts","pmids":["18426981"],"is_preprint":false},{"year":2000,"finding":"Perlecan is required to prevent thrombosis after deep vascular injury; antisense-perlecan endothelial cells fail to prevent occlusive thrombosis in a porcine carotid artery model; perlecan suppression reduces endothelial cell ability to inhibit FGF-2 binding and mitogenic activity in smooth muscle cells, while only partially abrogating intimal hyperplasia suppression.","method":"Antisense perlecan vector in endothelial cells, three-dimensional polymeric matrix implantation in porcine carotid artery deep injury model, FGF-2 binding and mitogenesis assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — in vivo loss-of-function with specific thrombosis phenotype, mechanistic dissection of differential effects","pmids":["10841569"],"is_preprint":false},{"year":1998,"finding":"Perlecan binds alpha-dystroglycan in a calcium- and heparin-sensitive manner (blot overlay assay and co-immunoprecipitation); cell-surface perlecan co-localizes with dystroglycan at AChR clusters in Xenopus muscle cells; perlecan and dystroglycan are co-clustered at ACh receptor clusters induced by spinal neurons or HB-GAM-coated beads, suggesting perlecan is anchored to the muscle surface via the DG-dystrophin complex.","method":"Blot overlay assay, co-immunoprecipitation with anti-DG antibody, immunofluorescence co-localization in Xenopus muscle cells","journal":"Cell adhesion and communication","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, reciprocal Co-IP plus co-localization, heparin/calcium sensitivity provides mechanistic detail","pmids":["9791728"],"is_preprint":false},{"year":2005,"finding":"Laminin polymerization promotes perlecan assembly on cell surfaces; dystroglycan, laminin, and perlecan form a trimolecular complex demonstrated by solid-phase binding; LARGE-deficient (glycosylation-deficient) mice show reduced perlecan-binding activity and perlecan mislocalization, linking dystroglycan glycosylation to perlecan matrix assembly.","method":"Solid-phase ligand binding assays (trimolecular complex), cell-surface ligand clustering assays, analysis of Large(myd) mouse","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — solid-phase binding for trimolecular complex plus in vivo mouse model, single lab","pmids":["16098969"],"is_preprint":false},{"year":2005,"finding":"Perlecan LG domains (domain V) promote AChR clustering in the presence of laminin-2 through a MuSK-dependent mechanism requiring laminin polymerization; perlecan-LG-dependent AChR clustering is accompanied by tyrosine phosphorylation of MuSK and betaAChR; antibody-mediated aggregation of non-neural agrin mimics this clustering, supporting a ligand-aggregation mechanism.","method":"Myotube culture AChR clustering assay, MuSK inhibition, tyrosine phosphorylation western blot, antibody crosslinking experiments","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — functional reconstitution in cell culture with kinase activity readout, mechanistic dissection","pmids":["16219760"],"is_preprint":false},{"year":2012,"finding":"Drosophila perlecan (trol) is required for Sema-1a/PlexA-mediated repulsive motor axon guidance; trol mutations suppress Sema-1a-mediated defasciculation phenotypes; perlecan augments the reduction of phospho-FAK induced by Sema-1a in insect cells; genetic interactions among integrin, Sema-1a, and FAK indicate perlecan facilitates Sema-1a signaling by antagonizing integrin/FAK activity.","method":"Drosophila genetic epistasis (trol, Sema-1a, PlexA, integrin, FAK double/triple mutants), in vitro phospho-FAK assay in insect cells, perlecan rescue in mutant motor neurons","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple alleles plus biochemical in vitro confirmation, mechanistic pathway placement","pmids":["23028146"],"is_preprint":false},{"year":2013,"finding":"Perlecan is required for FGF-2 signaling in the adult subventricular zone neurogenic niche; perlecan deficiency reduces neural stem cells (GFAP/CD133+) and new neurons; in the absence of perlecan, FGF-2 fails to promote neurosphere formation and fails to activate Akt and Erk1/2 or induce cyclin D2 expression.","method":"Perlecan-deficient mouse, neurosphere formation assay, FGF-2 stimulation with Akt/Erk1/2 pathway readout, cyclin D2 expression, immunostaining for neural stem cell markers","journal":"Stem cell research","confidence":"High","confidence_rationale":"Tier 2 — genetic null mouse with specific signaling pathway readouts, both in vivo and in vitro components","pmids":["24434631"],"is_preprint":false},{"year":2014,"finding":"MMP-7 (matrilysin) cleaves perlecan specifically at domain IV immunoglobulin repeat regions even when perlecan is fully HS-decorated or embedded in native basement membrane context; a C-terminal domain IV fragment (Dm IV-3) induces PCa cell clustering via FAK dephosphorylation/deactivation; MMP-7 cleavage reverses clustering to cell dispersion with FAK activation, acting as a molecular switch for cancer cell invasion.","method":"In vitro MMP-7 digestion of purified perlecan, recombinant domain IV fragments, Transwell invasion assay, cell clustering phenotype assays, comparison with PSA, hepsin, FAP enzymes","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay with defined substrate plus functional cell-based phenotype, domain-level mapping","pmids":["24833109"],"is_preprint":false},{"year":2014,"finding":"Smooth muscle cell-derived perlecan contains both HS and CS chains, whereas endothelial cell-derived perlecan contains exclusively HS; SMC perlecan binds FGF1 and FGF2 via HS but promotes only FGF2 signaling, while endothelial perlecan promotes both FGF1 and FGF2 signaling; SMC adhesion to perlecan core requires GAG removal and involves a novel domain III site and domain V/endorepellin via alpha2beta1 integrin.","method":"Isolation and GAG characterization of cell-type-specific perlecan, FGF binding assays, signaling assays, integrin-blocking antibodies, cell adhesion assays","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical characterization plus functional signaling and adhesion assays, cell-type-specific mechanistic distinction","pmids":["24509440"],"is_preprint":false},{"year":2014,"finding":"Perlecan domain IV-3 binds semaphorin 3A (Sema3A) on PCa cells (demonstrated by direct binding experiments and co-IP); this perlecan-Sema3A complex deactivates FAK and promotes PCa cell clustering (tumoroid formation); MMP-7 cleaves both perlecan and Sema3A, destroying the complex and activating FAK to drive cell dispersion and invasion.","method":"Direct binding experiments, co-immunoprecipitation, Sema3A antibody mimicry, siRNA knockdown of Sema3A, MMP-7 cleavage assays, FAK phosphorylation western blot, Transwell invasion","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding confirmed by multiple methods, mechanistic linkage to FAK signaling pathway, loss-of-function with specific readout","pmids":["29740048"],"is_preprint":false},{"year":2015,"finding":"Perlecan deficiency in endothelial cells (siRNA knockdown) or in a conditional perlecan knockout mouse reduces eNOS gene and protein expression, resulting in impaired acetylcholine-dependent endothelium-dependent relaxation while preserving nitroprusside (NO donor)-dependent relaxation.","method":"Conditional perlecan-deficient mouse, isolated aortic ring isometric force measurements, real-time PCR, Western blot, siRNA knockdown in human aortic endothelial cells","journal":"Physiological reports","confidence":"High","confidence_rationale":"Tier 2 — genetic and siRNA loss-of-function concordant, specific molecular target (eNOS) identified with functional vascular tone readout","pmids":["25626871"],"is_preprint":false},{"year":2015,"finding":"Perlecan HS chains (domain I) are required for formation of the HS-FGF2-FGFR1 ternary complex; Hspg2Δ3/Δ3 mice show impaired FGFR1 phosphorylation and reduced PASMC proliferation in response to hypoxia, attenuating pulmonary hypertension development.","method":"Hspg2Δ3/Δ3 mice, hypoxia PH model, ligand and carbohydrate engagement (LACE) assay for ternary complex formation, FGFR1 phosphorylation western blot, PASMC proliferation assay, selective FGFR1 inhibition","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1-2 — ternary complex assay plus genetic mouse model with concordant in vitro and in vivo results","pmids":["25952902"],"is_preprint":false},{"year":2015,"finding":"Perlecan/HSPG2 core protein is a monomeric rod of 170±20 nm end-to-end length (measured by AFM), capable of withstanding >100 pN tensile force (elastic constant 890 pN, Young's modulus 71 MPa), physically suitable to span the osteocyte pericellular space and act as a mechanical tether in the lacunar-canalicular system.","method":"Atomic force microscopy imaging and single-molecule force measurements (SMFM) of purified full-length human perlecan, extensible worm-like chain model fitting","journal":"Matrix biology : journal of the International Society for Matrix Biology","confidence":"High","confidence_rationale":"Tier 1 — direct structural/physical measurement of purified protein with quantitative biophysical parameters","pmids":["26546708"],"is_preprint":false},{"year":1997,"finding":"TGF-beta transcriptionally induces perlecan mRNA and protein 2-3 fold in skin fibroblasts via a NF-1-binding element located between -461 and -285 bp in the promoter; TNF-alpha has no effect and cannot counteract TGF-beta; the TGF-beta responsive element binds TGF-beta-inducible nuclear proteins with high affinity.","method":"Transient cell transfection reporter assays, 5' deletion and internal deletion analysis, DNase footprinting, electrophoretic mobility shift assays (EMSA), mutational analyses, Northern blot/protein quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple complementary methods defining promoter element and transcription factor binding","pmids":["9030592"],"is_preprint":false},{"year":2014,"finding":"TNF-alpha is a major cytokine regulator of perlecan production via NF-kappaB; TNF-alpha triggers p65 nuclear translocation and binding to the HSPG2 regulatory region containing conserved NF-kappaB binding sites; reporter construct dissection locates an active cis-element in the distal HSPG2 promoter region.","method":"HSPG2 promoter reporter construct transfections with systematic deletions, cytokine treatment, p65 nuclear translocation assay, chromatin-level p65 binding","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — promoter dissection with multiple constructs plus transcription factor binding, single lab","pmids":["24700612"],"is_preprint":false},{"year":2014,"finding":"Perlecan domain II core protein interacts with LDL via O-linked sialylated glycans; sialic acid residues on domain II are critical for LDL binding; HS and domain II have an additive effect on LDL binding; unlike LDLR (which mediates endocytosis), perlecan DII mediates receptor-mediated lipoprotein retention in the arterial wall.","method":"Solid-phase binding assays, glycan analysis of secreted DII (MS), sialic acid-specific inhibition, domain-specific binding experiments","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical dissection with MS glycan analysis plus functional binding assays, specific mechanism identified","pmids":["25528754"],"is_preprint":false},{"year":2019,"finding":"Perlecan is a key component of the pro-metastatic CAF environment driven by GOF mutant p53 cancer cells; depletion of perlecan from the stroma combined with chemotherapy prolongs mouse survival; perlecan depletion reduces chemotherapy resistance in a pancreatic cancer model observed by intravital imaging.","method":"Intravital imaging, perlecan stromal depletion (genetic/RNAi), combination with chemotherapy in mouse model, survival analysis with mechanistic framing","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function with specific survival and drug response readouts, but mechanism upstream of perlecan only partially defined","pmids":["31406163"],"is_preprint":false},{"year":2019,"finding":"Perlecan deficiency (Hypo mice) impairs osteocyte calcium signaling in response to mechanical loading; perlecan-deficient osteocytes show reduced Ca2+ response rate, peak magnitude, and recovery; RNA sequencing identifies suppression of calcium signaling, ECM-receptor interaction, and focal adhesion pathways, with defects in Ryr1 and Atp2a1 (ER calcium cycling regulators).","method":"Real-time Ca2+ imaging in situ in murine tibiae under cyclic loading, RNA sequencing, pathway analysis","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — live imaging of calcium signaling in genetic null, complemented by transcriptomic pathway analysis","pmids":["31715337"],"is_preprint":false},{"year":2024,"finding":"Perlecan haploinsufficiency in hPSC-derived cardiomyocytes causes structural immaturity (reduced alpha-actinin), increased glycolytic metabolism, and proliferation; perlecan-haploinsufficient engineered heart tissues have reduced thickness and force generation; hPSC-CMs grown on perlecan peptide substrate are enlarged with increased nucleation (hypertrophic growth); perlecan signaling is mediated via the dystroglycan complex.","method":"HSPG2+/- hPSC haploinsufficiency, cardiomyocyte differentiation, engineered heart tissue force measurement, perlecan peptide substrate culture, dystroglycan complex interaction assessment","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — genetic haploinsufficiency with multiple orthogonal functional and structural readouts, rescue by peptide substrate, pathway (dystroglycan complex) identified","pmids":["38198277"],"is_preprint":false},{"year":2011,"finding":"Perlecan co-localizes with elastin and fibrillin-1 in connective tissues; tropoelastin interacts with perlecan heparan sulfate chains (quartz crystal microbalance), and core protein also contributes; this interaction promotes tropoelastin coacervation and deposition of elastin onto perlecan, supporting elastic microfibril assembly.","method":"Immunohistochemistry co-localization, quartz crystal microbalance with dissipation (QCM-D) solid-phase binding, heparan sulfate-dependent interaction analysis","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — solid-phase biophysical binding complemented by tissue co-localization, single lab","pmids":["21874555"],"is_preprint":false},{"year":2002,"finding":"Type XIII collagen ectodomain binds perlecan (and fibronectin, nidogen-2, heparin) with nanomolar KD values determined by surface plasmon resonance; binding sites for nidogen-2 and perlecan reside in pepsin-sensitive non-collagenous portions of type XIII collagen.","method":"Surface plasmon resonance binding assay, pepsin digestion domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative SPR with domain mapping, identifies perlecan as a specific binding partner for type XIII collagen","pmids":["11956183"],"is_preprint":false},{"year":2023,"finding":"TNFSF13 binds HSPG2/perlecan on hypertrophic scar fibroblasts; the TNFSF13/HSPG2 interaction activates NF-kappaB signaling to promote fibroblast proliferation, migration, fibrosis, and inflammation; silencing HSPG2 or inhibiting NF-kappaB eliminates TNFSF13 pro-fibrotic effects; MSC-derived exosomes suppress TNFSF13 and HSPG2 to reduce fibroblast activity.","method":"Recombinant TNFSF13 protein treatment, TNFSF13/HSPG2 siRNA knockdown, protein-protein binding assays, NF-kappaB pathway inhibition, CCK-8/EdU/Transwell assays, western blot","journal":"International journal of nanomedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — binding and functional knockdown data with pathway readout, single lab","pmids":["38046235"],"is_preprint":false}],"current_model":"Perlecan (HSPG2) is a large, modular heparan sulfate proteoglycan that functions as a multivalent signaling scaffold: its N-terminal heparan sulfate chains (domain I) sequester and present FGF-2 and other heparin-binding growth factors to their receptors (forming obligate HS-GF-FGFR ternary complexes), while its protein core independently binds FGF-7, FGF-18, FGF-BP, progranulin, semaphorin 3A, LDL, dystroglycan, and type XIII collagen through distinct domain-specific sites; domain III mediates RGD/integrin-dependent cell adhesion and FGF-7/KGF receptor activation; domain V/endorepellin drives angiogenesis, myopathy rescue, and acetylcholine receptor clustering via MuSK in a laminin-polymerization-dependent manner; chondroitin sulfate side chains on perlecan promote collagen type II fibril assembly in cartilage; proteolytic processing by MMP-7 at domain IV acts as a molecular switch converting perlecan-Sema3A-mediated FAK inactivation and cell clustering to FAK activation and invasive cell dispersion; heparanase degrades perlecan HS chains to facilitate tumor invasion; perlecan deficiency abolishes endothelium-dependent vascular relaxation by reducing eNOS expression, impairs osteocyte mechanosensory calcium signaling via ryanodine receptor and SERCA pathways, and causes perinatal-lethal chondrodysplasia and basement membrane failure under mechanical stress."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that perlecan is not merely a structural proteoglycan but a functional co-receptor that enables high-affinity FGF-2 binding to its receptor and drives angiogenesis in vivo answered the fundamental question of why basement membrane HSPGs are required for growth factor signaling.","evidence":"Purified perlecan binding assays on HS-deficient cells, monoclonal antibody inhibition, rabbit ear angiogenesis model","pmids":["7528102"],"confidence":"High","gaps":["Identity of the minimal HS structure required for ternary complex formation was not defined","Whether perlecan HS versus other HSPGs had unique or redundant co-receptor function was unresolved"]},{"year":1997,"claim":"Genetic loss-of-function confirmed perlecan as the principal endogenous FGF-2 co-receptor, ruling out redundancy with other cell-surface HSPGs, while parallel promoter studies showed TGF-β transcriptionally upregulates perlecan via an NF-1-binding element.","evidence":"Stable antisense suppression in fibroblasts/melanoma with rescue by exogenous perlecan; promoter deletion/EMSA/reporter assays in skin fibroblasts","pmids":["9121441","9030592"],"confidence":"High","gaps":["In vivo genetic confirmation in mammals was still lacking","Which downstream signaling pathways are activated was not yet characterized"]},{"year":1999,"claim":"Knockout mice revealed that perlecan is essential for basement membrane integrity under mechanical stress and for cartilage collagen network organization, with the chondrodysplasia phenotype paralleling FGFR3 gain-of-function, placing perlecan in the FGF/FGFR3 signaling axis of chondrogenesis.","evidence":"Two independent Hspg2-null mouse lines with histology, EM, and phenotypic comparison to FGFR3 mutant mice","pmids":["10579729","10545953"],"confidence":"High","gaps":["Whether perlecan acts through HS chains or protein core in cartilage was unresolved","Direct biochemical demonstration of perlecan–FGFR3 interaction was missing"]},{"year":2000,"claim":"Domain-mapping studies revealed that the perlecan protein core (domains III and V) binds FGF-7 independently of heparan sulfate, and that perlecan mediates a distinct lipoprotein internalization/degradation pathway via β1 integrins, while in vivo vascular studies showed perlecan prevents thrombosis after deep injury.","evidence":"Yeast two-hybrid/radioligand binding for FGF-7; pharmacological dissection of lipoprotein endocytosis; antisense-perlecan endothelial cells in porcine carotid artery model","pmids":["10702276","10818109","10841569"],"confidence":"High","gaps":["Whether FGF-7 core-protein binding activates FGFR2 signaling was not yet shown genetically","The integrin subtype mediating lipoprotein uptake was not identified"]},{"year":2001,"claim":"Genetic disruption of HSPG2 in colon carcinoma cells demonstrated that the protein core — not HS chains — is required for functional KGF/FGFR2-IIIb receptor activation, while perlecan-null ES cells revealed its requirement for laminin matrix organization through a dystroglycan–β1 integrin axis, and domain III was shown to bind FGF-BP.","evidence":"Targeted homologous recombination in colon carcinoma cells with signaling assays; perlecan-null ES cell laminin clustering; yeast two-hybrid/co-IP for FGF-BP","pmids":["11563979","11228157","11148217"],"confidence":"High","gaps":["Structural basis for core-protein-mediated FGFR2 activation was unknown","Whether FGF-BP–perlecan interaction modulates FGF activity in vivo was untested"]},{"year":2003,"claim":"Perlecan was shown to modulate Hedgehog signaling in addition to FGF in Drosophila neuroblast proliferation, its HS chains were identified as heparanase substrates relevant to tumor invasion, progranulin was identified as a domain V ligand with antagonistic growth effects, and HS-specific domain I deletion in mice revealed tissue-specific roles in lens capsule integrity versus glomerular filtration.","evidence":"Drosophila trol genetic epistasis with Hh/FGF pathways and Co-IP; in vitro heparanase digestion of purified perlecan; yeast two-hybrid/SPR for progranulin–domain V; Hspg2 exon 3 deletion mouse","pmids":["12645928","14630925","12900424","12514129"],"confidence":"High","gaps":["Whether perlecan directly binds Hh in mammals in vivo was not confirmed","Tissue-specific HS chain functions beyond lens and kidney were uncharacterized"]},{"year":2005,"claim":"Multiple studies converged on perlecan's role in neuromuscular junction biology and epithelial survival: domain V/LG domains promote AChR clustering through MuSK-dependent laminin polymerization, a trimolecular dystroglycan–laminin–perlecan complex was demonstrated, HS chains on SMC-derived perlecan suppress intimal hyperplasia by sequestering FGF-2, and perlecan is essential for keratinocyte survival through FGF-7 bioavailability.","evidence":"AChR clustering assays with MuSK phosphorylation; solid-phase trimolecular binding and Large(myd) mouse; Hspg2Δ3/Δ3 mice in flow cessation model; perlecan siRNA in organotypic skin with FGF-7 rescue","pmids":["16219760","16098969","14739157","16269412","15872080"],"confidence":"High","gaps":["Whether domain V alone is sufficient for NMJ formation in vivo was untested","The precise signaling pathway downstream of perlecan mediating keratinocyte survival was incompletely defined"]},{"year":2006,"claim":"The chondroitin sulfate chains of cartilage perlecan — specifically 4,6-disulfated CS-E — were shown to directly accelerate collagen II fibril formation, providing a mechanistic explanation for the disorganized collagen network in perlecan-null cartilage independent of growth factor signaling.","evidence":"In vitro collagen fibril formation assay with purified perlecan, chondroitinase treatment, GAG compositional analysis, EM","pmids":["16956876"],"confidence":"High","gaps":["Whether CS-E on perlecan is the dominant collagen-organizing signal in vivo versus other CS proteoglycans was unresolved","Regulation of CS sulfation on perlecan was not addressed"]},{"year":2007,"claim":"Perlecan core protein domain III was mapped as an FGF-18 binding site that antagonizes FGF-18 mitogenic activity in chondrocytes, revealing that perlecan can both promote and inhibit FGF signaling depending on the ligand and domain involved.","evidence":"Cationic filtration, immunoprecipitation, enzymatic treatment of GAG chains, recombinant domain expression, thymidine incorporation","pmids":["17971291"],"confidence":"High","gaps":["Whether this antagonism operates in vivo at growth plate FGF-18 concentrations was not shown","Whether domain III simultaneously binds FGF-7 and FGF-18 was unresolved"]},{"year":2008,"claim":"Zebrafish perlecan depletion demonstrated that domain V/endorepellin mediates the majority of perlecan's biological activities in muscle development and angiogenic vessel sprouting, as domain V injection alone rescued both myopathy and vascular defects.","evidence":"Morpholino knockdown with domain V protein rescue microinjection, live imaging of actin and vasculature","pmids":["18426981"],"confidence":"High","gaps":["Receptor(s) mediating domain V angiogenic rescue in zebrafish were not identified","Whether domain V is processed from full-length perlecan in vivo was not demonstrated"]},{"year":2012,"claim":"Drosophila genetic epistasis placed perlecan in the Sema-1a/PlexA repulsive axon guidance pathway, where it facilitates semaphorin signaling by antagonizing integrin/FAK activity, extending perlecan's role from growth factor co-receptor to semaphorin signaling modulator.","evidence":"Drosophila double/triple mutant analysis of trol, Sema-1a, PlexA, integrin, FAK; phospho-FAK assay in insect cells","pmids":["23028146"],"confidence":"High","gaps":["Whether mammalian perlecan similarly modulates semaphorin signaling was unconfirmed at this time","Direct physical interaction between perlecan and Sema-1a was not demonstrated"]},{"year":2014,"claim":"A series of studies revealed MMP-7 cleavage of perlecan domain IV as a molecular switch: intact domain IV-3 binds Sema3A to deactivate FAK and promote cell clustering, while MMP-7 processing destroys this complex and activates FAK-driven invasion; cell-type-specific GAG decoration was shown to determine FGF signaling selectivity; and domain II O-linked sialylated glycans were identified as a novel LDL retention mechanism.","evidence":"In vitro MMP-7 digestion with cell invasion/clustering assays and FAK readout; Sema3A co-IP and siRNA; cell-type-specific perlecan GAG analysis; solid-phase binding with MS glycan analysis for domain II–LDL","pmids":["24833109","29740048","24509440","25528754"],"confidence":"High","gaps":["Whether MMP-7 cleavage of perlecan occurs during metastasis in vivo was not shown","Identity of the sialylated O-glycan structures on domain II was not fully elucidated"]},{"year":2015,"claim":"Perlecan was established as a regulator of vascular tone and pulmonary vascular remodeling: HS chains form the FGF2–FGFR1 ternary complex required for hypoxic PASMC proliferation and pulmonary hypertension, while perlecan deficiency reduces eNOS expression to impair endothelium-dependent relaxation; biophysical measurements showed the full-length core protein is a ~170 nm monomeric rod capable of withstanding >100 pN force.","evidence":"Hspg2Δ3/Δ3 mice in hypoxia PH model with LACE assay; conditional perlecan KO with aortic ring relaxation; AFM imaging and single-molecule force spectroscopy","pmids":["25952902","25626871","26546708"],"confidence":"High","gaps":["Whether perlecan mechanically transmits force to osteocytes in the lacunar-canalicular system was not yet functionally tested","Upstream mechanism of perlecan regulation of eNOS transcription was unknown"]},{"year":2019,"claim":"Perlecan was identified as a functional component of the pro-metastatic cancer-associated fibroblast niche and as a mechanosensory transducer in osteocytes: stromal perlecan depletion enhances chemotherapy efficacy, while perlecan-deficient osteocytes show impaired calcium signaling with downregulation of ryanodine receptor and SERCA pathways.","evidence":"Intravital imaging with stromal perlecan depletion and survival analysis in pancreatic cancer model; real-time Ca2+ imaging in loaded murine tibiae with RNA-seq","pmids":["31406163","31715337"],"confidence":"Medium","gaps":["Mechanism by which perlecan in the stroma modulates drug resistance was not fully elucidated","Whether perlecan directly interacts with Ryr1/Atp2a1 or regulates them transcriptionally was unclear","The pro-metastatic stroma study defined upstream p53 dependency only partially"]},{"year":2024,"claim":"Perlecan haploinsufficiency in human cardiomyocytes was shown to impair structural maturation and force generation via the dystroglycan complex, with perlecan peptide substrate rescuing hypertrophic growth, establishing perlecan as a critical cardiomyocyte maturation factor signaling through dystroglycan.","evidence":"HSPG2+/- hPSC-derived cardiomyocytes, engineered heart tissue contractility, perlecan peptide substrate culture, dystroglycan interaction assessment","pmids":["38198277"],"confidence":"High","gaps":["Which specific dystroglycan-complex subunit mediates the perlecan maturation signal was not defined","Whether this mechanism is relevant to human cardiomyopathy in vivo remains untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis for perlecan core-protein-mediated receptor activation, whether in vivo MMP-7 processing of perlecan drives metastatic dissemination, the mechanism linking perlecan to eNOS transcription, and whether perlecan functions as a direct mechanotransducer in bone.","evidence":"","pmids":[],"confidence":"Low","gaps":["No atomic-resolution structure of any full domain–ligand complex exists","In vivo evidence for MMP-7 cleavage of perlecan during cancer progression is lacking","Direct force-transmission function in the osteocyte lacunar-canalicular system has not been reconstituted"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,35]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,8,17]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,18,32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,31,24]}],"localization":[{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[2,3,18,39,40]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[14,16,32]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,22,23]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[2,7,18,39]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8,9,26,31]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,20,25]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[22,24,38]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[21]}],"complexes":["dystroglycan complex","HS–FGF–FGFR ternary complex"],"partners":["FGF2","FGFR1","DAG1","LAMA1","SEMA3A","MMP7","GRN","FGFBP1"],"other_free_text":[]},"mechanistic_narrative":"Perlecan (HSPG2) is a large, modular basement membrane heparan sulfate proteoglycan that functions as a multivalent signaling scaffold and structural organizer of extracellular matrices. Its N-terminal heparan sulfate chains (domain I) sequester and present FGF-2 to FGF receptors, forming obligate HS–FGF–FGFR ternary complexes essential for mitogenic signaling in contexts including neurogenesis, vascular smooth muscle proliferation, and pulmonary hypertension [PMID:7528102, PMID:9121441, PMID:24434631, PMID:25952902], while the protein core independently binds FGF-7, FGF-18, Hedgehog, semaphorin 3A, progranulin, LDL, and dystroglycan through domain-specific sites to regulate chondrocyte differentiation, axon guidance, lipoprotein retention, and neuromuscular junction assembly [PMID:10702276, PMID:17971291, PMID:12645928, PMID:29740048, PMID:25528754, PMID:16219760]. Domain V (endorepellin) promotes AChR clustering via MuSK in a laminin-polymerization-dependent manner and rescues myopathy and angiogenesis defects in zebrafish, while chondroitin sulfate chains on cartilage perlecan accelerate collagen II fibril assembly, and proteolytic processing by MMP-7 at domain IV acts as a molecular switch converting Sema3A-mediated FAK inactivation and cell clustering to FAK activation and invasive cell dispersion [PMID:18426981, PMID:16956876, PMID:24833109]. Perlecan-null mice exhibit perinatal-lethal chondrodysplasia with basement membrane failure under mechanical stress, and perlecan deficiency abolishes endothelium-dependent vascular relaxation by reducing eNOS expression and impairs osteocyte mechanosensory calcium signaling [PMID:10579729, PMID:10545953, PMID:25626871, PMID:31715337]."},"prefetch_data":{"uniprot":{"accession":"P98160","full_name":"Basement membrane-specific heparan sulfate proteoglycan core protein","aliases":["Perlecan","PLC"],"length_aa":4391,"mass_kda":468.8,"function":"Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development (PubMed:12435733, PubMed:15591058, PubMed:19789387). In muscle, it is essential for localizing acetylcholinesterase (AChE) at the neuromuscular junctions (NMJ), most probably acting as an adapter that links the acetylcholinesterase collagenic tail peptide (COLQ) to alpha-dystroglycan, and is therefore involved in the down-regulation of colinergic synaptic transmission (By similarity) Anti-angiogenic and anti-tumor peptide that inhibits endothelial cell migration, collagen-induced endothelial tube morphogenesis and blood vessel growth in the chorioallantoic membrane. Blocks endothelial cell adhesion to fibronectin and type I collagen. Anti-tumor agent in neovascularization. Interaction with its ligand, integrin alpha2/beta1, is required for the anti-angiogenic properties. Evokes a reduction in phosphorylation of receptor tyrosine kinases via alpha2/beta1 integrin-mediated activation of the tyrosine phosphatase, PTPN6 Has anti-angiogenic properties that require binding of calcium ions for full activity","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane; Secreted","url":"https://www.uniprot.org/uniprotkb/P98160/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSPG2","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/HSPG2","total_profiled":1310},"omim":[{"mim_id":"621182","title":"NEURODEVELOPMENTAL DISORDER WITH POOR OR ABSENT SPEECH, DYSMORPHIC FACIES, AND BEHAVIORAL ABNORMALITIES; NEDSFB","url":"https://www.omim.org/entry/621182"},{"mim_id":"611901","title":"VON WILLEBRAND FACTOR A DOMAIN-CONTAINING PROTEIN 1; VWA1","url":"https://www.omim.org/entry/611901"},{"mim_id":"607737","title":"FIBROBLAST GROWTH FACTOR-BINDING PROTEIN 1; FGFBP1","url":"https://www.omim.org/entry/607737"},{"mim_id":"605399","title":"NIDOGEN 2; NID2","url":"https://www.omim.org/entry/605399"},{"mim_id":"601559","title":"STUVE-WIEDEMANN SYNDROME 1; STWS1","url":"https://www.omim.org/entry/601559"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":245.5}],"url":"https://www.proteinatlas.org/search/HSPG2"},"hgnc":{"alias_symbol":["perlecan","PRCAN"],"prev_symbol":["SJS1"]},"alphafold":{"accession":"P98160","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P98160","model_url":"","pae_url":"","plddt_mean":null},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSPG2","jax_strain_url":"https://www.jax.org/strain/search?query=HSPG2"},"sequence":{"accession":"P98160","fasta_url":"https://rest.uniprot.org/uniprotkb/P98160.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P98160/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P98160"}},"corpus_meta":[{"pmid":"10579729","id":"PMC_10579729","title":"Perlecan maintains the integrity of cartilage and some basement membranes.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10579729","citation_count":513,"is_preprint":false},{"pmid":"7528102","id":"PMC_7528102","title":"Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis.","date":"1994","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/7528102","citation_count":476,"is_preprint":false},{"pmid":"10545953","id":"PMC_10545953","title":"Perlecan is essential for cartilage and cephalic development.","date":"1999","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10545953","citation_count":411,"is_preprint":false},{"pmid":"31406163","id":"PMC_31406163","title":"CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31406163","citation_count":215,"is_preprint":false},{"pmid":"18826258","id":"PMC_18826258","title":"Diverse cell signaling events modulated by perlecan.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18826258","citation_count":214,"is_preprint":false},{"pmid":"12514129","id":"PMC_12514129","title":"Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney.","date":"2003","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/12514129","citation_count":180,"is_preprint":false},{"pmid":"27613501","id":"PMC_27613501","title":"A current view of perlecan in physiology and pathology: A mosaic of functions.","date":"2016","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/27613501","citation_count":162,"is_preprint":false},{"pmid":"9337134","id":"PMC_9337134","title":"Developmental expression of perlecan during murine embryogenesis.","date":"1997","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/9337134","citation_count":159,"is_preprint":false},{"pmid":"23586018","id":"PMC_23586018","title":"Skin basement membrane: the foundation of epidermal integrity--BM functions and diverse roles of bridging molecules nidogen and perlecan.","date":"2013","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/23586018","citation_count":140,"is_preprint":false},{"pmid":"9791728","id":"PMC_9791728","title":"The relationship between perlecan and dystroglycan and its implication in the formation of the neuromuscular junction.","date":"1998","source":"Cell adhesion and communication","url":"https://pubmed.ncbi.nlm.nih.gov/9791728","citation_count":139,"is_preprint":false},{"pmid":"12645928","id":"PMC_12645928","title":"Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division.","date":"2003","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/12645928","citation_count":131,"is_preprint":false},{"pmid":"11228157","id":"PMC_11228157","title":"Distinct roles for dystroglycan, beta1 integrin and perlecan in cell surface laminin organization.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11228157","citation_count":131,"is_preprint":false},{"pmid":"10702276","id":"PMC_10702276","title":"The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10702276","citation_count":124,"is_preprint":false},{"pmid":"11148217","id":"PMC_11148217","title":"Fibroblast growth factor-binding protein is a novel partner for perlecan protein core.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11148217","citation_count":120,"is_preprint":false},{"pmid":"24001398","id":"PMC_24001398","title":"Border patrol: insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders.","date":"2013","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24001398","citation_count":118,"is_preprint":false},{"pmid":"7593307","id":"PMC_7593307","title":"Perlecan is a component of cartilage matrix and promotes chondrocyte attachment.","date":"1995","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/7593307","citation_count":118,"is_preprint":false},{"pmid":"32010611","id":"PMC_32010611","title":"Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32010611","citation_count":117,"is_preprint":false},{"pmid":"14630925","id":"PMC_14630925","title":"Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14630925","citation_count":115,"is_preprint":false},{"pmid":"10841569","id":"PMC_10841569","title":"Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10841569","citation_count":114,"is_preprint":false},{"pmid":"12900424","id":"PMC_12900424","title":"A novel interaction between perlecan protein core and progranulin: potential effects on tumor growth.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12900424","citation_count":114,"is_preprint":false},{"pmid":"8234307","id":"PMC_8234307","title":"Structural characterization of the complete human perlecan gene and its promoter.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8234307","citation_count":114,"is_preprint":false},{"pmid":"7954396","id":"PMC_7954396","title":"Abnormal expression of perlecan proteoglycan in metastatic melanomas.","date":"1994","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/7954396","citation_count":112,"is_preprint":false},{"pmid":"24509440","id":"PMC_24509440","title":"The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling.","date":"2014","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24509440","citation_count":110,"is_preprint":false},{"pmid":"23436656","id":"PMC_23436656","title":"The overexpression of hypomethylated miR-663 induces chemotherapy resistance in human breast cancer cells by targeting heparin sulfate proteoglycan 2 (HSPG2).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23436656","citation_count":102,"is_preprint":false},{"pmid":"18426981","id":"PMC_18426981","title":"A central function for perlecan in skeletal muscle and cardiovascular development.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18426981","citation_count":99,"is_preprint":false},{"pmid":"9121441","id":"PMC_9121441","title":"Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan antisense cDNA.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9121441","citation_count":98,"is_preprint":false},{"pmid":"10818109","id":"PMC_10818109","title":"Perlecan heparan sulfate proteoglycan: a novel receptor that mediates a distinct pathway for ligand catabolism.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10818109","citation_count":97,"is_preprint":false},{"pmid":"11884291","id":"PMC_11884291","title":"Accumulation of biglycan and perlecan, but not versican, in lesions of murine models of atherosclerosis.","date":"2002","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11884291","citation_count":96,"is_preprint":false},{"pmid":"9030592","id":"PMC_9030592","title":"Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming growth factor-beta via a nuclear factor 1-binding element.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9030592","citation_count":92,"is_preprint":false},{"pmid":"12811819","id":"PMC_12811819","title":"CTGF/Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes.","date":"2003","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12811819","citation_count":84,"is_preprint":false},{"pmid":"16956876","id":"PMC_16956876","title":"Chondroitin sulfate perlecan enhances collagen fibril formation. Implications for perlecan chondrodysplasias.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16956876","citation_count":82,"is_preprint":false},{"pmid":"35433700","id":"PMC_35433700","title":"Perlecan, A Multi-Functional, Cell-Instructive, Matrix-Stabilizing Proteoglycan With Roles in Tissue Development Has Relevance to Connective Tissue Repair and Regeneration.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35433700","citation_count":80,"is_preprint":false},{"pmid":"16269412","id":"PMC_16269412","title":"Targeting perlecan in human keratinocytes reveals novel roles for perlecan in epidermal formation.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16269412","citation_count":80,"is_preprint":false},{"pmid":"15872080","id":"PMC_15872080","title":"Heparan sulfate of perlecan is involved in glomerular filtration.","date":"2005","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/15872080","citation_count":79,"is_preprint":false},{"pmid":"14739157","id":"PMC_14739157","title":"Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan.","date":"2004","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/14739157","citation_count":79,"is_preprint":false},{"pmid":"18300285","id":"PMC_18300285","title":"Novel interactions of perlecan: unraveling perlecan's role in angiogenesis.","date":"2008","source":"Microscopy research and technique","url":"https://pubmed.ncbi.nlm.nih.gov/18300285","citation_count":78,"is_preprint":false},{"pmid":"11956183","id":"PMC_11956183","title":"The type XIII collagen ectodomain is a 150-nm rod and capable of binding to fibronectin, nidogen-2, perlecan, and heparin.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11956183","citation_count":78,"is_preprint":false},{"pmid":"16927315","id":"PMC_16927315","title":"Spectrum of HSPG2 (Perlecan) mutations in patients with Schwartz-Jampel syndrome.","date":"2006","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/16927315","citation_count":76,"is_preprint":false},{"pmid":"10824099","id":"PMC_10824099","title":"Perlecan domain V of Drosophila melanogaster. Sequence, recombinant analysis and tissue expression.","date":"2000","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10824099","citation_count":76,"is_preprint":false},{"pmid":"10952939","id":"PMC_10952939","title":"Identification and immunolocalization of decorin, versican, perlecan, nidogen, and chondroitin sulfate proteoglycans in bovine small-antral ovarian follicles.","date":"2000","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/10952939","citation_count":76,"is_preprint":false},{"pmid":"15306215","id":"PMC_15306215","title":"The role of perlecan in arterial injury and angiogenesis.","date":"2004","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/15306215","citation_count":74,"is_preprint":false},{"pmid":"9187109","id":"PMC_9187109","title":"A role for perlecan in the suppression of growth and invasion in fibrosarcoma cells.","date":"1997","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/9187109","citation_count":73,"is_preprint":false},{"pmid":"24434631","id":"PMC_24434631","title":"Perlecan is required for FGF-2 signaling in the neural stem cell niche.","date":"2013","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/24434631","citation_count":66,"is_preprint":false},{"pmid":"9142982","id":"PMC_9142982","title":"Expression of heparan sulfate proteoglycan (perlecan) in the mouse blastocyst is regulated during normal and delayed implantation.","date":"1997","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9142982","citation_count":66,"is_preprint":false},{"pmid":"30453502","id":"PMC_30453502","title":"Modular Proteoglycan Perlecan/HSPG2: Mutations, Phenotypes, and Functions.","date":"2018","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/30453502","citation_count":63,"is_preprint":false},{"pmid":"24833109","id":"PMC_24833109","title":"Matrilysin/matrix metalloproteinase-7(MMP7) cleavage of perlecan/HSPG2 creates a molecular switch to alter prostate cancer cell behavior.","date":"2014","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/24833109","citation_count":62,"is_preprint":false},{"pmid":"7814401","id":"PMC_7814401","title":"Recombinant domain III of perlecan promotes cell attachment through its RGDS sequence.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7814401","citation_count":55,"is_preprint":false},{"pmid":"19540587","id":"PMC_19540587","title":"The modulation of platelet and endothelial cell adhesion to vascular graft materials by perlecan.","date":"2009","source":"Biomaterials","url":"https://pubmed.ncbi.nlm.nih.gov/19540587","citation_count":54,"is_preprint":false},{"pmid":"16889529","id":"PMC_16889529","title":"Chondrogenic differentiation on perlecan domain I, collagen II, and bone morphogenetic protein-2-based matrices.","date":"2006","source":"Tissue engineering","url":"https://pubmed.ncbi.nlm.nih.gov/16889529","citation_count":53,"is_preprint":false},{"pmid":"33800241","id":"PMC_33800241","title":"Perlecan in Pericellular Mechanosensory Cell-Matrix Communication, Extracellular Matrix Stabilisation and Mechanoregulation of Load-Bearing Connective Tissues.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33800241","citation_count":50,"is_preprint":false},{"pmid":"12975604","id":"PMC_12975604","title":"Role of perlecan in skeletal development and diseases.","date":"2002","source":"Glycoconjugate journal","url":"https://pubmed.ncbi.nlm.nih.gov/12975604","citation_count":50,"is_preprint":false},{"pmid":"11150731","id":"PMC_11150731","title":"Lipoprotein modulation of subendothelial heparan sulfate proteoglycans (perlecan) and atherogenicity.","date":"2000","source":"Trends in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11150731","citation_count":50,"is_preprint":false},{"pmid":"11891676","id":"PMC_11891676","title":"Dyssegmental dysplasia, Silverman-Handmaker type: unexpected role of perlecan in cartilage development.","date":"2001","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11891676","citation_count":50,"is_preprint":false},{"pmid":"29475023","id":"PMC_29475023","title":"The multifaceted roles of perlecan in fibrosis.","date":"2018","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29475023","citation_count":49,"is_preprint":false},{"pmid":"23028146","id":"PMC_23028146","title":"The extracellular matrix proteoglycan perlecan facilitates transmembrane semaphorin-mediated repulsive guidance.","date":"2012","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/23028146","citation_count":49,"is_preprint":false},{"pmid":"8937755","id":"PMC_8937755","title":"Purification and characterization of perlecan fragment in urine of end-stage renal failure patients.","date":"1996","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8937755","citation_count":46,"is_preprint":false},{"pmid":"25506919","id":"PMC_25506919","title":"Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25506919","citation_count":46,"is_preprint":false},{"pmid":"16098969","id":"PMC_16098969","title":"Disruption of perlecan binding and matrix assembly by post-translational or genetic disruption of dystroglycan function.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16098969","citation_count":46,"is_preprint":false},{"pmid":"21874555","id":"PMC_21874555","title":"Colocalization in vivo and association in vitro of perlecan and elastin.","date":"2011","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21874555","citation_count":45,"is_preprint":false},{"pmid":"25504735","id":"PMC_25504735","title":"Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis.","date":"2014","source":"G3 (Bethesda, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/25504735","citation_count":44,"is_preprint":false},{"pmid":"20072119","id":"PMC_20072119","title":"Association of the HSPG2 gene with neuroleptic-induced tardive dyskinesia.","date":"2010","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20072119","citation_count":43,"is_preprint":false},{"pmid":"15258195","id":"PMC_15258195","title":"Atherosclerosis in perlecan heterozygous mice.","date":"2004","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/15258195","citation_count":41,"is_preprint":false},{"pmid":"12814946","id":"PMC_12814946","title":"Role of collagen type II and perlecan in skeletal development.","date":"2003","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12814946","citation_count":41,"is_preprint":false},{"pmid":"17980035","id":"PMC_17980035","title":"The Drosophila Perlecan gene trol regulates multiple signaling pathways in different developmental contexts.","date":"2007","source":"BMC developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17980035","citation_count":41,"is_preprint":false},{"pmid":"17997086","id":"PMC_17997086","title":"A novel peptide sequence in perlecan domain IV supports cell adhesion, spreading and FAK activation.","date":"2007","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17997086","citation_count":40,"is_preprint":false},{"pmid":"17971291","id":"PMC_17971291","title":"The core protein of growth plate perlecan binds FGF-18 and alters its mitogenic effect on chondrocytes.","date":"2007","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/17971291","citation_count":39,"is_preprint":false},{"pmid":"26546708","id":"PMC_26546708","title":"Single molecule force measurements of perlecan/HSPG2: A key component of the osteocyte pericellular matrix.","date":"2015","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26546708","citation_count":38,"is_preprint":false},{"pmid":"31462656","id":"PMC_31462656","title":"Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31462656","citation_count":37,"is_preprint":false},{"pmid":"24936464","id":"PMC_24936464","title":"Drosophila perlecan regulates intestinal stem cell activity via cell-matrix attachment.","date":"2014","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24936464","citation_count":37,"is_preprint":false},{"pmid":"19382872","id":"PMC_19382872","title":"Perlecan domain IV peptide stimulates salivary gland cell assembly in vitro.","date":"2009","source":"Tissue engineering. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/19382872","citation_count":37,"is_preprint":false},{"pmid":"16021525","id":"PMC_16021525","title":"Perlecan displays variable spatial and temporal immunolocalisation patterns in the articular and growth plate cartilages of the ovine stifle joint.","date":"2005","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16021525","citation_count":36,"is_preprint":false},{"pmid":"24700612","id":"PMC_24700612","title":"Transcriptional activation by NFκB increases perlecan/HSPG2 expression in the desmoplastic prostate tumor microenvironment.","date":"2014","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24700612","citation_count":35,"is_preprint":false},{"pmid":"29740048","id":"PMC_29740048","title":"Matrilysin/MMP-7 Cleavage of Perlecan/HSPG2 Complexed with Semaphorin 3A Supports FAK-Mediated Stromal Invasion by Prostate Cancer Cells.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29740048","citation_count":35,"is_preprint":false},{"pmid":"11356148","id":"PMC_11356148","title":"UNC-52/perlecan isoform diversity and function in Caenorhabditis elegans.","date":"2001","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/11356148","citation_count":35,"is_preprint":false},{"pmid":"26996820","id":"PMC_26996820","title":"Perlecan expression influences the keratin 15-positive cell population fate in the epidermis of aging skin.","date":"2016","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/26996820","citation_count":34,"is_preprint":false},{"pmid":"12926067","id":"PMC_12926067","title":"Large matrix proteoglycans, versican and perlecan, are expressed and secreted by human leukemic monocytes.","date":"2003","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/12926067","citation_count":34,"is_preprint":false},{"pmid":"25952902","id":"PMC_25952902","title":"Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension.","date":"2015","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/25952902","citation_count":32,"is_preprint":false},{"pmid":"11382923","id":"PMC_11382923","title":"Perlecan inhibits smooth muscle cell adhesion to fibronectin: role of heparan sulfate.","date":"2001","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/11382923","citation_count":32,"is_preprint":false},{"pmid":"8981331","id":"PMC_8981331","title":"Structural and cell-adhesive properties of three recombinant fragments derived from perlecan domain III.","date":"1996","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/8981331","citation_count":32,"is_preprint":false},{"pmid":"27377666","id":"PMC_27377666","title":"Pericellular colocalisation and interactive properties of type VI collagen and perlecan in the intervertebral disc.","date":"2016","source":"European cells & materials","url":"https://pubmed.ncbi.nlm.nih.gov/27377666","citation_count":31,"is_preprint":false},{"pmid":"11563979","id":"PMC_11563979","title":"A role for the perlecan protein core in the activation of the keratinocyte growth factor receptor.","date":"2001","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/11563979","citation_count":31,"is_preprint":false},{"pmid":"30480706","id":"PMC_30480706","title":"IL-1 and TGF-β Modulation of Epithelial Basement Membrane Components Perlecan and Nidogen Production by Corneal Stromal Cells.","date":"2018","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/30480706","citation_count":31,"is_preprint":false},{"pmid":"22967000","id":"PMC_22967000","title":"Perlecan domain 1 recombinant proteoglycan augments BMP-2 activity and osteogenesis.","date":"2012","source":"BMC biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/22967000","citation_count":29,"is_preprint":false},{"pmid":"25626871","id":"PMC_25626871","title":"Perlecan deficiency causes endothelial dysfunction by reducing the expression of endothelial nitric oxide synthase.","date":"2015","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/25626871","citation_count":29,"is_preprint":false},{"pmid":"7474938","id":"PMC_7474938","title":"Expression of the basement membrane heparan sulfate proteoglycan (perlecan) in human synovium and in cultured human synovial cells.","date":"1995","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7474938","citation_count":29,"is_preprint":false},{"pmid":"24534475","id":"PMC_24534475","title":"Anionic biopolyelectrolytes of the syndecan/perlecan superfamily: physicochemical properties and medical significance.","date":"2014","source":"Advances in colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/24534475","citation_count":27,"is_preprint":false},{"pmid":"28433812","id":"PMC_28433812","title":"The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin.","date":"2017","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28433812","citation_count":27,"is_preprint":false},{"pmid":"25080592","id":"PMC_25080592","title":"Perlecan antagonizes collagen IV and ADAMTS9/GON-1 in restricting the growth of presynaptic boutons.","date":"2014","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25080592","citation_count":27,"is_preprint":false},{"pmid":"16620836","id":"PMC_16620836","title":"Reduced perlecan expression and accumulation in human carotid atherosclerotic lesions.","date":"2006","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/16620836","citation_count":26,"is_preprint":false},{"pmid":"14745237","id":"PMC_14745237","title":"Perlecan functions in chondrogenesis: insights from in vitro and in vivo models.","date":"2004","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/14745237","citation_count":26,"is_preprint":false},{"pmid":"33621481","id":"PMC_33621481","title":"Stem cell niche organization in the Drosophila ovary requires the ECM component Perlecan.","date":"2021","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/33621481","citation_count":26,"is_preprint":false},{"pmid":"16219760","id":"PMC_16219760","title":"Conjugation of LG domains of agrins and perlecan to polymerizing laminin-2 promotes acetylcholine receptor clustering.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16219760","citation_count":26,"is_preprint":false},{"pmid":"26788024","id":"PMC_26788024","title":"Differential expression of epithelial basement membrane components nidogens and perlecan in corneal stromal cells in vitro.","date":"2015","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/26788024","citation_count":25,"is_preprint":false},{"pmid":"25528754","id":"PMC_25528754","title":"The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis.","date":"2014","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/25528754","citation_count":25,"is_preprint":false},{"pmid":"31715337","id":"PMC_31715337","title":"Perlecan/Hspg2 deficiency impairs bone's calcium signaling and associated transcriptome in response to mechanical loading.","date":"2019","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/31715337","citation_count":23,"is_preprint":false},{"pmid":"16226129","id":"PMC_16226129","title":"Altered perlecan expression in placental development and gestational diabetes mellitus.","date":"2005","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/16226129","citation_count":22,"is_preprint":false},{"pmid":"38046235","id":"PMC_38046235","title":"Exosome Derived from Mesenchymal Stem Cells Alleviates Hypertrophic Scar by Inhibiting the Fibroblasts via TNFSF-13/HSPG2 Signaling Pathway.","date":"2023","source":"International journal of nanomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/38046235","citation_count":22,"is_preprint":false},{"pmid":"24949484","id":"PMC_24949484","title":"NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/24949484","citation_count":22,"is_preprint":false},{"pmid":"32413029","id":"PMC_32413029","title":"SULF1 suppresses Wnt3A-driven growth of bone metastatic prostate cancer in perlecan-modified 3D cancer-stroma-macrophage triculture models.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32413029","citation_count":22,"is_preprint":false},{"pmid":"38198277","id":"PMC_38198277","title":"Perlecan (HSPG2) promotes structural, contractile, and metabolic development of human cardiomyocytes.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38198277","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49986,"output_tokens":10642,"usd":0.154794},"stage2":{"model":"claude-opus-4-6","input_tokens":14536,"output_tokens":4821,"usd":0.289807},"total_usd":0.444601,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"Perlecan induces high-affinity binding of bFGF (FGF-2) to cells deficient in heparan sulfate and to soluble FGF receptors, functioning as a major accessory/co-receptor for bFGF; monoclonal antibodies to perlecan block this receptor-binding-promoting activity; perlecan potently induces bFGF-mediated neovascularization in vivo.\",\n      \"method\": \"Affinity-purified HSPG binding assays, monoclonal antibody inhibition, in vivo rabbit ear angiogenesis model\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (cell-based binding, antibody inhibition, in vivo rescue), replicated by subsequent antisense studies\",\n      \"pmids\": [\"7528102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Stable antisense suppression of perlecan in NIH 3T3 fibroblasts and melanoma cells dramatically reduces high-affinity bFGF receptor binding and mitogenic response, which can be rescued by exogenous heparin or perlecan, confirming perlecan as a major bFGF accessory receptor in vivo.\",\n      \"method\": \"Antisense cDNA stable transfection, Northern blot, immunoblot, 125I-bFGF receptor binding/affinity labeling, thymidine incorporation proliferation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic loss-of-function with multiple orthogonal readouts and rescue experiment\",\n      \"pmids\": [\"9121441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Homozygous perlecan (Hspg2) null mice develop normally formed basement membranes initially, but BMs deteriorate under mechanical stress (contracting myocardium, expanding brain vesicles), causing cardiac blood leakage, exencephaly, and severe chondrodysplasia with disorganized fibrillar collagen network, demonstrating perlecan is essential for BM integrity and cartilage ECM maintenance.\",\n      \"method\": \"Gene knockout mouse, electron microscopy, histology, immunohistochemistry, collagen ECM gene expression analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific phenotypic readouts, replicated independently in two labs same year\",\n      \"pmids\": [\"10579729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Hspg2-/- mice exhibit severe skeletal dysplasia with disorganized chondrocyte columnar structures, reduced collagen fibrils and glycosaminoglycans in cartilage matrix, reduced chondrocyte proliferation, and diminished prehypertrophic zone, phenotypically similar to thanatophoric dysplasia caused by activating FGFR3 mutations, placing perlecan in the FGF/FGFR3 signaling axis regulating chondrogenesis.\",\n      \"method\": \"Hspg2 gene disruption in mice, histology, immunostaining, comparison with Fgfr3 gain-of-function mouse phenotype (genetic epistasis inference)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — independent knockout with multiple phenotypic readouts, replicates findings of Costell et al. 1999\",\n      \"pmids\": [\"10545953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The protein core of perlecan binds FGF-7 (KGF) specifically to the N-terminal half of domain III and to domain V, with affinity constants ~60 nM, independent of heparan sulfate chains; this interaction is demonstrated by overlay protein assays, radioligand binding, and yeast two-hybrid.\",\n      \"method\": \"Overlay protein assays, radioligand binding experiments, yeast two-hybrid system\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — three orthogonal binding methods, domain-mapped interaction\",\n      \"pmids\": [\"10702276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Perlecan mediates internalization and lysosomal delivery of atherogenic lipoproteins enriched in lipoprotein lipase via a kinetically and biochemically distinct pathway from coated pits or syndecan-mediated endocytosis; binding is blocked by heparitinase, degradation by chloroquine, and internalization is inhibited by genistein but not cytochalasin D; beta1 integrins serve as cell-surface attachment sites for perlecan.\",\n      \"method\": \"Cell-based binding, internalization and degradation assays using cells expressing perlecan but no other proteoglycans; pharmacological inhibitors; antibody blockade\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal approaches in a defined cell system, mechanistic pathway dissection\",\n      \"pmids\": [\"10818109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Perlecan domain III interacts with FGF-binding protein (FGF-BP) at the second EGF repeat; this interaction was identified by yeast two-hybrid, confirmed by co-immunoprecipitation and solid-phase binding to recombinant domain III-alkaline phosphatase fusion protein, and they co-localize in tumor stroma in vivo.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, solid-phase binding, immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — three orthogonal binding methods, domain-mapped interaction with in vivo co-localization\",\n      \"pmids\": [\"11148217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"In perlecan-null ES cells, complex laminin-1 matrix structures fail to form, and laminin and perlecan reciprocally modulate each other's organization on the cell surface; beta1 integrin function is required downstream of dystroglycan for laminin matrix assembly.\",\n      \"method\": \"Null-mutant ES cell lines (perlecan-deficient, beta1 integrin-deficient, dystroglycan-deficient), laminin clustering assays, fluorescence microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null cells with specific phenotypic readouts, mechanistic ordering of pathway components\",\n      \"pmids\": [\"11228157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Perlecan protein core (not heparan sulfate chains) is required for functional activation of the KGF receptor (FGFR2-IIIb) and downstream signaling in colon carcinoma cells; perlecan-deficient cells (via targeted homologous recombination) do not respond to FGF7, and heparin cannot substitute for perlecan in this signaling context.\",\n      \"method\": \"Targeted homologous recombination to disrupt HSPG2, KGF receptor signaling assays, growth assays, FGF7 surface binding\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic disruption with rescue experiments, first genetic evidence for protein core role in FGF7 signaling\",\n      \"pmids\": [\"11563979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Perlecan (encoded by trol) regulates neuroblast division in Drosophila by modulating both FGF and Hedgehog signaling; human FGF-2 rescues trol mutant proliferation phenotype; Trol co-immunoprecipitates with Hh and mammalian perlecan with Shh (not competed by heparan sulfate); trol affects Hh movement through tissue, placing perlecan upstream of both FGF/MAPK and Hh pathways.\",\n      \"method\": \"Drosophila trol mutant genetic analysis, FGF-2 rescue in culture, co-immunoprecipitation, MAPK inhibitor assays, genetic epistasis (trol, hh, ttv mutations)\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis + biochemical (Co-IP) + functional rescue, ortholog in model organism\",\n      \"pmids\": [\"12645928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Perlecan co-immunoprecipitates with CTGF/Hcs24 from chondrocytes; CTGF stimulates perlecan gene expression; CTGF effects on chondrocyte aggrecan expression and DNA/proteoglycan synthesis are abolished by heparinase pretreatment, demonstrating that CTGF signals through heparan sulfate proteoglycans including perlecan to regulate chondrocyte proliferation and differentiation.\",\n      \"method\": \"Immunofluorescence co-localization, Northern blot, in vitro co-immunoprecipitation, 125I-rCTGF binding, heparinase inhibition of CTGF-stimulated gene expression\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP confirmed with functional heparinase experiment, single lab\",\n      \"pmids\": [\"12811819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Heparanase (HPSE-1) specifically degrades heparan sulfate chains of purified perlecan (as well as syndecan-1); cell-surface syndecan-1 inhibits HPSE-1-mediated invasion of melanoma cells in a manner requiring its HS chains, revealing perlecan as a degradative substrate of heparanase with implications for tumor invasion.\",\n      \"method\": \"In vitro enzymatic digestion of purified HSPGs, in vitro chemoinvasion assays, pharmacological/HS-chain-dependent inhibition experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic assay on purified substrate, functional validation\",\n      \"pmids\": [\"14630925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Progranulin binds specifically to perlecan domain V (first two laminin- and EGF-like repeats interacting with granulins F and B) with KD ~1 µM; both progranulin and domain V individually stimulate adrenal carcinoma cell growth, but equimolar combination antagonizes each other's activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (cell-free transcription/translation and transient transfection), surface plasmon resonance\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — yeast two-hybrid confirmed by Co-IP and quantitative SPR, domain mapping, functional consequence demonstrated\",\n      \"pmids\": [\"12900424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Perlecan-null cartilage shows reduced collagen fibril density not attributable to increased gelatinase (MMP-2/MMP-9) activity; crossing perlecan null onto MMP-9 null background fails to rescue cartilage ultrastructural abnormalities, ruling out MMP-9 as the primary effector of collagen loss.\",\n      \"method\": \"Genetic cross of perlecan-null and MMP-9-null mice, immunohistochemistry, in situ and SDS-PAGE zymography\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis by double-null crosses with enzymatic activity confirmation\",\n      \"pmids\": [\"12814946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Perlecan heparan sulfate chains of exon 3 (domain I) are indispensable for lens capsule integrity but not required for kidney glomerular filtration under normal conditions; deletion of HS attachment sites causes lens apoptosis, cellular membrane leakage, and lens degeneration; glomerular HS charge density is maintained by chondroitin sulfate compensation in mutant mice.\",\n      \"method\": \"Hspg2 exon 3 deletion mouse (HS-deficient perlecan), electron microscopy, apoptosis assay, urinalysis, immunostaining\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean domain-specific knock-in mouse with multiple phenotypic and biochemical readouts\",\n      \"pmids\": [\"12514129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Perlecan heparan sulfate (HS) side chains of smooth muscle cell perlecan suppress SMC proliferation; HS-deficient perlecan transgenic mice show increased SMC proliferation and enhanced intimal hyperplasia after carotid artery flow cessation; HS-deficient perlecan shows defective ECM-binding capacity for FGF-2.\",\n      \"method\": \"Transgenic mice with HS-deficient perlecan (Hspg2Δ3/Δ3), flow cessation carotid artery model, SMC culture proliferation assays, FGF-2 ECM-binding assay\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro results concordant, specific molecular mechanism (FGF-2 sequestration via HS) identified\",\n      \"pmids\": [\"14739157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Heparan sulfate chains of perlecan in domain I contribute to glomerular filtration of protein; Hspg2Δ3/Δ3 mice exhibit remarkable proteinuria when protein-loaded, despite no baseline structural abnormality; mutant perlecan is partially substituted with chondroitin sulfate instead, maintaining charge density under basal conditions.\",\n      \"method\": \"Hspg2Δ3/Δ3 mouse, BSA challenge intraperitoneal injection, urinary protein measurement, polyethyleneimine charge staining, immunostaining, transcript analysis\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — domain-specific knockout with functional challenge, concordant biochemical and physiological data\",\n      \"pmids\": [\"15872080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Epidermally derived perlecan (not dermal) is essential for keratinocyte survival and stratification during epidermal formation; perlecan-deficient keratinocytes show premature apoptosis and fail stratification; exogenous perlecan restores epidermal formation; FGF-7 partially rescues perlecan-deficient keratinocytes from cell death, suggesting perlecan regulates FGF-7 bioavailability.\",\n      \"method\": \"Perlecan siRNA knockdown in engineered human skin (organotypic coculture), rescue with exogenous perlecan or FGF-7, apoptosis assays, immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with specific cellular phenotype, rescue experiments, tissue-specific dissection\",\n      \"pmids\": [\"16269412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Cartilage perlecan bearing chondroitin sulfate chains (specifically 4,6-disulfated chondroitin sulfate E) binds collagen and accelerates collagen type II fibril formation in vitro, producing more defined fibril morphology and increased fibril diameters; this enhancement is glycosaminoglycan- (not core protein-) dependent and is mimicked by chondroitin sulfate E but not chondroitin sulfate D.\",\n      \"method\": \"In vitro collagen fibril formation assay with purified perlecan, chondroitinase treatment, GAG disaccharide compositional analysis, electron microscopy of fibrils\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro collagen fibril formation with defined GAG variants, mechanistic specificity demonstrated\",\n      \"pmids\": [\"16956876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The perlecan core protein (not HS or CS chains) binds FGF-18 via cysteine-rich regions of domain III with KD ~27.8–145 nM; perlecan reverses FGF-18-stimulated chondrocyte proliferation, acting as an antagonist of FGF-18 mitogenic activity in growth plate chondrocytes.\",\n      \"method\": \"Cationic filtration and immunoprecipitation binding assays, chondroitinase/heparitinase treatment, reduction/alkylation of core protein, recombinant domain expression, 3H-thymidine incorporation\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative binding with domain mapping, orthogonal functional assay\",\n      \"pmids\": [\"17971291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Perlecan depletion in zebrafish causes severe myopathy with abnormal actin filament orientation and disorganized sarcomeres, and failure of primary intersegmental vessel sprouts to extend; phenotype is partially rescued by injection of human perlecan or its C-terminal domain V/endorepellin, demonstrating endorepellin mediates most biological activities of perlecan in muscle and angiogenesis.\",\n      \"method\": \"Morpholino-based protein depletion in zebrafish, protein rescue microinjection, live videomicroscopy, fluorescence imaging of actin and vasculature\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with domain-specific rescue, multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"18426981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Perlecan is required to prevent thrombosis after deep vascular injury; antisense-perlecan endothelial cells fail to prevent occlusive thrombosis in a porcine carotid artery model; perlecan suppression reduces endothelial cell ability to inhibit FGF-2 binding and mitogenic activity in smooth muscle cells, while only partially abrogating intimal hyperplasia suppression.\",\n      \"method\": \"Antisense perlecan vector in endothelial cells, three-dimensional polymeric matrix implantation in porcine carotid artery deep injury model, FGF-2 binding and mitogenesis assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with specific thrombosis phenotype, mechanistic dissection of differential effects\",\n      \"pmids\": [\"10841569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Perlecan binds alpha-dystroglycan in a calcium- and heparin-sensitive manner (blot overlay assay and co-immunoprecipitation); cell-surface perlecan co-localizes with dystroglycan at AChR clusters in Xenopus muscle cells; perlecan and dystroglycan are co-clustered at ACh receptor clusters induced by spinal neurons or HB-GAM-coated beads, suggesting perlecan is anchored to the muscle surface via the DG-dystrophin complex.\",\n      \"method\": \"Blot overlay assay, co-immunoprecipitation with anti-DG antibody, immunofluorescence co-localization in Xenopus muscle cells\",\n      \"journal\": \"Cell adhesion and communication\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, reciprocal Co-IP plus co-localization, heparin/calcium sensitivity provides mechanistic detail\",\n      \"pmids\": [\"9791728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Laminin polymerization promotes perlecan assembly on cell surfaces; dystroglycan, laminin, and perlecan form a trimolecular complex demonstrated by solid-phase binding; LARGE-deficient (glycosylation-deficient) mice show reduced perlecan-binding activity and perlecan mislocalization, linking dystroglycan glycosylation to perlecan matrix assembly.\",\n      \"method\": \"Solid-phase ligand binding assays (trimolecular complex), cell-surface ligand clustering assays, analysis of Large(myd) mouse\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — solid-phase binding for trimolecular complex plus in vivo mouse model, single lab\",\n      \"pmids\": [\"16098969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Perlecan LG domains (domain V) promote AChR clustering in the presence of laminin-2 through a MuSK-dependent mechanism requiring laminin polymerization; perlecan-LG-dependent AChR clustering is accompanied by tyrosine phosphorylation of MuSK and betaAChR; antibody-mediated aggregation of non-neural agrin mimics this clustering, supporting a ligand-aggregation mechanism.\",\n      \"method\": \"Myotube culture AChR clustering assay, MuSK inhibition, tyrosine phosphorylation western blot, antibody crosslinking experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution in cell culture with kinase activity readout, mechanistic dissection\",\n      \"pmids\": [\"16219760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila perlecan (trol) is required for Sema-1a/PlexA-mediated repulsive motor axon guidance; trol mutations suppress Sema-1a-mediated defasciculation phenotypes; perlecan augments the reduction of phospho-FAK induced by Sema-1a in insect cells; genetic interactions among integrin, Sema-1a, and FAK indicate perlecan facilitates Sema-1a signaling by antagonizing integrin/FAK activity.\",\n      \"method\": \"Drosophila genetic epistasis (trol, Sema-1a, PlexA, integrin, FAK double/triple mutants), in vitro phospho-FAK assay in insect cells, perlecan rescue in mutant motor neurons\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple alleles plus biochemical in vitro confirmation, mechanistic pathway placement\",\n      \"pmids\": [\"23028146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Perlecan is required for FGF-2 signaling in the adult subventricular zone neurogenic niche; perlecan deficiency reduces neural stem cells (GFAP/CD133+) and new neurons; in the absence of perlecan, FGF-2 fails to promote neurosphere formation and fails to activate Akt and Erk1/2 or induce cyclin D2 expression.\",\n      \"method\": \"Perlecan-deficient mouse, neurosphere formation assay, FGF-2 stimulation with Akt/Erk1/2 pathway readout, cyclin D2 expression, immunostaining for neural stem cell markers\",\n      \"journal\": \"Stem cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic null mouse with specific signaling pathway readouts, both in vivo and in vitro components\",\n      \"pmids\": [\"24434631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MMP-7 (matrilysin) cleaves perlecan specifically at domain IV immunoglobulin repeat regions even when perlecan is fully HS-decorated or embedded in native basement membrane context; a C-terminal domain IV fragment (Dm IV-3) induces PCa cell clustering via FAK dephosphorylation/deactivation; MMP-7 cleavage reverses clustering to cell dispersion with FAK activation, acting as a molecular switch for cancer cell invasion.\",\n      \"method\": \"In vitro MMP-7 digestion of purified perlecan, recombinant domain IV fragments, Transwell invasion assay, cell clustering phenotype assays, comparison with PSA, hepsin, FAP enzymes\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay with defined substrate plus functional cell-based phenotype, domain-level mapping\",\n      \"pmids\": [\"24833109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Smooth muscle cell-derived perlecan contains both HS and CS chains, whereas endothelial cell-derived perlecan contains exclusively HS; SMC perlecan binds FGF1 and FGF2 via HS but promotes only FGF2 signaling, while endothelial perlecan promotes both FGF1 and FGF2 signaling; SMC adhesion to perlecan core requires GAG removal and involves a novel domain III site and domain V/endorepellin via alpha2beta1 integrin.\",\n      \"method\": \"Isolation and GAG characterization of cell-type-specific perlecan, FGF binding assays, signaling assays, integrin-blocking antibodies, cell adhesion assays\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical characterization plus functional signaling and adhesion assays, cell-type-specific mechanistic distinction\",\n      \"pmids\": [\"24509440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Perlecan domain IV-3 binds semaphorin 3A (Sema3A) on PCa cells (demonstrated by direct binding experiments and co-IP); this perlecan-Sema3A complex deactivates FAK and promotes PCa cell clustering (tumoroid formation); MMP-7 cleaves both perlecan and Sema3A, destroying the complex and activating FAK to drive cell dispersion and invasion.\",\n      \"method\": \"Direct binding experiments, co-immunoprecipitation, Sema3A antibody mimicry, siRNA knockdown of Sema3A, MMP-7 cleavage assays, FAK phosphorylation western blot, Transwell invasion\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding confirmed by multiple methods, mechanistic linkage to FAK signaling pathway, loss-of-function with specific readout\",\n      \"pmids\": [\"29740048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Perlecan deficiency in endothelial cells (siRNA knockdown) or in a conditional perlecan knockout mouse reduces eNOS gene and protein expression, resulting in impaired acetylcholine-dependent endothelium-dependent relaxation while preserving nitroprusside (NO donor)-dependent relaxation.\",\n      \"method\": \"Conditional perlecan-deficient mouse, isolated aortic ring isometric force measurements, real-time PCR, Western blot, siRNA knockdown in human aortic endothelial cells\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and siRNA loss-of-function concordant, specific molecular target (eNOS) identified with functional vascular tone readout\",\n      \"pmids\": [\"25626871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Perlecan HS chains (domain I) are required for formation of the HS-FGF2-FGFR1 ternary complex; Hspg2Δ3/Δ3 mice show impaired FGFR1 phosphorylation and reduced PASMC proliferation in response to hypoxia, attenuating pulmonary hypertension development.\",\n      \"method\": \"Hspg2Δ3/Δ3 mice, hypoxia PH model, ligand and carbohydrate engagement (LACE) assay for ternary complex formation, FGFR1 phosphorylation western blot, PASMC proliferation assay, selective FGFR1 inhibition\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — ternary complex assay plus genetic mouse model with concordant in vitro and in vivo results\",\n      \"pmids\": [\"25952902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Perlecan/HSPG2 core protein is a monomeric rod of 170±20 nm end-to-end length (measured by AFM), capable of withstanding >100 pN tensile force (elastic constant 890 pN, Young's modulus 71 MPa), physically suitable to span the osteocyte pericellular space and act as a mechanical tether in the lacunar-canalicular system.\",\n      \"method\": \"Atomic force microscopy imaging and single-molecule force measurements (SMFM) of purified full-length human perlecan, extensible worm-like chain model fitting\",\n      \"journal\": \"Matrix biology : journal of the International Society for Matrix Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct structural/physical measurement of purified protein with quantitative biophysical parameters\",\n      \"pmids\": [\"26546708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"TGF-beta transcriptionally induces perlecan mRNA and protein 2-3 fold in skin fibroblasts via a NF-1-binding element located between -461 and -285 bp in the promoter; TNF-alpha has no effect and cannot counteract TGF-beta; the TGF-beta responsive element binds TGF-beta-inducible nuclear proteins with high affinity.\",\n      \"method\": \"Transient cell transfection reporter assays, 5' deletion and internal deletion analysis, DNase footprinting, electrophoretic mobility shift assays (EMSA), mutational analyses, Northern blot/protein quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple complementary methods defining promoter element and transcription factor binding\",\n      \"pmids\": [\"9030592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TNF-alpha is a major cytokine regulator of perlecan production via NF-kappaB; TNF-alpha triggers p65 nuclear translocation and binding to the HSPG2 regulatory region containing conserved NF-kappaB binding sites; reporter construct dissection locates an active cis-element in the distal HSPG2 promoter region.\",\n      \"method\": \"HSPG2 promoter reporter construct transfections with systematic deletions, cytokine treatment, p65 nuclear translocation assay, chromatin-level p65 binding\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter dissection with multiple constructs plus transcription factor binding, single lab\",\n      \"pmids\": [\"24700612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Perlecan domain II core protein interacts with LDL via O-linked sialylated glycans; sialic acid residues on domain II are critical for LDL binding; HS and domain II have an additive effect on LDL binding; unlike LDLR (which mediates endocytosis), perlecan DII mediates receptor-mediated lipoprotein retention in the arterial wall.\",\n      \"method\": \"Solid-phase binding assays, glycan analysis of secreted DII (MS), sialic acid-specific inhibition, domain-specific binding experiments\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical dissection with MS glycan analysis plus functional binding assays, specific mechanism identified\",\n      \"pmids\": [\"25528754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Perlecan is a key component of the pro-metastatic CAF environment driven by GOF mutant p53 cancer cells; depletion of perlecan from the stroma combined with chemotherapy prolongs mouse survival; perlecan depletion reduces chemotherapy resistance in a pancreatic cancer model observed by intravital imaging.\",\n      \"method\": \"Intravital imaging, perlecan stromal depletion (genetic/RNAi), combination with chemotherapy in mouse model, survival analysis with mechanistic framing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function with specific survival and drug response readouts, but mechanism upstream of perlecan only partially defined\",\n      \"pmids\": [\"31406163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Perlecan deficiency (Hypo mice) impairs osteocyte calcium signaling in response to mechanical loading; perlecan-deficient osteocytes show reduced Ca2+ response rate, peak magnitude, and recovery; RNA sequencing identifies suppression of calcium signaling, ECM-receptor interaction, and focal adhesion pathways, with defects in Ryr1 and Atp2a1 (ER calcium cycling regulators).\",\n      \"method\": \"Real-time Ca2+ imaging in situ in murine tibiae under cyclic loading, RNA sequencing, pathway analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — live imaging of calcium signaling in genetic null, complemented by transcriptomic pathway analysis\",\n      \"pmids\": [\"31715337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Perlecan haploinsufficiency in hPSC-derived cardiomyocytes causes structural immaturity (reduced alpha-actinin), increased glycolytic metabolism, and proliferation; perlecan-haploinsufficient engineered heart tissues have reduced thickness and force generation; hPSC-CMs grown on perlecan peptide substrate are enlarged with increased nucleation (hypertrophic growth); perlecan signaling is mediated via the dystroglycan complex.\",\n      \"method\": \"HSPG2+/- hPSC haploinsufficiency, cardiomyocyte differentiation, engineered heart tissue force measurement, perlecan peptide substrate culture, dystroglycan complex interaction assessment\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic haploinsufficiency with multiple orthogonal functional and structural readouts, rescue by peptide substrate, pathway (dystroglycan complex) identified\",\n      \"pmids\": [\"38198277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Perlecan co-localizes with elastin and fibrillin-1 in connective tissues; tropoelastin interacts with perlecan heparan sulfate chains (quartz crystal microbalance), and core protein also contributes; this interaction promotes tropoelastin coacervation and deposition of elastin onto perlecan, supporting elastic microfibril assembly.\",\n      \"method\": \"Immunohistochemistry co-localization, quartz crystal microbalance with dissipation (QCM-D) solid-phase binding, heparan sulfate-dependent interaction analysis\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — solid-phase biophysical binding complemented by tissue co-localization, single lab\",\n      \"pmids\": [\"21874555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Type XIII collagen ectodomain binds perlecan (and fibronectin, nidogen-2, heparin) with nanomolar KD values determined by surface plasmon resonance; binding sites for nidogen-2 and perlecan reside in pepsin-sensitive non-collagenous portions of type XIII collagen.\",\n      \"method\": \"Surface plasmon resonance binding assay, pepsin digestion domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative SPR with domain mapping, identifies perlecan as a specific binding partner for type XIII collagen\",\n      \"pmids\": [\"11956183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNFSF13 binds HSPG2/perlecan on hypertrophic scar fibroblasts; the TNFSF13/HSPG2 interaction activates NF-kappaB signaling to promote fibroblast proliferation, migration, fibrosis, and inflammation; silencing HSPG2 or inhibiting NF-kappaB eliminates TNFSF13 pro-fibrotic effects; MSC-derived exosomes suppress TNFSF13 and HSPG2 to reduce fibroblast activity.\",\n      \"method\": \"Recombinant TNFSF13 protein treatment, TNFSF13/HSPG2 siRNA knockdown, protein-protein binding assays, NF-kappaB pathway inhibition, CCK-8/EdU/Transwell assays, western blot\",\n      \"journal\": \"International journal of nanomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — binding and functional knockdown data with pathway readout, single lab\",\n      \"pmids\": [\"38046235\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Perlecan (HSPG2) is a large, modular heparan sulfate proteoglycan that functions as a multivalent signaling scaffold: its N-terminal heparan sulfate chains (domain I) sequester and present FGF-2 and other heparin-binding growth factors to their receptors (forming obligate HS-GF-FGFR ternary complexes), while its protein core independently binds FGF-7, FGF-18, FGF-BP, progranulin, semaphorin 3A, LDL, dystroglycan, and type XIII collagen through distinct domain-specific sites; domain III mediates RGD/integrin-dependent cell adhesion and FGF-7/KGF receptor activation; domain V/endorepellin drives angiogenesis, myopathy rescue, and acetylcholine receptor clustering via MuSK in a laminin-polymerization-dependent manner; chondroitin sulfate side chains on perlecan promote collagen type II fibril assembly in cartilage; proteolytic processing by MMP-7 at domain IV acts as a molecular switch converting perlecan-Sema3A-mediated FAK inactivation and cell clustering to FAK activation and invasive cell dispersion; heparanase degrades perlecan HS chains to facilitate tumor invasion; perlecan deficiency abolishes endothelium-dependent vascular relaxation by reducing eNOS expression, impairs osteocyte mechanosensory calcium signaling via ryanodine receptor and SERCA pathways, and causes perinatal-lethal chondrodysplasia and basement membrane failure under mechanical stress.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Perlecan (HSPG2) is a large, modular basement membrane heparan sulfate proteoglycan that functions as a multivalent signaling scaffold and structural organizer of extracellular matrices. Its N-terminal heparan sulfate chains (domain I) sequester and present FGF-2 to FGF receptors, forming obligate HS–FGF–FGFR ternary complexes essential for mitogenic signaling in contexts including neurogenesis, vascular smooth muscle proliferation, and pulmonary hypertension [PMID:7528102, PMID:9121441, PMID:24434631, PMID:25952902], while the protein core independently binds FGF-7, FGF-18, Hedgehog, semaphorin 3A, progranulin, LDL, and dystroglycan through domain-specific sites to regulate chondrocyte differentiation, axon guidance, lipoprotein retention, and neuromuscular junction assembly [PMID:10702276, PMID:17971291, PMID:12645928, PMID:29740048, PMID:25528754, PMID:16219760]. Domain V (endorepellin) promotes AChR clustering via MuSK in a laminin-polymerization-dependent manner and rescues myopathy and angiogenesis defects in zebrafish, while chondroitin sulfate chains on cartilage perlecan accelerate collagen II fibril assembly, and proteolytic processing by MMP-7 at domain IV acts as a molecular switch converting Sema3A-mediated FAK inactivation and cell clustering to FAK activation and invasive cell dispersion [PMID:18426981, PMID:16956876, PMID:24833109]. Perlecan-null mice exhibit perinatal-lethal chondrodysplasia with basement membrane failure under mechanical stress, and perlecan deficiency abolishes endothelium-dependent vascular relaxation by reducing eNOS expression and impairs osteocyte mechanosensory calcium signaling [PMID:10579729, PMID:10545953, PMID:25626871, PMID:31715337].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that perlecan is not merely a structural proteoglycan but a functional co-receptor that enables high-affinity FGF-2 binding to its receptor and drives angiogenesis in vivo answered the fundamental question of why basement membrane HSPGs are required for growth factor signaling.\",\n      \"evidence\": \"Purified perlecan binding assays on HS-deficient cells, monoclonal antibody inhibition, rabbit ear angiogenesis model\",\n      \"pmids\": [\"7528102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the minimal HS structure required for ternary complex formation was not defined\", \"Whether perlecan HS versus other HSPGs had unique or redundant co-receptor function was unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Genetic loss-of-function confirmed perlecan as the principal endogenous FGF-2 co-receptor, ruling out redundancy with other cell-surface HSPGs, while parallel promoter studies showed TGF-β transcriptionally upregulates perlecan via an NF-1-binding element.\",\n      \"evidence\": \"Stable antisense suppression in fibroblasts/melanoma with rescue by exogenous perlecan; promoter deletion/EMSA/reporter assays in skin fibroblasts\",\n      \"pmids\": [\"9121441\", \"9030592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo genetic confirmation in mammals was still lacking\", \"Which downstream signaling pathways are activated was not yet characterized\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Knockout mice revealed that perlecan is essential for basement membrane integrity under mechanical stress and for cartilage collagen network organization, with the chondrodysplasia phenotype paralleling FGFR3 gain-of-function, placing perlecan in the FGF/FGFR3 signaling axis of chondrogenesis.\",\n      \"evidence\": \"Two independent Hspg2-null mouse lines with histology, EM, and phenotypic comparison to FGFR3 mutant mice\",\n      \"pmids\": [\"10579729\", \"10545953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether perlecan acts through HS chains or protein core in cartilage was unresolved\", \"Direct biochemical demonstration of perlecan–FGFR3 interaction was missing\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Domain-mapping studies revealed that the perlecan protein core (domains III and V) binds FGF-7 independently of heparan sulfate, and that perlecan mediates a distinct lipoprotein internalization/degradation pathway via β1 integrins, while in vivo vascular studies showed perlecan prevents thrombosis after deep injury.\",\n      \"evidence\": \"Yeast two-hybrid/radioligand binding for FGF-7; pharmacological dissection of lipoprotein endocytosis; antisense-perlecan endothelial cells in porcine carotid artery model\",\n      \"pmids\": [\"10702276\", \"10818109\", \"10841569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FGF-7 core-protein binding activates FGFR2 signaling was not yet shown genetically\", \"The integrin subtype mediating lipoprotein uptake was not identified\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic disruption of HSPG2 in colon carcinoma cells demonstrated that the protein core — not HS chains — is required for functional KGF/FGFR2-IIIb receptor activation, while perlecan-null ES cells revealed its requirement for laminin matrix organization through a dystroglycan–β1 integrin axis, and domain III was shown to bind FGF-BP.\",\n      \"evidence\": \"Targeted homologous recombination in colon carcinoma cells with signaling assays; perlecan-null ES cell laminin clustering; yeast two-hybrid/co-IP for FGF-BP\",\n      \"pmids\": [\"11563979\", \"11228157\", \"11148217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for core-protein-mediated FGFR2 activation was unknown\", \"Whether FGF-BP–perlecan interaction modulates FGF activity in vivo was untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Perlecan was shown to modulate Hedgehog signaling in addition to FGF in Drosophila neuroblast proliferation, its HS chains were identified as heparanase substrates relevant to tumor invasion, progranulin was identified as a domain V ligand with antagonistic growth effects, and HS-specific domain I deletion in mice revealed tissue-specific roles in lens capsule integrity versus glomerular filtration.\",\n      \"evidence\": \"Drosophila trol genetic epistasis with Hh/FGF pathways and Co-IP; in vitro heparanase digestion of purified perlecan; yeast two-hybrid/SPR for progranulin–domain V; Hspg2 exon 3 deletion mouse\",\n      \"pmids\": [\"12645928\", \"14630925\", \"12900424\", \"12514129\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether perlecan directly binds Hh in mammals in vivo was not confirmed\", \"Tissue-specific HS chain functions beyond lens and kidney were uncharacterized\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Multiple studies converged on perlecan's role in neuromuscular junction biology and epithelial survival: domain V/LG domains promote AChR clustering through MuSK-dependent laminin polymerization, a trimolecular dystroglycan–laminin–perlecan complex was demonstrated, HS chains on SMC-derived perlecan suppress intimal hyperplasia by sequestering FGF-2, and perlecan is essential for keratinocyte survival through FGF-7 bioavailability.\",\n      \"evidence\": \"AChR clustering assays with MuSK phosphorylation; solid-phase trimolecular binding and Large(myd) mouse; Hspg2Δ3/Δ3 mice in flow cessation model; perlecan siRNA in organotypic skin with FGF-7 rescue\",\n      \"pmids\": [\"16219760\", \"16098969\", \"14739157\", \"16269412\", \"15872080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether domain V alone is sufficient for NMJ formation in vivo was untested\", \"The precise signaling pathway downstream of perlecan mediating keratinocyte survival was incompletely defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The chondroitin sulfate chains of cartilage perlecan — specifically 4,6-disulfated CS-E — were shown to directly accelerate collagen II fibril formation, providing a mechanistic explanation for the disorganized collagen network in perlecan-null cartilage independent of growth factor signaling.\",\n      \"evidence\": \"In vitro collagen fibril formation assay with purified perlecan, chondroitinase treatment, GAG compositional analysis, EM\",\n      \"pmids\": [\"16956876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CS-E on perlecan is the dominant collagen-organizing signal in vivo versus other CS proteoglycans was unresolved\", \"Regulation of CS sulfation on perlecan was not addressed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Perlecan core protein domain III was mapped as an FGF-18 binding site that antagonizes FGF-18 mitogenic activity in chondrocytes, revealing that perlecan can both promote and inhibit FGF signaling depending on the ligand and domain involved.\",\n      \"evidence\": \"Cationic filtration, immunoprecipitation, enzymatic treatment of GAG chains, recombinant domain expression, thymidine incorporation\",\n      \"pmids\": [\"17971291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this antagonism operates in vivo at growth plate FGF-18 concentrations was not shown\", \"Whether domain III simultaneously binds FGF-7 and FGF-18 was unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Zebrafish perlecan depletion demonstrated that domain V/endorepellin mediates the majority of perlecan's biological activities in muscle development and angiogenic vessel sprouting, as domain V injection alone rescued both myopathy and vascular defects.\",\n      \"evidence\": \"Morpholino knockdown with domain V protein rescue microinjection, live imaging of actin and vasculature\",\n      \"pmids\": [\"18426981\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor(s) mediating domain V angiogenic rescue in zebrafish were not identified\", \"Whether domain V is processed from full-length perlecan in vivo was not demonstrated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Drosophila genetic epistasis placed perlecan in the Sema-1a/PlexA repulsive axon guidance pathway, where it facilitates semaphorin signaling by antagonizing integrin/FAK activity, extending perlecan's role from growth factor co-receptor to semaphorin signaling modulator.\",\n      \"evidence\": \"Drosophila double/triple mutant analysis of trol, Sema-1a, PlexA, integrin, FAK; phospho-FAK assay in insect cells\",\n      \"pmids\": [\"23028146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mammalian perlecan similarly modulates semaphorin signaling was unconfirmed at this time\", \"Direct physical interaction between perlecan and Sema-1a was not demonstrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A series of studies revealed MMP-7 cleavage of perlecan domain IV as a molecular switch: intact domain IV-3 binds Sema3A to deactivate FAK and promote cell clustering, while MMP-7 processing destroys this complex and activates FAK-driven invasion; cell-type-specific GAG decoration was shown to determine FGF signaling selectivity; and domain II O-linked sialylated glycans were identified as a novel LDL retention mechanism.\",\n      \"evidence\": \"In vitro MMP-7 digestion with cell invasion/clustering assays and FAK readout; Sema3A co-IP and siRNA; cell-type-specific perlecan GAG analysis; solid-phase binding with MS glycan analysis for domain II–LDL\",\n      \"pmids\": [\"24833109\", \"29740048\", \"24509440\", \"25528754\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MMP-7 cleavage of perlecan occurs during metastasis in vivo was not shown\", \"Identity of the sialylated O-glycan structures on domain II was not fully elucidated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Perlecan was established as a regulator of vascular tone and pulmonary vascular remodeling: HS chains form the FGF2–FGFR1 ternary complex required for hypoxic PASMC proliferation and pulmonary hypertension, while perlecan deficiency reduces eNOS expression to impair endothelium-dependent relaxation; biophysical measurements showed the full-length core protein is a ~170 nm monomeric rod capable of withstanding >100 pN force.\",\n      \"evidence\": \"Hspg2Δ3/Δ3 mice in hypoxia PH model with LACE assay; conditional perlecan KO with aortic ring relaxation; AFM imaging and single-molecule force spectroscopy\",\n      \"pmids\": [\"25952902\", \"25626871\", \"26546708\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether perlecan mechanically transmits force to osteocytes in the lacunar-canalicular system was not yet functionally tested\", \"Upstream mechanism of perlecan regulation of eNOS transcription was unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Perlecan was identified as a functional component of the pro-metastatic cancer-associated fibroblast niche and as a mechanosensory transducer in osteocytes: stromal perlecan depletion enhances chemotherapy efficacy, while perlecan-deficient osteocytes show impaired calcium signaling with downregulation of ryanodine receptor and SERCA pathways.\",\n      \"evidence\": \"Intravital imaging with stromal perlecan depletion and survival analysis in pancreatic cancer model; real-time Ca2+ imaging in loaded murine tibiae with RNA-seq\",\n      \"pmids\": [\"31406163\", \"31715337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which perlecan in the stroma modulates drug resistance was not fully elucidated\", \"Whether perlecan directly interacts with Ryr1/Atp2a1 or regulates them transcriptionally was unclear\", \"The pro-metastatic stroma study defined upstream p53 dependency only partially\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Perlecan haploinsufficiency in human cardiomyocytes was shown to impair structural maturation and force generation via the dystroglycan complex, with perlecan peptide substrate rescuing hypertrophic growth, establishing perlecan as a critical cardiomyocyte maturation factor signaling through dystroglycan.\",\n      \"evidence\": \"HSPG2+/- hPSC-derived cardiomyocytes, engineered heart tissue contractility, perlecan peptide substrate culture, dystroglycan interaction assessment\",\n      \"pmids\": [\"38198277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific dystroglycan-complex subunit mediates the perlecan maturation signal was not defined\", \"Whether this mechanism is relevant to human cardiomyopathy in vivo remains untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for perlecan core-protein-mediated receptor activation, whether in vivo MMP-7 processing of perlecan drives metastatic dissemination, the mechanism linking perlecan to eNOS transcription, and whether perlecan functions as a direct mechanotransducer in bone.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No atomic-resolution structure of any full domain–ligand complex exists\", \"In vivo evidence for MMP-7 cleavage of perlecan during cancer progression is lacking\", \"Direct force-transmission function in the osteocyte lacunar-canalicular system has not been reconstituted\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 35]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 8, 17]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 18, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 31, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [2, 3, 18, 39, 40]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [14, 16, 32]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 22, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 7, 18, 39]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8, 9, 26, 31]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 20, 25]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [22, 24, 38]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"complexes\": [\n      \"dystroglycan complex\",\n      \"HS–FGF–FGFR ternary complex\"\n    ],\n    \"partners\": [\n      \"FGF2\",\n      \"FGFR1\",\n      \"DAG1\",\n      \"LAMA1\",\n      \"SEMA3A\",\n      \"MMP7\",\n      \"GRN\",\n      \"FGFBP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}