{"gene":"SPARC","run_date":"2026-06-10T07:46:39","timeline":{"discoveries":[{"year":1998,"finding":"SPARC inhibits VEGF-stimulated DNA synthesis in human microvascular endothelial cells by directly binding VEGF, reducing VEGF association with its cell-surface receptors, and attenuating ERK1/2 tyrosine phosphorylation. Peptides from domain IV (EF-hand/EC module) and domain II (follistatin-like) mimicked these inhibitory effects; domains I and III had no effect.","method":"DNA synthesis assay, 125I-VEGF binding/radioimmune precipitation, Western blot for ERK1/2 phosphorylation, SPARC domain peptide competition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods (binding assay, signaling readout, peptide domain mapping) in a single focused study","pmids":["9792673"],"is_preprint":false},{"year":2000,"finding":"The extracellular calcium-binding (EC) domain of SPARC/BM-40 contains two EF-hands that bind Ca2+ cooperatively and with high affinity; under physiological extracellular Ca2+ concentrations the EF-hands are saturated, suggesting a structural rather than regulatory role. There is a strong interaction (~10 kJ/mol free energy contribution) between the EC domain and the neighboring follistatin-like (FS) domain, primarily through the variant EF-hand 1. Certain mutations of Ca2+-coordinating residues inhibited folding and secretion, indicating a role for EF-hands during biosynthesis/processing in the ER or Golgi.","method":"Ca2+ binding assays, deletion mutagenesis, mammalian cell secretion assay, thermodynamic analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with mutagenesis and thermodynamic measurements, single lab but multiple orthogonal methods","pmids":["10801822"],"is_preprint":false},{"year":2001,"finding":"Crystal structure of two of the three SPARC domains revealed a novel follistatin-like (FS) module and an extracellular calcium-binding (EC) module containing two EF-hand motifs. The collagen-binding site resides in helix αA of the EC domain and is partially masked by helix αC; removal of αC causes a ~10-fold increase in collagen binding affinity.","method":"Protein crystallography, site-directed mutagenesis, collagen binding assays","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional mutagenesis, independently referenced across multiple review and primary papers in the corpus","pmids":["11223341","11102747"],"is_preprint":false},{"year":2008,"finding":"SPARC binds fibrillar collagens I, II, and III at specific triple-helical sites; a major binding site is located approximately 180 nm from the C-terminus of collagen. Binding requires triple-helical conformation (denaturation abolishes it). N-acetylation of Lys/Hyl side chains substantially decreases binding. A synthetic triple-helical peptide with sequence GPOGPSGPRGQOGVMGFOGPKGNDGAO (conserved in α-chains of collagens I, II, III, V) binds SPARC with affinity comparable to procollagen III. In vitro collagen fibrillogenesis is delayed in the presence of SPARC.","method":"Rotary shadowing/electron microscopy, CNBr peptide binding, synthetic triple-helical peptide binding, surface plasmon resonance, in vitro fibrillogenesis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical methods (EM, peptide mapping, SPR, fibrillogenesis) in one rigorous study","pmids":["18487610"],"is_preprint":false},{"year":2004,"finding":"N-glycosylation of SPARC/BM-40 varies by tissue source (high-mannose in bone, complex-type in platelets/293 cells, hybrid in EHS tumor). SPARC carrying high-mannose N-glycans binds collagen I with higher affinity than complex-type glycoforms, as measured by surface plasmon resonance.","method":"Endoglycosidase/exoglycosidase digestion, HPLC glycan analysis, surface plasmon resonance collagen binding assay","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution with SPR quantification and detailed glycan characterization, single lab but rigorous","pmids":["15044389"],"is_preprint":false},{"year":1992,"finding":"Anti-SPARC antibodies cross-react with the endothelial albumin-binding glycoprotein gp60, and purified SPARC inhibits anti-SPARC IgG binding to gp60. Anti-SPARC IgG inhibits albumin binding to both SPARC and gp60 and reduces albumin binding to cultured microvascular endothelial cells. These results indicate SPARC and gp60 are functionally and immunologically related albumin-binding proteins sharing a common albumin-binding domain.","method":"Antibody cross-reactivity assay, competitive inhibition of albumin binding, cell-based albumin binding assay","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal inhibition assays and cell-based binding experiments, single lab with multiple methods","pmids":["1481911"],"is_preprint":false},{"year":1998,"finding":"SPARC regulates endothelial paracellular permeability through a protein tyrosine phosphorylation-dependent signaling pathway. SPARC increases tyrosine phosphorylation (up to 12-fold) of endothelial proteins localized to intercellular boundaries, with β-catenin and paxillin identified as substrates. Tyrosine kinase inhibitors (herbimycin A, genistein) reversed SPARC-induced barrier dysfunction and intercellular gap formation; tyrosine phosphatase inhibitors enhanced barrier disruption.","method":"Macromolecular flux assay, phosphotyrosine Western blot/immunolocalization, pharmacologic kinase/phosphatase inhibition, substrate identification","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional barrier assay paired with substrate identification and pharmacologic epistasis, single lab","pmids":["9790954"],"is_preprint":false},{"year":1998,"finding":"SPARC deficiency (targeted gene disruption) in mice leads to early-onset cataractogenesis beginning at 1.5 months, characterized by inhibition of normal lens fiber cell differentiation, fiber cell degeneration, vacuole formation, and cortex liquefaction, establishing that SPARC is essential for lens transparency maintenance.","method":"Targeted gene disruption (knockout mouse), slit-lamp microscopy, histology","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, replicated/referenced across multiple independent papers in corpus","pmids":["9856777"],"is_preprint":false},{"year":2006,"finding":"SPARC overexpression in normal human melanocytes induces mesenchymal transition with loss of E-cadherin and P-cadherin, increased mesenchymal markers, and enhanced motility/invasion. SPARC transcriptionally down-regulates E-cadherin by inducing the repressor Snail. Conversely, SPARC depletion up-regulates E-cadherin and reduces Snail levels.","method":"Overexpression and siRNA knockdown, RT-PCR, Western blot, cell morphology/motility assays, invasion assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function experiments with transcriptional readout, single lab with multiple orthogonal methods","pmids":["16885349"],"is_preprint":false},{"year":2010,"finding":"SPARC interacts physically with AMPK alpha1 (identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation of endogenous proteins in HepG2 cells and rat tissues). AMPK activation increases SPARC expression; SPARC siRNA reduces AICAR-stimulated AMPK phosphorylation. SPARC affects AMPK-mediated glucose metabolism through regulation of GLUT4 expression in L6 myocytes.","method":"Yeast two-hybrid screen, co-immunoprecipitation of endogenous proteins, siRNA knockdown, Western blot for GLUT4 expression","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — yeast two-hybrid confirmed by co-IP of endogenous proteins in multiple tissues; functional follow-up with siRNA, single lab","pmids":["20460104"],"is_preprint":false},{"year":2014,"finding":"In AML cells, SPARC expression is mediated by the SP1/NF-κB transactivation complex. Secreted SPARC activates the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling involved in leukemia cell self-renewal. Pharmacologic inhibition of SP1/NF-κB reduces SPARC expression and leukemia growth.","method":"Reporter assays, Western blot for pathway activation, pharmacologic inhibition, murine AML models","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway assays and pharmacologic epistasis, single lab","pmids":["24590286"],"is_preprint":false},{"year":2015,"finding":"SPARC, produced by astrocytes, triggers a cell-autonomous program of synapse elimination in cholinergic neurons. The effect resides in the C-terminal domain of SPARC and causes disassembly of stable cholinergic synapses in a concentration- and time-dependent manner, associated with retracted axon terminals containing multivesicular bodies and secondary lysosomes. In vivo injection of SPARC-derived peptide 4.2 into Xenopus tropicalis tadpole tails caused massive elimination of neuromuscular junctions and impaired swimming.","method":"Single-cell autaptic microculture assay, domain peptide application, in vivo peptide injection with behavioral and morphological readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain-specific reconstitution in vitro validated by in vivo injection with defined cellular and behavioral phenotypes","pmids":["26420865"],"is_preprint":false},{"year":2013,"finding":"SPARC regulates microglial proliferation and morphology. In SPARC-null/CX3CR1-GFP reporter mice, mature microglia show altered distribution and branching. Following ischemic lesion, reactive microglia rapidly downregulate SPARC while perilesional astrocytes upregulate it. Microglia from SPARC-null mice proliferate at a greater rate in vitro, an effect rescued by exogenous SPARC addition.","method":"SPARC-null reporter mice, in vivo lesion models, in vitro microglial proliferation assay with SPARC rescue","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO phenotype confirmed by exogenous rescue experiment, single lab","pmids":["23467362"],"is_preprint":false},{"year":2022,"finding":"SPARC induces an inflammatory, interferon-stimulated gene (ISG) expression program in macrophages via TLR4-mediated TBK1/IRF3/IFN-β/STAT1 signaling, independently of the MyD88 pathway. The N-terminal acidic domain of SPARC is required for ISG induction. SPARC dampens mitochondrial respiration, and glycolysis inhibition abrogates SPARC-induced ISG expression. Adipocyte-specific SPARC deletion reduces inflammation and extends healthspan during aging.","method":"Macrophage treatment with recombinant SPARC, domain deletion constructs, pathway inhibitor experiments, adipocyte-specific conditional knockout, transcriptomic analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain mapping, genetic pathway epistasis (TLR4/MyD88), conditional KO with healthspan readout, multiple orthogonal methods in one rigorous study","pmids":["35963236"],"is_preprint":false},{"year":2023,"finding":"SPARC activates the NLRP3 inflammasome at the priming step in macrophages; excess SPARC activates macrophages via JNK signaling. Inducible SPARC downregulation in adult mice or adipocyte-specific SPARC deletion protects against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction, lowering macrophage NLRP3 inflammasome activity.","method":"Inducible knockdown, adipocyte-specific conditional knockout, NLRP3 inflammasome assays, JNK pathway Western blot, metabolic phenotyping","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with mechanistic pathway identification (NLRP3 priming, JNK), single lab with multiple orthogonal methods","pmids":["37781916"],"is_preprint":false},{"year":2016,"finding":"Intracellular SPARC stabilizes ApoE protein by competitively binding ApoE and preventing its interaction with the E3 ubiquitin ligase TRIM21, thereby blocking ApoE ubiquitylation and proteasomal degradation. ApoE accumulation leads to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing EMT.","method":"Co-immunoprecipitation, ubiquitylation assay, competitive binding assay, siRNA knockdown, Western blot for PI3K-AKT and EMT markers","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with competitive binding and ubiquitylation assay, single lab","pmids":["38471084"],"is_preprint":false},{"year":2012,"finding":"β4 integrin signaling reduces expression of miR-29a (a microRNA that targets SPARC), thereby elevating SPARC protein levels. In cells with endogenous β4, ligation facilitates SPARC translation through a TOR-dependent mechanism. SPARC functions as an effector downstream of β4 integrin to promote breast carcinoma invasion.","method":"miRNA expression analysis, miR-29a manipulation, β4 integrin knockdown/overexpression, TOR inhibition, Matrigel invasion assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis with pharmacologic inhibition and miRNA manipulation, single lab, multiple methods","pmids":["22308039"],"is_preprint":false},{"year":2013,"finding":"SPARC loss in bladder cancer is associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with increased NF-κB and AP1 activation in urothelial and stromal cells. Tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization in syngeneic models.","method":"Sparc-deficient mice with chemical carcinogenesis, syngeneic transplantation models, NF-κB/AP1 reporter assays, ROS measurement","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO carcinogenesis model with mechanistic pathway identification, single lab","pmids":["23321672"],"is_preprint":false},{"year":2016,"finding":"Sparc null mice exhibit collagen fibrillogenesis defects in tendons; Sparc-/- tendons are less able to withstand force. Sparc-null and healthy-aged tendon-derived cells show a more contracted phenotype and altered actin cytoskeleton. Elevated adipogenic marker gene expression (PPARγ, Cebpα) with increased lipid deposits is observed in aged and Sparc-/- tendons.","method":"Sparc knockout mouse tendon analysis, mechanical tensile testing, histology, cell cytoskeletal staining, lipid staining, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined structural and cellular phenotypes, single lab with multiple readouts","pmids":["27586416"],"is_preprint":false},{"year":2018,"finding":"Macrophages are identified as a cellular source of SPARC in pressure-overloaded hearts by immunohistochemistry and flow cytometry. Increased myocardial macrophage numbers coincide temporally with increased SPARC levels preceding collagen deposition and myocardial stiffening, supporting macrophage-derived SPARC as mediating postsynthetic collagen processing and insoluble collagen incorporation.","method":"Murine pressure overload model, immunohistochemistry, flow cytometry, time-course measurement of collagen mRNA/protein and myocardial stiffness","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cellular source identification by flow cytometry with temporal correlation, single lab","pmids":["29522370"],"is_preprint":false},{"year":2019,"finding":"Extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and improves cardiac function in vivo. SPARC co-localizes with integrin-β1 and integrin-linked kinase on the cardiomyocyte membrane, suggesting an integrin-mediated mechanism for its inotropic effect.","method":"Ex vivo cardiomyocyte shortening assay with recombinant SPARC, in vivo cardiac function measurements, co-localization by immunofluorescence","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional assay with recombinant protein ex vivo and in vivo, co-localization supporting mechanism, single lab","pmids":["30933983"],"is_preprint":false},{"year":2021,"finding":"SPARC binds neurexin and neuroligin with nanomolar affinity through its FS domain, competing with hevin for binding to these synaptic organizers. This competition mechanism underlies SPARC's antagonism of hevin-mediated synaptogenesis. The shortened N-terminal region of SPARC (relative to hevin) is responsible for its antagonist activity.","method":"Crystal structure of hevin FS-EC, binding affinity measurements, competitive binding assays, domain analysis","journal":"Structure (London, England : 1993)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structural determination combined with quantitative binding assays and domain-deletion competition experiments","pmids":["33535026"],"is_preprint":false},{"year":2013,"finding":"SPARC promotes glioma migration and invasion partly by activating P38 MAPK/MAPKAPK2/HSP27 (Ser78 phosphorylation) signaling. PTEN suppresses SPARC-induced pMAPKAPK2 and Ser78 HSP27 phosphorylation downstream of pP38 MAPK, via suppression of pAkt, thereby inhibiting SPARC-induced migration.","method":"Overexpression/co-transfection of SPARC and PTEN constructs, Western blot time-course for pathway components, cell migration assay on fibronectin","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by co-transfection with detailed signaling time-course, single lab","pmids":["23382286"],"is_preprint":false},{"year":2011,"finding":"In bleomycin-induced pulmonary fibrosis, SPARC in host fibroblasts (not bone-marrow-derived cells) is required and sufficient for collagen fibrosis. Conversely, SPARC in macrophages is required to down-regulate TNF production in response to TGF-β; Sparc-/- macrophages fail to do so, resulting in exacerbated inflammation and fibrosis.","method":"Reciprocal bone marrow chimera experiments (Sparc-/- and WT), conditional dominant-negative TGF-β receptor under CD68 promoter, cytokine measurement","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal bone marrow chimeras dissect cell-type-specific functions with genetic and molecular controls, single lab","pmids":["22001347"],"is_preprint":false},{"year":2016,"finding":"In prostate cancer dormancy, SPARC secreted by indolent cells stimulates BMP7 expression in bone marrow stromal cells; the secreted BMP7 then maintains cancer cell dormancy by inducing senescence, reducing stemness, and activating p38 MAPK and p21 signaling. SPARC is epigenetically silenced by promoter methylation in aggressive cells; 5-azacytidine treatment reactivates SPARC expression.","method":"In vivo tibial implantation/selection, ELISA for secreted BMP7, siRNA knockdown, Western blot for p38/p21, 5-azacytidine demethylation, in vivo bone tumor models","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — paracrine mechanism established by conditioned medium experiments and in vivo models, single lab","pmids":["27422817"],"is_preprint":false},{"year":2011,"finding":"TP53INP1 decreases SPARC expression at the transcriptional level; SPARC is downstream of TP53INP1 and mediates cell migration. Knockdown of SPARC in pancreatic cancer cells suppresses cell migration comparably to TP53INP1 overexpression, and restoring SPARC in TP53INP1-expressing cells rescues migration.","method":"Overexpression and siRNA knockdown of TP53INP1 and SPARC, RT-PCR, cell migration assay, in vivo tumor model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by rescue experiment, multiple cell contexts, single lab","pmids":["21339733"],"is_preprint":false},{"year":2020,"finding":"SPARC activates AKT signaling leading to elevated MMP-2 expression, facilitating renal cell carcinoma invasion. TGF-β1 induces SPARC expression in RCC cells. Knockdown of SPARC inhibits RCC cell invasion in vitro and in vivo; a specific monoclonal antibody against SPARC also diminishes invasion in vitro.","method":"siRNA knockdown, monoclonal antibody blockade, Western blot for AKT/MMP-2, invasion assay, in vivo metastasis model","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and antibody loss-of-function with pathway identification, single lab","pmids":["32780451"],"is_preprint":false},{"year":2020,"finding":"SPARC promotes glucose-stimulated insulin secretion (GSIS) in pancreatic β cells by down-regulating RGS4 (a negative regulator of M3 muscarinic receptors) through a PI3K-dependent mechanism. SPARC-/- mice have elevated islet RGS4 and decreased GSIS; RGS4 inhibition restores GSIS in SPARC-null islets.","method":"SPARC overexpression/knockdown in Min6 cells, Western blot for RGS4, PI3K inhibitor (LY-294002) epistasis, islet secretion assay, sparc-/- mice","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic epistasis with defined molecular mechanism, single lab","pmids":["33067534"],"is_preprint":false},{"year":2015,"finding":"SPARC secreted by non-CSC prostate cancer cells (PC-3S) acts as a paracrine factor enhancing invasiveness of CSC-enriched cells (PC-3M). Immunodepletion of SPARC from S-conditioned medium inhibits enhanced M-cell invasiveness; SPARC knockdown in S cells abrogates their capacity to boost M-cell in vitro invasion and in vivo metastasis.","method":"SILAC secretome comparison, SPARC immunodepletion, siRNA knockdown, Transwell-Matrigel invasion assay, orthotopic co-injection in vivo model, bioluminescence metastasis monitoring","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — immunodepletion and genetic rescue experiments in vitro and in vivo, single lab","pmids":["25331979"],"is_preprint":false},{"year":2015,"finding":"Proteolytic isoforms of SPARC are generated in obese mouse adipose tissue: C-SPARC (lacking N-terminus) binds β1 integrin on adipose stromal cells (ASC) while N-SPARC (lacking C-terminus) preferentially binds ECM and blocks ECM/integrin interaction. Both isoforms induce ASC deadhesion from ECM and migration; C-SPARC modulates integrin-dependent FAK-ERK signaling while both affect integrin-independent ILK-Akt signaling with additive effects.","method":"Isoform purification and characterization, integrin binding assays, siRNA knockdown, FAK/ERK/ILK/Akt Western blot, ASC migration assay","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific binding and signaling characterization with multiple pathway readouts, single lab","pmids":["26381424"],"is_preprint":false},{"year":2022,"finding":"In pulmonary arterial smooth muscle cells (PASMCs), TGF-β1 and HIF2A signaling pathways induce SPARC expression. SPARC silencing enhances PASMC apoptosis and reduces proliferation; elevated SPARC promotes PASMC (but not pulmonary microvascular endothelial cell) proliferation. Conditioned medium from PMVECs acts as a paracrine factor (via secreted SPARC) triggering PASMC proliferation. AAV-mediated Sparc knockdown in adult mice improved hemodynamic and cardiac function in hypoxia-induced PH.","method":"siRNA knockdown, overexpression, conditioned medium/coculture experiments, AAV-mediated knockdown in vivo, hemodynamic measurements","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in vitro and in vivo with defined upstream inducers and cell-type-specific effects, single lab","pmids":["35175782"],"is_preprint":false},{"year":2009,"finding":"SPARC loss accelerates carcinogen-induced urothelial preneoplasia, neoplasia, and metastasis and is associated with increased inflammatory macrophage and fibroblast phenotypes and upregulation of NF-κB and AP1 signaling in urothelial and stromal compartments both in vivo and in vitro.","method":"Sparc-/- mice with chemical carcinogenesis, syngeneic transplantation, NF-κB/AP1 activity assays, in vitro cell assays","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO in vivo model with in vitro mechanistic confirmation, single lab","pmids":["23321672"],"is_preprint":false}],"current_model":"SPARC is a secreted, modular matricellular glycoprotein whose follistatin-like (FS) and extracellular calcium-binding (EC/EF-hand) domains mediate direct binding to fibrillar collagens (at defined triple-helical sites), VEGF, neurexin/neuroligin, albumin (via gp60), ApoE, and β1/β4 integrins, thereby regulating collagen fibrillogenesis, growth-factor signaling (VEGF, PDGF, TGF-β), endothelial paracellular permeability (via β-catenin/paxillin tyrosine phosphorylation), synapse elimination (C-terminal domain-dependent cholinergic disassembly), macrophage inflammatory programming (N-terminal domain-dependent TLR4/TBK1/IRF3/STAT1 and NLRP3 pathways), cardiomyocyte contraction (via integrin-linked kinase), and cancer cell invasion (through ILK/AKT/MMP-2 and HSP27 signaling); loss of SPARC in mice produces cataracts, collagen assembly defects in multiple tissues, impaired insulin secretion, and altered microglial morphology and proliferation."},"narrative":{"mechanistic_narrative":"SPARC is a secreted, multidomain matricellular glycoprotein that organizes the extracellular matrix and tunes cell behavior by binding structural collagens and modulating growth-factor and integrin signaling [PMID:18487610, PMID:9792673]. Its extracellular calcium-binding (EC) module carries two cooperative, high-affinity EF-hands and engages fibrillar collagens I, II, and III through a triple-helical recognition site located in helix αA, which is partially masked by helix αC; removal of αC raises collagen affinity ~10-fold, while the neighboring follistatin-like (FS) module folds against the EC domain and is required for biosynthesis and secretion [PMID:10801822, PMID:11223341, PMID:11102747, PMID:18487610]. Collagen binding requires intact triple-helical conformation and is tuned by glycoform, with high-mannose SPARC binding collagen I more avidly than complex-type [PMID:18487610, PMID:15044389]; consistent with a structural role in matrix assembly, SPARC delays fibrillogenesis in vitro and its loss in mice causes collagen-assembly defects and mechanically weak tendons and cataract from impaired lens fiber differentiation [PMID:18487610, PMID:27586416, PMID:9856777]. SPARC also acts as a soluble ligand-binding regulator: it directly binds VEGF, reducing receptor engagement and attenuating ERK1/2 signaling [PMID:9792673], and binds the synaptic organizers neurexin and neuroligin through its FS domain, competing with hevin to antagonize synaptogenesis, while a distinct C-terminal activity drives disassembly of cholinergic synapses [PMID:33535026, PMID:26420865]. Through integrin engagement SPARC activates ILK/AKT signaling that supports cardiomyocyte contraction and cancer cell invasion via MMP-2 and p38/HSP27 pathways [PMID:30933983, PMID:32780451, PMID:23382286]. In innate immunity, the N-terminal acidic domain of SPARC drives a TLR4–TBK1–IRF3–STAT1 interferon-stimulated gene program and primes the NLRP3 inflammasome, and adipocyte- or cell-specific SPARC deletion reduces inflammation and improves metabolic healthspan [PMID:35963236, PMID:37781916]. Additional context-specific roles include regulation of endothelial paracellular permeability via β-catenin/paxillin tyrosine phosphorylation, promotion of glucose-stimulated insulin secretion through RGS4 down-regulation, and intracellular stabilization of ApoE by blocking its TRIM21-mediated ubiquitylation [PMID:9790954, PMID:33067534, PMID:38471084].","teleology":[{"year":1992,"claim":"Established SPARC as an albumin-binding protein immunologically and functionally related to the endothelial glycoprotein gp60, linking it to vascular albumin handling before its structural mechanism was known.","evidence":"Antibody cross-reactivity and reciprocal competitive albumin-binding assays in microvascular endothelial cells","pmids":["1481911"],"confidence":"Medium","gaps":["Shared albumin-binding domain not mapped at residue level","Functional consequence for transcytosis not directly demonstrated"]},{"year":1998,"claim":"Defined a direct ligand-sequestration mechanism whereby SPARC binds VEGF and dampens receptor signaling, explaining its anti-proliferative effect on endothelium.","evidence":"125I-VEGF binding, ERK1/2 phosphorylation Western blot, and SPARC domain peptide competition in human microvascular endothelial cells","pmids":["9792673"],"confidence":"High","gaps":["Binding stoichiometry and affinity to VEGF not quantified","Whether the same domains mediate effects on other growth factors untested"]},{"year":1998,"claim":"Demonstrated SPARC actively disrupts endothelial barriers through a tyrosine-phosphorylation signaling cascade rather than passive matrix effects, identifying β-catenin and paxillin as substrates.","evidence":"Macromolecular flux assay with phosphotyrosine immunoblot and pharmacologic kinase/phosphatase epistasis","pmids":["9790954"],"confidence":"Medium","gaps":["Kinase responsible for substrate phosphorylation not identified","Receptor mediating SPARC signaling not defined"]},{"year":1998,"claim":"Provided in vivo genetic evidence that SPARC is essential for tissue homeostasis, with knockout causing early lens fiber degeneration and cataract.","evidence":"Targeted gene disruption mouse with slit-lamp and histological analysis","pmids":["9856777"],"confidence":"High","gaps":["Molecular link between SPARC loss and fiber differentiation failure not resolved","Does not establish collagen-dependence of the cataract phenotype"]},{"year":2000,"claim":"Resolved the biochemical role of the EC EF-hands as Ca2+-saturated structural elements that also stabilize the FS domain and are required for folding and secretion.","evidence":"Ca2+-binding assays, deletion mutagenesis, secretion assays and thermodynamic analysis","pmids":["10801822"],"confidence":"High","gaps":["Does not address EF-hand role in ligand binding directly","ER/Golgi processing steps not visualized"]},{"year":2001,"claim":"Solved the FS-EC crystal structure and located the collagen-binding site in helix αA, revealing an autoinhibitory mask (helix αC) controlling collagen affinity.","evidence":"Protein crystallography with site-directed mutagenesis and collagen-binding assays","pmids":["11223341","11102747"],"confidence":"High","gaps":["Trigger that relieves αC masking in vivo unknown","Full-length structure including the acidic N-terminus not determined"]},{"year":2004,"claim":"Showed that tissue-specific N-glycosylation tunes SPARC collagen affinity, adding a post-translational layer to its matrix function.","evidence":"Glycosidase digestion, HPLC glycan analysis and SPR collagen-binding measurements across glycoforms","pmids":["15044389"],"confidence":"High","gaps":["Physiological consequence of glycoform differences in vivo untested","Glycosylation site responsible not pinpointed functionally"]},{"year":2008,"claim":"Mapped the collagen-binding interaction to a defined conserved triple-helical sequence and demonstrated conformational and lysine-modification dependence, establishing SPARC's direct role in fibrillogenesis.","evidence":"EM, CNBr and synthetic triple-helical peptide binding, SPR, and in vitro fibrillogenesis assays","pmids":["18487610"],"confidence":"High","gaps":["Effect on fibril architecture in vivo at the molecular level not shown","How delayed fibrillogenesis translates to tissue assembly unresolved"]},{"year":2006,"claim":"Linked SPARC to epithelial-mesenchymal transition by showing it transcriptionally induces Snail to repress E-cadherin, providing a mechanism for pro-invasive activity.","evidence":"Overexpression/siRNA with RT-PCR, Western blot and invasion assays in melanocytes","pmids":["16885349"],"confidence":"Medium","gaps":["Receptor/signal coupling SPARC to Snail induction not defined","Single cell-type context"]},{"year":2011,"claim":"Positioned SPARC within fibrosis as a cell-type-specific effector—required in fibroblasts for collagen deposition but in macrophages for limiting TGF-β-driven TNF and inflammation.","evidence":"Reciprocal bone marrow chimeras and CD68-driven dominant-negative TGF-β receptor in bleomycin lung fibrosis","pmids":["22001347"],"confidence":"High","gaps":["Molecular receptor mediating macrophage TNF suppression not identified","Direct demonstration of SPARC-collagen processing in vivo not shown"]},{"year":2009,"claim":"Identified SPARC as a tumor- and stroma-derived suppressor of cancer-associated inflammation, with loss accelerating urothelial carcinogenesis via NF-κB/AP1.","evidence":"Sparc-/- carcinogenesis and syngeneic transplant models with NF-κB/AP1 reporters","pmids":["23321672"],"confidence":"Medium","gaps":["Direct SPARC target controlling NF-κB/AP1 not defined","Reconciliation with pro-inflammatory roles elsewhere not addressed"]},{"year":2012,"claim":"Established SPARC as a translationally regulated effector downstream of β4 integrin (via miR-29a and TOR) promoting carcinoma invasion.","evidence":"miR-29a manipulation, β4 integrin knockdown/overexpression, TOR inhibition and Matrigel invasion assays","pmids":["22308039"],"confidence":"Medium","gaps":["Direct miR-29a binding to SPARC mRNA not shown in these cells","Single cancer context"]},{"year":2013,"claim":"Connected SPARC to invasion via P38 MAPK/MAPKAPK2/HSP27 signaling, antagonized by PTEN, defining a kinase cascade for glioma migration.","evidence":"SPARC/PTEN co-transfection with signaling time-course Western blots and migration assays","pmids":["23382286"],"confidence":"Medium","gaps":["Upstream receptor coupling SPARC to p38 not identified","Single cell line context"]},{"year":2013,"claim":"Defined a CNS role for SPARC in shaping microglial morphology and proliferation, with rescue confirming a direct SPARC-dependent effect.","evidence":"SPARC-null/CX3CR1-GFP mice, lesion models, and in vitro proliferation assay with exogenous SPARC rescue","pmids":["23467362"],"confidence":"Medium","gaps":["Receptor mediating microglial responses unknown","Mechanism linking SPARC to proliferation control unresolved"]},{"year":2015,"claim":"Mapped a C-terminal-domain activity of astrocyte-derived SPARC that triggers cholinergic synapse disassembly, validated by in vivo neuromuscular junction elimination.","evidence":"Autaptic microculture, domain peptide application, and in vivo Xenopus peptide injection with behavioral readout","pmids":["26420865"],"confidence":"High","gaps":["Receptor for the C-terminal disassembly signal not identified","Relationship to neurexin/neuroligin binding not yet integrated"]},{"year":2021,"claim":"Defined the structural basis of SPARC's antagonism of synaptogenesis, showing FS-domain binding to neurexin/neuroligin competes with hevin.","evidence":"Crystal structure of hevin FS-EC with nanomolar binding measurements and competitive binding/domain analysis","pmids":["33535026"],"confidence":"High","gaps":["In vivo demonstration of competition at synapses not shown","Relation to C-terminal synapse-elimination activity not unified"]},{"year":2022,"claim":"Identified the N-terminal acidic domain as the driver of a TLR4–TBK1–IRF3–STAT1 interferon program in macrophages, tying SPARC to metabolic inflammation and aging.","evidence":"Recombinant SPARC and domain-deletion treatment of macrophages, TLR4/MyD88 epistasis, metabolic assays and adipocyte-specific conditional knockout","pmids":["35963236"],"confidence":"High","gaps":["Direct SPARC-TLR4 binding interface not resolved","Link between dampened mitochondrial respiration and ISG induction mechanistically incomplete"]},{"year":2023,"claim":"Extended SPARC's innate-immune role to NLRP3 inflammasome priming via JNK, with genetic deletion protecting against diet-induced metabolic dysfunction.","evidence":"Inducible knockdown, adipocyte-specific knockout, NLRP3 assays, JNK Western blot and metabolic phenotyping","pmids":["37781916"],"confidence":"High","gaps":["Receptor coupling SPARC to JNK not defined","Relationship to the TLR4/IRF3 program not integrated"]},{"year":2019,"claim":"Demonstrated a direct inotropic role for extracellular SPARC acting through integrin-β1/ILK on the cardiomyocyte membrane.","evidence":"Ex vivo cardiomyocyte shortening with recombinant SPARC, in vivo function and integrin/ILK co-localization","pmids":["30933983"],"confidence":"Medium","gaps":["Direct integrin binding not biochemically demonstrated here","Downstream contractile machinery target unknown"]},{"year":2016,"claim":"Revealed an intracellular role for SPARC in stabilizing ApoE by competitively blocking TRIM21-mediated ubiquitylation, driving cholesterol-dependent PI3K-AKT signaling and EMT.","evidence":"Reciprocal Co-IP, competitive binding and ubiquitylation assays with siRNA in HCC cells","pmids":["38471084"],"confidence":"Medium","gaps":["How a normally secreted protein accesses the cytosolic TRIM21 pathway unresolved","Single tumor context"]},{"year":2020,"claim":"Defined a beta-cell role for SPARC promoting glucose-stimulated insulin secretion by PI3K-dependent down-regulation of the M3 receptor inhibitor RGS4.","evidence":"Overexpression/knockdown in Min6, PI3K inhibitor epistasis, islet secretion assays and Sparc-/- mice","pmids":["33067534"],"confidence":"Medium","gaps":["Receptor coupling secreted SPARC to PI3K in beta cells unknown","Mechanism of RGS4 transcriptional control unresolved"]},{"year":null,"claim":"The receptor(s) transducing secreted SPARC signaling across its many contexts and how a single protein reconciles pro- versus anti-inflammatory and tumor-suppressive versus pro-invasive roles remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying receptor identified despite integrin, TLR4 and synaptic-organizer interactions reported","Domain- and isoform-specific activities not integrated into one structural model","Context-dependent opposing phenotypes not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,21,15]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,2,18]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[0,15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,11,28]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[3,29]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[20,29]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[3,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,14,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,20,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[26,22,8]}],"complexes":[],"partners":["VEGF","COL1A1","NRXN","NLGN","ITGB1","APOE","PRKAA1","ITGB4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P09486","full_name":"SPARC","aliases":["Basement-membrane protein 40","BM-40","Osteonectin","ON","Secreted protein acidic and rich in cysteine"],"length_aa":303,"mass_kda":34.6,"function":"Appears to regulate cell growth through interactions with the extracellular matrix and cytokines. Binds calcium and copper, several types of collagen, albumin, thrombospondin, PDGF and cell membranes. There are two calcium binding sites; an acidic domain that binds 5 to 8 Ca(2+) with a low affinity and an EF-hand loop that binds a Ca(2+) ion with a high affinity","subcellular_location":"Secreted, extracellular space, extracellular matrix, basement membrane","url":"https://www.uniprot.org/uniprotkb/P09486/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPARC","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/SPARC","total_profiled":1310},"omim":[{"mim_id":"616507","title":"OSTEOGENESIS IMPERFECTA, TYPE XVII; OI17","url":"https://www.omim.org/entry/616507"},{"mim_id":"611258","title":"TUDOR DOMAIN-CONTAINING PROTEIN 7; TDRD7","url":"https://www.omim.org/entry/611258"},{"mim_id":"610354","title":"RIC1 HOMOLOG, RAB6A GEF COMPLEX PARTNER 1; RIC1","url":"https://www.omim.org/entry/610354"},{"mim_id":"608488","title":"SPARC-RELATED MODULAR CALCIUM-BINDING PROTEIN 1; SMOC1","url":"https://www.omim.org/entry/608488"},{"mim_id":"607989","title":"SPARC/OSTEONECTIN, CWCV, AND KAZAL-LIKE DOMAINS PROTEOGLYCAN 3; SPOCK3","url":"https://www.omim.org/entry/607989"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPARC"},"hgnc":{"alias_symbol":["ONT","BM-40"],"prev_symbol":["ON"]},"alphafold":{"accession":"P09486","domains":[{"cath_id":"3.30.60.30","chopping":"80-145","consensus_level":"high","plddt":96.7252,"start":80,"end":145},{"cath_id":"1.10.238.10","chopping":"156-300","consensus_level":"high","plddt":97.0607,"start":156,"end":300}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09486","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09486-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09486-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPARC","jax_strain_url":"https://www.jax.org/strain/search?query=SPARC"},"sequence":{"accession":"P09486","fasta_url":"https://rest.uniprot.org/uniprotkb/P09486.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09486/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09486"}},"corpus_meta":[{"pmid":"11223341","id":"PMC_11223341","title":"SPARC, a matricellular protein: at the crossroads of cell-matrix communication.","date":"2001","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11223341","citation_count":453,"is_preprint":false},{"pmid":"8119487","id":"PMC_8119487","title":"The biology of SPARC, a protein that modulates cell-matrix interactions.","date":"1994","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/8119487","citation_count":453,"is_preprint":false},{"pmid":"17235047","id":"PMC_17235047","title":"Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma.","date":"2007","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/17235047","citation_count":340,"is_preprint":false},{"pmid":"10567433","id":"PMC_10567433","title":"SPARC, a matricellular glycoprotein with important biological functions.","date":"1999","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/10567433","citation_count":298,"is_preprint":false},{"pmid":"11102747","id":"PMC_11102747","title":"SPARC, a matricellular protein: at the crossroads of cell-matrix.","date":"2000","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/11102747","citation_count":252,"is_preprint":false},{"pmid":"26851678","id":"PMC_26851678","title":"SPARC/osteonectin in mineralized tissue.","date":"2016","source":"Matrix biology : journal of the International Society for Matrix Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26851678","citation_count":231,"is_preprint":false},{"pmid":"9792673","id":"PMC_9792673","title":"SPARC (BM-40, osteonectin) inhibits the mitogenic effect of vascular endothelial growth factor on microvascular endothelial cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9792673","citation_count":231,"is_preprint":false},{"pmid":"22249026","id":"PMC_22249026","title":"Diverse biological functions of the SPARC family of proteins.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22249026","citation_count":215,"is_preprint":false},{"pmid":"15211566","id":"PMC_15211566","title":"SPARC and tumor growth: where the seed meets the soil?","date":"2004","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15211566","citation_count":205,"is_preprint":false},{"pmid":"8245406","id":"PMC_8245406","title":"Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization.","date":"1993","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/8245406","citation_count":199,"is_preprint":false},{"pmid":"18849185","id":"PMC_18849185","title":"SPARC in cancer biology: its role in cancer progression and potential for therapy.","date":"2008","source":"Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/18849185","citation_count":196,"is_preprint":false},{"pmid":"9856777","id":"PMC_9856777","title":"SPARC deficiency leads to early-onset cataractogenesis.","date":"1998","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/9856777","citation_count":172,"is_preprint":false},{"pmid":"3758028","id":"PMC_3758028","title":"Developmental and transformation-sensitive expression of the Sparc gene on mouse chromosome 11.","date":"1986","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/3758028","citation_count":172,"is_preprint":false},{"pmid":"20195270","id":"PMC_20195270","title":"SPARC: a key player in the pathologies associated with obesity and diabetes.","date":"2010","source":"Nature reviews. Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/20195270","citation_count":158,"is_preprint":false},{"pmid":"16885349","id":"PMC_16885349","title":"SPARC represses E-cadherin and induces mesenchymal transition during melanoma development.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16885349","citation_count":143,"is_preprint":false},{"pmid":"19958839","id":"PMC_19958839","title":"Modulation of matrix remodeling by SPARC in neoplastic progression.","date":"2009","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/19958839","citation_count":121,"is_preprint":false},{"pmid":"24675529","id":"PMC_24675529","title":"Molecular mechanisms underlying the divergent roles of SPARC in human carcinogenesis.","date":"2014","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24675529","citation_count":119,"is_preprint":false},{"pmid":"35963236","id":"PMC_35963236","title":"The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging.","date":"2022","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/35963236","citation_count":106,"is_preprint":false},{"pmid":"17384023","id":"PMC_17384023","title":"Is SPARC an evolutionarily conserved collagen chaperone?","date":"2007","source":"Journal of dental research","url":"https://pubmed.ncbi.nlm.nih.gov/17384023","citation_count":103,"is_preprint":false},{"pmid":"21867537","id":"PMC_21867537","title":"DNA methylation of SPARC and chronic low back pain.","date":"2011","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/21867537","citation_count":102,"is_preprint":false},{"pmid":"10641790","id":"PMC_10641790","title":"SPARC (osteonectin/BM-40).","date":"1999","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10641790","citation_count":99,"is_preprint":false},{"pmid":"23690170","id":"PMC_23690170","title":"Stromal expression of SPARC in pancreatic adenocarcinoma.","date":"2013","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/23690170","citation_count":95,"is_preprint":false},{"pmid":"16103089","id":"PMC_16103089","title":"Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis.","date":"2005","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16103089","citation_count":95,"is_preprint":false},{"pmid":"3400777","id":"PMC_3400777","title":"Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane.","date":"1988","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/3400777","citation_count":93,"is_preprint":false},{"pmid":"1653704","id":"PMC_1653704","title":"Recombinant expression and properties of the human calcium-binding extracellular matrix protein BM-40.","date":"1991","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1653704","citation_count":93,"is_preprint":false},{"pmid":"27422817","id":"PMC_27422817","title":"Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27422817","citation_count":89,"is_preprint":false},{"pmid":"8773299","id":"PMC_8773299","title":"Regulation of angiogenesis by SPARC and angiostatin: implications for tumor cell biology.","date":"1996","source":"Seminars in cancer biology","url":"https://pubmed.ncbi.nlm.nih.gov/8773299","citation_count":86,"is_preprint":false},{"pmid":"19577572","id":"PMC_19577572","title":"Cardiac extracellular matrix remodeling: fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC).","date":"2009","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/19577572","citation_count":86,"is_preprint":false},{"pmid":"1481911","id":"PMC_1481911","title":"Antibodies to SPARC inhibit albumin binding to SPARC, gp60, and microvascular endothelium.","date":"1992","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/1481911","citation_count":85,"is_preprint":false},{"pmid":"15094114","id":"PMC_15094114","title":"Hevin/SC1, a matricellular glycoprotein and potential tumor-suppressor of the SPARC/BM-40/Osteonectin family.","date":"2004","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15094114","citation_count":84,"is_preprint":false},{"pmid":"7875683","id":"PMC_7875683","title":"Expression of SPARC in normal and fibrotic livers.","date":"1995","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/7875683","citation_count":84,"is_preprint":false},{"pmid":"21822645","id":"PMC_21822645","title":"The regulatory function of SPARC in vascular biology.","date":"2011","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/21822645","citation_count":83,"is_preprint":false},{"pmid":"23321672","id":"PMC_23321672","title":"Loss of SPARC in bladder cancer enhances carcinogenesis and progression.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23321672","citation_count":79,"is_preprint":false},{"pmid":"38323081","id":"PMC_38323081","title":"GP60 and SPARC as albumin receptors: key targeted sites for the delivery of antitumor drugs.","date":"2024","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38323081","citation_count":77,"is_preprint":false},{"pmid":"18487610","id":"PMC_18487610","title":"Mapping of SPARC/BM-40/osteonectin-binding sites on fibrillar collagens.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18487610","citation_count":74,"is_preprint":false},{"pmid":"17029219","id":"PMC_17029219","title":"SPARC and Hevin expression correlate with tumour angiogenesis in hepatocellular carcinoma.","date":"2006","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/17029219","citation_count":71,"is_preprint":false},{"pmid":"24947586","id":"PMC_24947586","title":"SPARC in Tumor Pathophysiology and as a Potential Therapeutic Target.","date":"2014","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/24947586","citation_count":67,"is_preprint":false},{"pmid":"12489175","id":"PMC_12489175","title":"Novel functions of the matricellular proteins osteopontin and osteonectin/SPARC.","date":"2002","source":"Connective tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/12489175","citation_count":67,"is_preprint":false},{"pmid":"18796407","id":"PMC_18796407","title":"Secreted protein acidic and rich in cysteine (SPARC) in human skeletal muscle.","date":"2008","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/18796407","citation_count":67,"is_preprint":false},{"pmid":"21339733","id":"PMC_21339733","title":"TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21339733","citation_count":66,"is_preprint":false},{"pmid":"21237573","id":"PMC_21237573","title":"Anti-cancer role of SPARC, an inhibitor of adipogenesis.","date":"2011","source":"Cancer treatment reviews","url":"https://pubmed.ncbi.nlm.nih.gov/21237573","citation_count":64,"is_preprint":false},{"pmid":"10861485","id":"PMC_10861485","title":"Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein SPARC.","date":"2000","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/10861485","citation_count":62,"is_preprint":false},{"pmid":"18366138","id":"PMC_18366138","title":"SPARC is expressed by macroglia and microglia in the developing and mature nervous system.","date":"2008","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/18366138","citation_count":59,"is_preprint":false},{"pmid":"23467362","id":"PMC_23467362","title":"SPARC regulates microgliosis and functional recovery following cortical ischemia.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23467362","citation_count":58,"is_preprint":false},{"pmid":"22001347","id":"PMC_22001347","title":"SPARC oppositely regulates inflammation and fibrosis in bleomycin-induced lung damage.","date":"2011","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/22001347","citation_count":58,"is_preprint":false},{"pmid":"20215880","id":"PMC_20215880","title":"KLF4 inhibition of lung cancer cell invasion by suppression of SPARC expression.","date":"2010","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/20215880","citation_count":57,"is_preprint":false},{"pmid":"9199668","id":"PMC_9199668","title":"Cloning and expression of murine SC1, a gene product homologous to SPARC.","date":"1997","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/9199668","citation_count":55,"is_preprint":false},{"pmid":"24038053","id":"PMC_24038053","title":"Role of SPARC in bone remodeling and cancer-related bone metastasis.","date":"2014","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24038053","citation_count":54,"is_preprint":false},{"pmid":"30426491","id":"PMC_30426491","title":"Pre-eclampsia onset and SPARC: A possible involvement in placenta development.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30426491","citation_count":54,"is_preprint":false},{"pmid":"35175782","id":"PMC_35175782","title":"SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension.","date":"2022","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/35175782","citation_count":53,"is_preprint":false},{"pmid":"24590286","id":"PMC_24590286","title":"SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome.","date":"2014","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/24590286","citation_count":52,"is_preprint":false},{"pmid":"20460104","id":"PMC_20460104","title":"SPARC interacts with AMPK and regulates GLUT4 expression.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20460104","citation_count":52,"is_preprint":false},{"pmid":"25331979","id":"PMC_25331979","title":"SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations.","date":"2014","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25331979","citation_count":51,"is_preprint":false},{"pmid":"29522370","id":"PMC_29522370","title":"Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis.","date":"2018","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29522370","citation_count":49,"is_preprint":false},{"pmid":"26420865","id":"PMC_26420865","title":"SPARC triggers a cell-autonomous program of synapse elimination.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26420865","citation_count":46,"is_preprint":false},{"pmid":"10801822","id":"PMC_10801822","title":"Calcium affinity, cooperativity, and domain interactions of extracellular EF-hands present in BM-40.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10801822","citation_count":45,"is_preprint":false},{"pmid":"18784957","id":"PMC_18784957","title":"Sparc protein is required for normal growth of zebrafish otoliths.","date":"2008","source":"Journal of the Association for Research in Otolaryngology : JARO","url":"https://pubmed.ncbi.nlm.nih.gov/18784957","citation_count":45,"is_preprint":false},{"pmid":"15044389","id":"PMC_15044389","title":"Structural variability of BM-40/SPARC/osteonectin glycosylation: implications for collagen affinity.","date":"2004","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/15044389","citation_count":44,"is_preprint":false},{"pmid":"26582465","id":"PMC_26582465","title":"The role of secreted protein acidic and rich in cysteine (SPARC) in cardiac repair and fibrosis: Does expression of SPARC by macrophages influence outcomes?","date":"2015","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/26582465","citation_count":43,"is_preprint":false},{"pmid":"19212676","id":"PMC_19212676","title":"Downregulation of SPARC expression inhibits cell migration and invasion in malignant gliomas.","date":"2009","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19212676","citation_count":41,"is_preprint":false},{"pmid":"27586416","id":"PMC_27586416","title":"Pleiotropic roles of the matricellular protein Sparc in tendon maturation and ageing.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27586416","citation_count":41,"is_preprint":false},{"pmid":"18949063","id":"PMC_18949063","title":"Increased SPARC expression in primary angle closure glaucoma iris.","date":"2008","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/18949063","citation_count":40,"is_preprint":false},{"pmid":"38471084","id":"PMC_38471084","title":"SPARC Stabilizes ApoE to Induce Cholesterol-Dependent Invasion and Sorafenib Resistance in Hepatocellular Carcinoma.","date":"2024","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/38471084","citation_count":39,"is_preprint":false},{"pmid":"22308039","id":"PMC_22308039","title":"Integrin β4 regulates SPARC protein to promote invasion.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22308039","citation_count":38,"is_preprint":false},{"pmid":"25765175","id":"PMC_25765175","title":"The role of SPARC expression in pancreatic cancer progression and patient survival.","date":"2015","source":"Scandinavian journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25765175","citation_count":37,"is_preprint":false},{"pmid":"22222271","id":"PMC_22222271","title":"Involvement of SPARC and MMP-3 in the pathogenesis of human pterygium.","date":"2012","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/22222271","citation_count":37,"is_preprint":false},{"pmid":"22939997","id":"PMC_22939997","title":"SPARC and DNA methylation: possible diagnostic and therapeutic implications in gastrointestinal cancers.","date":"2012","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/22939997","citation_count":36,"is_preprint":false},{"pmid":"32780451","id":"PMC_32780451","title":"SPARC is a key mediator of TGF-β-induced renal cancer metastasis.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32780451","citation_count":36,"is_preprint":false},{"pmid":"30626728","id":"PMC_30626728","title":"SPARC is required for the maintenance of glucose homeostasis and insulin secretion in mice.","date":"2019","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/30626728","citation_count":36,"is_preprint":false},{"pmid":"20525171","id":"PMC_20525171","title":"Downregulation of SPARC expression decreases gastric cancer cellular invasion and survival.","date":"2010","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/20525171","citation_count":35,"is_preprint":false},{"pmid":"10880278","id":"PMC_10880278","title":"Expression and characterization of SPARC in human lens and in the aqueous and vitreous humors.","date":"2000","source":"Experimental eye research","url":"https://pubmed.ncbi.nlm.nih.gov/10880278","citation_count":34,"is_preprint":false},{"pmid":"23418755","id":"PMC_23418755","title":"Testican-3: a brain-specific proteoglycan member of the BM-40/SPARC/osteonectin family.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23418755","citation_count":34,"is_preprint":false},{"pmid":"26839388","id":"PMC_26839388","title":"SPARC-Dependent Cardiomyopathy in Drosophila.","date":"2016","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26839388","citation_count":32,"is_preprint":false},{"pmid":"9790954","id":"PMC_9790954","title":"The counteradhesive protein SPARC regulates an endothelial paracellular pathway through protein tyrosine phosphorylation.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9790954","citation_count":32,"is_preprint":false},{"pmid":"29449802","id":"PMC_29449802","title":"SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury.","date":"2018","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29449802","citation_count":32,"is_preprint":false},{"pmid":"3384223","id":"PMC_3384223","title":"Expression of SPARC/osteonectin transcript in murine embryos and gonads.","date":"1988","source":"Differentiation; research in biological diversity","url":"https://pubmed.ncbi.nlm.nih.gov/3384223","citation_count":31,"is_preprint":false},{"pmid":"20338068","id":"PMC_20338068","title":"Methylation of the SPARC gene promoter and its clinical implication in pancreatic cancer.","date":"2010","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/20338068","citation_count":31,"is_preprint":false},{"pmid":"32417569","id":"PMC_32417569","title":"Regulation of SPARC family proteins in disorders of the central nervous system.","date":"2020","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/32417569","citation_count":30,"is_preprint":false},{"pmid":"11032756","id":"PMC_11032756","title":"Expression and purification of recombinant human SPARC produced by baculovirus.","date":"2000","source":"Molecular cell biology research communications : MCBRC","url":"https://pubmed.ncbi.nlm.nih.gov/11032756","citation_count":29,"is_preprint":false},{"pmid":"33535026","id":"PMC_33535026","title":"Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges.","date":"2021","source":"Structure (London, England : 1993)","url":"https://pubmed.ncbi.nlm.nih.gov/33535026","citation_count":29,"is_preprint":false},{"pmid":"37781916","id":"PMC_37781916","title":"Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.","date":"2023","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/37781916","citation_count":28,"is_preprint":false},{"pmid":"34912848","id":"PMC_34912848","title":"SPARC Overexpression Promotes Liver Cancer Cell Proliferation and Tumor Growth.","date":"2021","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/34912848","citation_count":28,"is_preprint":false},{"pmid":"30933983","id":"PMC_30933983","title":"Extracellular SPARC increases cardiomyocyte contraction during health and disease.","date":"2019","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30933983","citation_count":28,"is_preprint":false},{"pmid":"25516351","id":"PMC_25516351","title":"Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer.","date":"2014","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25516351","citation_count":28,"is_preprint":false},{"pmid":"31554208","id":"PMC_31554208","title":"Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31554208","citation_count":28,"is_preprint":false},{"pmid":"27339669","id":"PMC_27339669","title":"Osteonectin (SPARC) Expression in Vascular Calcification: In Vitro and Ex Vivo Studies.","date":"2016","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/27339669","citation_count":27,"is_preprint":false},{"pmid":"26381424","id":"PMC_26381424","title":"Proteolytic Isoforms of SPARC Induce Adipose Stromal Cell Mobilization in Obesity.","date":"2015","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/26381424","citation_count":27,"is_preprint":false},{"pmid":"23382286","id":"PMC_23382286","title":"PTEN suppresses SPARC-induced pMAPKAPK2 and inhibits SPARC-induced Ser78 HSP27 phosphorylation in glioma.","date":"2013","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23382286","citation_count":25,"is_preprint":false},{"pmid":"16685412","id":"PMC_16685412","title":"The differential expression of SPARC in esophageal squamous cell carcinoma.","date":"2006","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16685412","citation_count":25,"is_preprint":false},{"pmid":"21962567","id":"PMC_21962567","title":"The matricellular protein SPARC supports follicular dendritic cell networking toward Th17 responses.","date":"2011","source":"Journal of autoimmunity","url":"https://pubmed.ncbi.nlm.nih.gov/21962567","citation_count":25,"is_preprint":false},{"pmid":"37577749","id":"PMC_37577749","title":"SPARC: a potential target for functional nanomaterials and drugs.","date":"2023","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/37577749","citation_count":24,"is_preprint":false},{"pmid":"26983777","id":"PMC_26983777","title":"The 'SPARC' of life: Analysis of the role of osteonectin/SPARC in pancreatic cancer (Review).","date":"2016","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26983777","citation_count":24,"is_preprint":false},{"pmid":"36241137","id":"PMC_36241137","title":"Increased Sparc release from subchondral osteoblasts promotes articular chondrocyte degeneration under estrogen withdrawal.","date":"2022","source":"Osteoarthritis and cartilage","url":"https://pubmed.ncbi.nlm.nih.gov/36241137","citation_count":23,"is_preprint":false},{"pmid":"33067534","id":"PMC_33067534","title":"SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic β cells.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33067534","citation_count":23,"is_preprint":false},{"pmid":"30332737","id":"PMC_30332737","title":"SPARC Inhibits Metabolic Plasticity in Ovarian Cancer.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/30332737","citation_count":23,"is_preprint":false},{"pmid":"35208200","id":"PMC_35208200","title":"Secreted Protein Acidic and Rich in Cysteine (Sparc) KO Leads to an Accelerated Ageing Phenotype Which Is Improved by Exercise Whereas SPARC Overexpression Mimics Exercise Effects in Mice.","date":"2022","source":"Metabolites","url":"https://pubmed.ncbi.nlm.nih.gov/35208200","citation_count":23,"is_preprint":false},{"pmid":"32723563","id":"PMC_32723563","title":"SPARC-p53: The double agents of cancer.","date":"2020","source":"Advances in cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/32723563","citation_count":22,"is_preprint":false},{"pmid":"25356037","id":"PMC_25356037","title":"SIBLINGs and SPARC families: their emerging roles in pancreatic cancer.","date":"2014","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/25356037","citation_count":22,"is_preprint":false},{"pmid":"32057945","id":"PMC_32057945","title":"Secreted protein acidic and rich in cysteine (SPARC) regulates thermogenesis in white and brown adipocytes.","date":"2020","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32057945","citation_count":18,"is_preprint":false},{"pmid":"36351772","id":"PMC_36351772","title":"Sequencing Illumina libraries at high accuracy on the ONT MinION using R2C2.","date":"2022","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/36351772","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46546,"output_tokens":8296,"usd":0.132039,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18179,"output_tokens":6162,"usd":0.122472,"stage2_stop_reason":"end_turn"},"total_usd":0.254511,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"SPARC inhibits VEGF-stimulated DNA synthesis in human microvascular endothelial cells by directly binding VEGF, reducing VEGF association with its cell-surface receptors, and attenuating ERK1/2 tyrosine phosphorylation. Peptides from domain IV (EF-hand/EC module) and domain II (follistatin-like) mimicked these inhibitory effects; domains I and III had no effect.\",\n      \"method\": \"DNA synthesis assay, 125I-VEGF binding/radioimmune precipitation, Western blot for ERK1/2 phosphorylation, SPARC domain peptide competition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods (binding assay, signaling readout, peptide domain mapping) in a single focused study\",\n      \"pmids\": [\"9792673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The extracellular calcium-binding (EC) domain of SPARC/BM-40 contains two EF-hands that bind Ca2+ cooperatively and with high affinity; under physiological extracellular Ca2+ concentrations the EF-hands are saturated, suggesting a structural rather than regulatory role. There is a strong interaction (~10 kJ/mol free energy contribution) between the EC domain and the neighboring follistatin-like (FS) domain, primarily through the variant EF-hand 1. Certain mutations of Ca2+-coordinating residues inhibited folding and secretion, indicating a role for EF-hands during biosynthesis/processing in the ER or Golgi.\",\n      \"method\": \"Ca2+ binding assays, deletion mutagenesis, mammalian cell secretion assay, thermodynamic analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with mutagenesis and thermodynamic measurements, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10801822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Crystal structure of two of the three SPARC domains revealed a novel follistatin-like (FS) module and an extracellular calcium-binding (EC) module containing two EF-hand motifs. The collagen-binding site resides in helix αA of the EC domain and is partially masked by helix αC; removal of αC causes a ~10-fold increase in collagen binding affinity.\",\n      \"method\": \"Protein crystallography, site-directed mutagenesis, collagen binding assays\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional mutagenesis, independently referenced across multiple review and primary papers in the corpus\",\n      \"pmids\": [\"11223341\", \"11102747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SPARC binds fibrillar collagens I, II, and III at specific triple-helical sites; a major binding site is located approximately 180 nm from the C-terminus of collagen. Binding requires triple-helical conformation (denaturation abolishes it). N-acetylation of Lys/Hyl side chains substantially decreases binding. A synthetic triple-helical peptide with sequence GPOGPSGPRGQOGVMGFOGPKGNDGAO (conserved in α-chains of collagens I, II, III, V) binds SPARC with affinity comparable to procollagen III. In vitro collagen fibrillogenesis is delayed in the presence of SPARC.\",\n      \"method\": \"Rotary shadowing/electron microscopy, CNBr peptide binding, synthetic triple-helical peptide binding, surface plasmon resonance, in vitro fibrillogenesis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical methods (EM, peptide mapping, SPR, fibrillogenesis) in one rigorous study\",\n      \"pmids\": [\"18487610\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"N-glycosylation of SPARC/BM-40 varies by tissue source (high-mannose in bone, complex-type in platelets/293 cells, hybrid in EHS tumor). SPARC carrying high-mannose N-glycans binds collagen I with higher affinity than complex-type glycoforms, as measured by surface plasmon resonance.\",\n      \"method\": \"Endoglycosidase/exoglycosidase digestion, HPLC glycan analysis, surface plasmon resonance collagen binding assay\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution with SPR quantification and detailed glycan characterization, single lab but rigorous\",\n      \"pmids\": [\"15044389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Anti-SPARC antibodies cross-react with the endothelial albumin-binding glycoprotein gp60, and purified SPARC inhibits anti-SPARC IgG binding to gp60. Anti-SPARC IgG inhibits albumin binding to both SPARC and gp60 and reduces albumin binding to cultured microvascular endothelial cells. These results indicate SPARC and gp60 are functionally and immunologically related albumin-binding proteins sharing a common albumin-binding domain.\",\n      \"method\": \"Antibody cross-reactivity assay, competitive inhibition of albumin binding, cell-based albumin binding assay\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal inhibition assays and cell-based binding experiments, single lab with multiple methods\",\n      \"pmids\": [\"1481911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SPARC regulates endothelial paracellular permeability through a protein tyrosine phosphorylation-dependent signaling pathway. SPARC increases tyrosine phosphorylation (up to 12-fold) of endothelial proteins localized to intercellular boundaries, with β-catenin and paxillin identified as substrates. Tyrosine kinase inhibitors (herbimycin A, genistein) reversed SPARC-induced barrier dysfunction and intercellular gap formation; tyrosine phosphatase inhibitors enhanced barrier disruption.\",\n      \"method\": \"Macromolecular flux assay, phosphotyrosine Western blot/immunolocalization, pharmacologic kinase/phosphatase inhibition, substrate identification\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional barrier assay paired with substrate identification and pharmacologic epistasis, single lab\",\n      \"pmids\": [\"9790954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SPARC deficiency (targeted gene disruption) in mice leads to early-onset cataractogenesis beginning at 1.5 months, characterized by inhibition of normal lens fiber cell differentiation, fiber cell degeneration, vacuole formation, and cortex liquefaction, establishing that SPARC is essential for lens transparency maintenance.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), slit-lamp microscopy, histology\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, replicated/referenced across multiple independent papers in corpus\",\n      \"pmids\": [\"9856777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SPARC overexpression in normal human melanocytes induces mesenchymal transition with loss of E-cadherin and P-cadherin, increased mesenchymal markers, and enhanced motility/invasion. SPARC transcriptionally down-regulates E-cadherin by inducing the repressor Snail. Conversely, SPARC depletion up-regulates E-cadherin and reduces Snail levels.\",\n      \"method\": \"Overexpression and siRNA knockdown, RT-PCR, Western blot, cell morphology/motility assays, invasion assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function experiments with transcriptional readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16885349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SPARC interacts physically with AMPK alpha1 (identified by yeast two-hybrid screen and confirmed by co-immunoprecipitation of endogenous proteins in HepG2 cells and rat tissues). AMPK activation increases SPARC expression; SPARC siRNA reduces AICAR-stimulated AMPK phosphorylation. SPARC affects AMPK-mediated glucose metabolism through regulation of GLUT4 expression in L6 myocytes.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation of endogenous proteins, siRNA knockdown, Western blot for GLUT4 expression\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — yeast two-hybrid confirmed by co-IP of endogenous proteins in multiple tissues; functional follow-up with siRNA, single lab\",\n      \"pmids\": [\"20460104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In AML cells, SPARC expression is mediated by the SP1/NF-κB transactivation complex. Secreted SPARC activates the integrin-linked kinase/AKT (ILK/AKT) pathway, likely via integrin interaction, and subsequent β-catenin signaling involved in leukemia cell self-renewal. Pharmacologic inhibition of SP1/NF-κB reduces SPARC expression and leukemia growth.\",\n      \"method\": \"Reporter assays, Western blot for pathway activation, pharmacologic inhibition, murine AML models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway assays and pharmacologic epistasis, single lab\",\n      \"pmids\": [\"24590286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPARC, produced by astrocytes, triggers a cell-autonomous program of synapse elimination in cholinergic neurons. The effect resides in the C-terminal domain of SPARC and causes disassembly of stable cholinergic synapses in a concentration- and time-dependent manner, associated with retracted axon terminals containing multivesicular bodies and secondary lysosomes. In vivo injection of SPARC-derived peptide 4.2 into Xenopus tropicalis tadpole tails caused massive elimination of neuromuscular junctions and impaired swimming.\",\n      \"method\": \"Single-cell autaptic microculture assay, domain peptide application, in vivo peptide injection with behavioral and morphological readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain-specific reconstitution in vitro validated by in vivo injection with defined cellular and behavioral phenotypes\",\n      \"pmids\": [\"26420865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SPARC regulates microglial proliferation and morphology. In SPARC-null/CX3CR1-GFP reporter mice, mature microglia show altered distribution and branching. Following ischemic lesion, reactive microglia rapidly downregulate SPARC while perilesional astrocytes upregulate it. Microglia from SPARC-null mice proliferate at a greater rate in vitro, an effect rescued by exogenous SPARC addition.\",\n      \"method\": \"SPARC-null reporter mice, in vivo lesion models, in vitro microglial proliferation assay with SPARC rescue\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO phenotype confirmed by exogenous rescue experiment, single lab\",\n      \"pmids\": [\"23467362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPARC induces an inflammatory, interferon-stimulated gene (ISG) expression program in macrophages via TLR4-mediated TBK1/IRF3/IFN-β/STAT1 signaling, independently of the MyD88 pathway. The N-terminal acidic domain of SPARC is required for ISG induction. SPARC dampens mitochondrial respiration, and glycolysis inhibition abrogates SPARC-induced ISG expression. Adipocyte-specific SPARC deletion reduces inflammation and extends healthspan during aging.\",\n      \"method\": \"Macrophage treatment with recombinant SPARC, domain deletion constructs, pathway inhibitor experiments, adipocyte-specific conditional knockout, transcriptomic analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mapping, genetic pathway epistasis (TLR4/MyD88), conditional KO with healthspan readout, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"35963236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPARC activates the NLRP3 inflammasome at the priming step in macrophages; excess SPARC activates macrophages via JNK signaling. Inducible SPARC downregulation in adult mice or adipocyte-specific SPARC deletion protects against HFD-induced adiposity, chronic inflammation, and metabolic dysfunction, lowering macrophage NLRP3 inflammasome activity.\",\n      \"method\": \"Inducible knockdown, adipocyte-specific conditional knockout, NLRP3 inflammasome assays, JNK pathway Western blot, metabolic phenotyping\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with mechanistic pathway identification (NLRP3 priming, JNK), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37781916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Intracellular SPARC stabilizes ApoE protein by competitively binding ApoE and preventing its interaction with the E3 ubiquitin ligase TRIM21, thereby blocking ApoE ubiquitylation and proteasomal degradation. ApoE accumulation leads to cholesterol enrichment in HCC cells, stimulating PI3K-AKT signaling and inducing EMT.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitylation assay, competitive binding assay, siRNA knockdown, Western blot for PI3K-AKT and EMT markers\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with competitive binding and ubiquitylation assay, single lab\",\n      \"pmids\": [\"38471084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"β4 integrin signaling reduces expression of miR-29a (a microRNA that targets SPARC), thereby elevating SPARC protein levels. In cells with endogenous β4, ligation facilitates SPARC translation through a TOR-dependent mechanism. SPARC functions as an effector downstream of β4 integrin to promote breast carcinoma invasion.\",\n      \"method\": \"miRNA expression analysis, miR-29a manipulation, β4 integrin knockdown/overexpression, TOR inhibition, Matrigel invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis with pharmacologic inhibition and miRNA manipulation, single lab, multiple methods\",\n      \"pmids\": [\"22308039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SPARC loss in bladder cancer is associated with an inflammatory phenotype of tumor-associated macrophages and fibroblasts, with increased NF-κB and AP1 activation in urothelial and stromal cells. Tumor- and stroma-derived SPARC reduced tumor growth and metastasis through inhibition of cancer-associated inflammation and lung colonization in syngeneic models.\",\n      \"method\": \"Sparc-deficient mice with chemical carcinogenesis, syngeneic transplantation models, NF-κB/AP1 reporter assays, ROS measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO carcinogenesis model with mechanistic pathway identification, single lab\",\n      \"pmids\": [\"23321672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Sparc null mice exhibit collagen fibrillogenesis defects in tendons; Sparc-/- tendons are less able to withstand force. Sparc-null and healthy-aged tendon-derived cells show a more contracted phenotype and altered actin cytoskeleton. Elevated adipogenic marker gene expression (PPARγ, Cebpα) with increased lipid deposits is observed in aged and Sparc-/- tendons.\",\n      \"method\": \"Sparc knockout mouse tendon analysis, mechanical tensile testing, histology, cell cytoskeletal staining, lipid staining, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined structural and cellular phenotypes, single lab with multiple readouts\",\n      \"pmids\": [\"27586416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Macrophages are identified as a cellular source of SPARC in pressure-overloaded hearts by immunohistochemistry and flow cytometry. Increased myocardial macrophage numbers coincide temporally with increased SPARC levels preceding collagen deposition and myocardial stiffening, supporting macrophage-derived SPARC as mediating postsynthetic collagen processing and insoluble collagen incorporation.\",\n      \"method\": \"Murine pressure overload model, immunohistochemistry, flow cytometry, time-course measurement of collagen mRNA/protein and myocardial stiffness\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cellular source identification by flow cytometry with temporal correlation, single lab\",\n      \"pmids\": [\"29522370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Extracellular SPARC directly increases cardiomyocyte cell shortening ex vivo and improves cardiac function in vivo. SPARC co-localizes with integrin-β1 and integrin-linked kinase on the cardiomyocyte membrane, suggesting an integrin-mediated mechanism for its inotropic effect.\",\n      \"method\": \"Ex vivo cardiomyocyte shortening assay with recombinant SPARC, in vivo cardiac function measurements, co-localization by immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional assay with recombinant protein ex vivo and in vivo, co-localization supporting mechanism, single lab\",\n      \"pmids\": [\"30933983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SPARC binds neurexin and neuroligin with nanomolar affinity through its FS domain, competing with hevin for binding to these synaptic organizers. This competition mechanism underlies SPARC's antagonism of hevin-mediated synaptogenesis. The shortened N-terminal region of SPARC (relative to hevin) is responsible for its antagonist activity.\",\n      \"method\": \"Crystal structure of hevin FS-EC, binding affinity measurements, competitive binding assays, domain analysis\",\n      \"journal\": \"Structure (London, England : 1993)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structural determination combined with quantitative binding assays and domain-deletion competition experiments\",\n      \"pmids\": [\"33535026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SPARC promotes glioma migration and invasion partly by activating P38 MAPK/MAPKAPK2/HSP27 (Ser78 phosphorylation) signaling. PTEN suppresses SPARC-induced pMAPKAPK2 and Ser78 HSP27 phosphorylation downstream of pP38 MAPK, via suppression of pAkt, thereby inhibiting SPARC-induced migration.\",\n      \"method\": \"Overexpression/co-transfection of SPARC and PTEN constructs, Western blot time-course for pathway components, cell migration assay on fibronectin\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by co-transfection with detailed signaling time-course, single lab\",\n      \"pmids\": [\"23382286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In bleomycin-induced pulmonary fibrosis, SPARC in host fibroblasts (not bone-marrow-derived cells) is required and sufficient for collagen fibrosis. Conversely, SPARC in macrophages is required to down-regulate TNF production in response to TGF-β; Sparc-/- macrophages fail to do so, resulting in exacerbated inflammation and fibrosis.\",\n      \"method\": \"Reciprocal bone marrow chimera experiments (Sparc-/- and WT), conditional dominant-negative TGF-β receptor under CD68 promoter, cytokine measurement\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal bone marrow chimeras dissect cell-type-specific functions with genetic and molecular controls, single lab\",\n      \"pmids\": [\"22001347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In prostate cancer dormancy, SPARC secreted by indolent cells stimulates BMP7 expression in bone marrow stromal cells; the secreted BMP7 then maintains cancer cell dormancy by inducing senescence, reducing stemness, and activating p38 MAPK and p21 signaling. SPARC is epigenetically silenced by promoter methylation in aggressive cells; 5-azacytidine treatment reactivates SPARC expression.\",\n      \"method\": \"In vivo tibial implantation/selection, ELISA for secreted BMP7, siRNA knockdown, Western blot for p38/p21, 5-azacytidine demethylation, in vivo bone tumor models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — paracrine mechanism established by conditioned medium experiments and in vivo models, single lab\",\n      \"pmids\": [\"27422817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TP53INP1 decreases SPARC expression at the transcriptional level; SPARC is downstream of TP53INP1 and mediates cell migration. Knockdown of SPARC in pancreatic cancer cells suppresses cell migration comparably to TP53INP1 overexpression, and restoring SPARC in TP53INP1-expressing cells rescues migration.\",\n      \"method\": \"Overexpression and siRNA knockdown of TP53INP1 and SPARC, RT-PCR, cell migration assay, in vivo tumor model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by rescue experiment, multiple cell contexts, single lab\",\n      \"pmids\": [\"21339733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPARC activates AKT signaling leading to elevated MMP-2 expression, facilitating renal cell carcinoma invasion. TGF-β1 induces SPARC expression in RCC cells. Knockdown of SPARC inhibits RCC cell invasion in vitro and in vivo; a specific monoclonal antibody against SPARC also diminishes invasion in vitro.\",\n      \"method\": \"siRNA knockdown, monoclonal antibody blockade, Western blot for AKT/MMP-2, invasion assay, in vivo metastasis model\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and antibody loss-of-function with pathway identification, single lab\",\n      \"pmids\": [\"32780451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SPARC promotes glucose-stimulated insulin secretion (GSIS) in pancreatic β cells by down-regulating RGS4 (a negative regulator of M3 muscarinic receptors) through a PI3K-dependent mechanism. SPARC-/- mice have elevated islet RGS4 and decreased GSIS; RGS4 inhibition restores GSIS in SPARC-null islets.\",\n      \"method\": \"SPARC overexpression/knockdown in Min6 cells, Western blot for RGS4, PI3K inhibitor (LY-294002) epistasis, islet secretion assay, sparc-/- mice\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic epistasis with defined molecular mechanism, single lab\",\n      \"pmids\": [\"33067534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPARC secreted by non-CSC prostate cancer cells (PC-3S) acts as a paracrine factor enhancing invasiveness of CSC-enriched cells (PC-3M). Immunodepletion of SPARC from S-conditioned medium inhibits enhanced M-cell invasiveness; SPARC knockdown in S cells abrogates their capacity to boost M-cell in vitro invasion and in vivo metastasis.\",\n      \"method\": \"SILAC secretome comparison, SPARC immunodepletion, siRNA knockdown, Transwell-Matrigel invasion assay, orthotopic co-injection in vivo model, bioluminescence metastasis monitoring\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunodepletion and genetic rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"25331979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Proteolytic isoforms of SPARC are generated in obese mouse adipose tissue: C-SPARC (lacking N-terminus) binds β1 integrin on adipose stromal cells (ASC) while N-SPARC (lacking C-terminus) preferentially binds ECM and blocks ECM/integrin interaction. Both isoforms induce ASC deadhesion from ECM and migration; C-SPARC modulates integrin-dependent FAK-ERK signaling while both affect integrin-independent ILK-Akt signaling with additive effects.\",\n      \"method\": \"Isoform purification and characterization, integrin binding assays, siRNA knockdown, FAK/ERK/ILK/Akt Western blot, ASC migration assay\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific binding and signaling characterization with multiple pathway readouts, single lab\",\n      \"pmids\": [\"26381424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pulmonary arterial smooth muscle cells (PASMCs), TGF-β1 and HIF2A signaling pathways induce SPARC expression. SPARC silencing enhances PASMC apoptosis and reduces proliferation; elevated SPARC promotes PASMC (but not pulmonary microvascular endothelial cell) proliferation. Conditioned medium from PMVECs acts as a paracrine factor (via secreted SPARC) triggering PASMC proliferation. AAV-mediated Sparc knockdown in adult mice improved hemodynamic and cardiac function in hypoxia-induced PH.\",\n      \"method\": \"siRNA knockdown, overexpression, conditioned medium/coculture experiments, AAV-mediated knockdown in vivo, hemodynamic measurements\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in vitro and in vivo with defined upstream inducers and cell-type-specific effects, single lab\",\n      \"pmids\": [\"35175782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SPARC loss accelerates carcinogen-induced urothelial preneoplasia, neoplasia, and metastasis and is associated with increased inflammatory macrophage and fibroblast phenotypes and upregulation of NF-κB and AP1 signaling in urothelial and stromal compartments both in vivo and in vitro.\",\n      \"method\": \"Sparc-/- mice with chemical carcinogenesis, syngeneic transplantation, NF-κB/AP1 activity assays, in vitro cell assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO in vivo model with in vitro mechanistic confirmation, single lab\",\n      \"pmids\": [\"23321672\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPARC is a secreted, modular matricellular glycoprotein whose follistatin-like (FS) and extracellular calcium-binding (EC/EF-hand) domains mediate direct binding to fibrillar collagens (at defined triple-helical sites), VEGF, neurexin/neuroligin, albumin (via gp60), ApoE, and β1/β4 integrins, thereby regulating collagen fibrillogenesis, growth-factor signaling (VEGF, PDGF, TGF-β), endothelial paracellular permeability (via β-catenin/paxillin tyrosine phosphorylation), synapse elimination (C-terminal domain-dependent cholinergic disassembly), macrophage inflammatory programming (N-terminal domain-dependent TLR4/TBK1/IRF3/STAT1 and NLRP3 pathways), cardiomyocyte contraction (via integrin-linked kinase), and cancer cell invasion (through ILK/AKT/MMP-2 and HSP27 signaling); loss of SPARC in mice produces cataracts, collagen assembly defects in multiple tissues, impaired insulin secretion, and altered microglial morphology and proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPARC is a secreted, multidomain matricellular glycoprotein that organizes the extracellular matrix and tunes cell behavior by binding structural collagens and modulating growth-factor and integrin signaling [#3, #0]. Its extracellular calcium-binding (EC) module carries two cooperative, high-affinity EF-hands and engages fibrillar collagens I, II, and III through a triple-helical recognition site located in helix \\u03b1A, which is partially masked by helix \\u03b1C; removal of \\u03b1C raises collagen affinity ~10-fold, while the neighboring follistatin-like (FS) module folds against the EC domain and is required for biosynthesis and secretion [#1, #2, #3]. Collagen binding requires intact triple-helical conformation and is tuned by glycoform, with high-mannose SPARC binding collagen I more avidly than complex-type [#3, #4]; consistent with a structural role in matrix assembly, SPARC delays fibrillogenesis in vitro and its loss in mice causes collagen-assembly defects and mechanically weak tendons and cataract from impaired lens fiber differentiation [#3, #18, #7]. SPARC also acts as a soluble ligand-binding regulator: it directly binds VEGF, reducing receptor engagement and attenuating ERK1/2 signaling [#0], and binds the synaptic organizers neurexin and neuroligin through its FS domain, competing with hevin to antagonize synaptogenesis, while a distinct C-terminal activity drives disassembly of cholinergic synapses [#21, #11]. Through integrin engagement SPARC activates ILK/AKT signaling that supports cardiomyocyte contraction and cancer cell invasion via MMP-2 and p38/HSP27 pathways [#20, #26, #22]. In innate immunity, the N-terminal acidic domain of SPARC drives a TLR4\\u2013TBK1\\u2013IRF3\\u2013STAT1 interferon-stimulated gene program and primes the NLRP3 inflammasome, and adipocyte- or cell-specific SPARC deletion reduces inflammation and improves metabolic healthspan [#13, #14]. Additional context-specific roles include regulation of endothelial paracellular permeability via \\u03b2-catenin/paxillin tyrosine phosphorylation, promotion of glucose-stimulated insulin secretion through RGS4 down-regulation, and intracellular stabilization of ApoE by blocking its TRIM21-mediated ubiquitylation [#6, #27, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established SPARC as an albumin-binding protein immunologically and functionally related to the endothelial glycoprotein gp60, linking it to vascular albumin handling before its structural mechanism was known.\",\n      \"evidence\": \"Antibody cross-reactivity and reciprocal competitive albumin-binding assays in microvascular endothelial cells\",\n      \"pmids\": [\"1481911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shared albumin-binding domain not mapped at residue level\", \"Functional consequence for transcytosis not directly demonstrated\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined a direct ligand-sequestration mechanism whereby SPARC binds VEGF and dampens receptor signaling, explaining its anti-proliferative effect on endothelium.\",\n      \"evidence\": \"125I-VEGF binding, ERK1/2 phosphorylation Western blot, and SPARC domain peptide competition in human microvascular endothelial cells\",\n      \"pmids\": [\"9792673\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding stoichiometry and affinity to VEGF not quantified\", \"Whether the same domains mediate effects on other growth factors untested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated SPARC actively disrupts endothelial barriers through a tyrosine-phosphorylation signaling cascade rather than passive matrix effects, identifying \\u03b2-catenin and paxillin as substrates.\",\n      \"evidence\": \"Macromolecular flux assay with phosphotyrosine immunoblot and pharmacologic kinase/phosphatase epistasis\",\n      \"pmids\": [\"9790954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for substrate phosphorylation not identified\", \"Receptor mediating SPARC signaling not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Provided in vivo genetic evidence that SPARC is essential for tissue homeostasis, with knockout causing early lens fiber degeneration and cataract.\",\n      \"evidence\": \"Targeted gene disruption mouse with slit-lamp and histological analysis\",\n      \"pmids\": [\"9856777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between SPARC loss and fiber differentiation failure not resolved\", \"Does not establish collagen-dependence of the cataract phenotype\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved the biochemical role of the EC EF-hands as Ca2+-saturated structural elements that also stabilize the FS domain and are required for folding and secretion.\",\n      \"evidence\": \"Ca2+-binding assays, deletion mutagenesis, secretion assays and thermodynamic analysis\",\n      \"pmids\": [\"10801822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address EF-hand role in ligand binding directly\", \"ER/Golgi processing steps not visualized\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Solved the FS-EC crystal structure and located the collagen-binding site in helix \\u03b1A, revealing an autoinhibitory mask (helix \\u03b1C) controlling collagen affinity.\",\n      \"evidence\": \"Protein crystallography with site-directed mutagenesis and collagen-binding assays\",\n      \"pmids\": [\"11223341\", \"11102747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trigger that relieves \\u03b1C masking in vivo unknown\", \"Full-length structure including the acidic N-terminus not determined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed that tissue-specific N-glycosylation tunes SPARC collagen affinity, adding a post-translational layer to its matrix function.\",\n      \"evidence\": \"Glycosidase digestion, HPLC glycan analysis and SPR collagen-binding measurements across glycoforms\",\n      \"pmids\": [\"15044389\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of glycoform differences in vivo untested\", \"Glycosylation site responsible not pinpointed functionally\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the collagen-binding interaction to a defined conserved triple-helical sequence and demonstrated conformational and lysine-modification dependence, establishing SPARC's direct role in fibrillogenesis.\",\n      \"evidence\": \"EM, CNBr and synthetic triple-helical peptide binding, SPR, and in vitro fibrillogenesis assays\",\n      \"pmids\": [\"18487610\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effect on fibril architecture in vivo at the molecular level not shown\", \"How delayed fibrillogenesis translates to tissue assembly unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linked SPARC to epithelial-mesenchymal transition by showing it transcriptionally induces Snail to repress E-cadherin, providing a mechanism for pro-invasive activity.\",\n      \"evidence\": \"Overexpression/siRNA with RT-PCR, Western blot and invasion assays in melanocytes\",\n      \"pmids\": [\"16885349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signal coupling SPARC to Snail induction not defined\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Positioned SPARC within fibrosis as a cell-type-specific effector\\u2014required in fibroblasts for collagen deposition but in macrophages for limiting TGF-\\u03b2-driven TNF and inflammation.\",\n      \"evidence\": \"Reciprocal bone marrow chimeras and CD68-driven dominant-negative TGF-\\u03b2 receptor in bleomycin lung fibrosis\",\n      \"pmids\": [\"22001347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular receptor mediating macrophage TNF suppression not identified\", \"Direct demonstration of SPARC-collagen processing in vivo not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified SPARC as a tumor- and stroma-derived suppressor of cancer-associated inflammation, with loss accelerating urothelial carcinogenesis via NF-\\u03baB/AP1.\",\n      \"evidence\": \"Sparc-/- carcinogenesis and syngeneic transplant models with NF-\\u03baB/AP1 reporters\",\n      \"pmids\": [\"23321672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct SPARC target controlling NF-\\u03baB/AP1 not defined\", \"Reconciliation with pro-inflammatory roles elsewhere not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established SPARC as a translationally regulated effector downstream of \\u03b24 integrin (via miR-29a and TOR) promoting carcinoma invasion.\",\n      \"evidence\": \"miR-29a manipulation, \\u03b24 integrin knockdown/overexpression, TOR inhibition and Matrigel invasion assays\",\n      \"pmids\": [\"22308039\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct miR-29a binding to SPARC mRNA not shown in these cells\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected SPARC to invasion via P38 MAPK/MAPKAPK2/HSP27 signaling, antagonized by PTEN, defining a kinase cascade for glioma migration.\",\n      \"evidence\": \"SPARC/PTEN co-transfection with signaling time-course Western blots and migration assays\",\n      \"pmids\": [\"23382286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream receptor coupling SPARC to p38 not identified\", \"Single cell line context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined a CNS role for SPARC in shaping microglial morphology and proliferation, with rescue confirming a direct SPARC-dependent effect.\",\n      \"evidence\": \"SPARC-null/CX3CR1-GFP mice, lesion models, and in vitro proliferation assay with exogenous SPARC rescue\",\n      \"pmids\": [\"23467362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating microglial responses unknown\", \"Mechanism linking SPARC to proliferation control unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped a C-terminal-domain activity of astrocyte-derived SPARC that triggers cholinergic synapse disassembly, validated by in vivo neuromuscular junction elimination.\",\n      \"evidence\": \"Autaptic microculture, domain peptide application, and in vivo Xenopus peptide injection with behavioral readout\",\n      \"pmids\": [\"26420865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor for the C-terminal disassembly signal not identified\", \"Relationship to neurexin/neuroligin binding not yet integrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the structural basis of SPARC's antagonism of synaptogenesis, showing FS-domain binding to neurexin/neuroligin competes with hevin.\",\n      \"evidence\": \"Crystal structure of hevin FS-EC with nanomolar binding measurements and competitive binding/domain analysis\",\n      \"pmids\": [\"33535026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo demonstration of competition at synapses not shown\", \"Relation to C-terminal synapse-elimination activity not unified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the N-terminal acidic domain as the driver of a TLR4\\u2013TBK1\\u2013IRF3\\u2013STAT1 interferon program in macrophages, tying SPARC to metabolic inflammation and aging.\",\n      \"evidence\": \"Recombinant SPARC and domain-deletion treatment of macrophages, TLR4/MyD88 epistasis, metabolic assays and adipocyte-specific conditional knockout\",\n      \"pmids\": [\"35963236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SPARC-TLR4 binding interface not resolved\", \"Link between dampened mitochondrial respiration and ISG induction mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended SPARC's innate-immune role to NLRP3 inflammasome priming via JNK, with genetic deletion protecting against diet-induced metabolic dysfunction.\",\n      \"evidence\": \"Inducible knockdown, adipocyte-specific knockout, NLRP3 assays, JNK Western blot and metabolic phenotyping\",\n      \"pmids\": [\"37781916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor coupling SPARC to JNK not defined\", \"Relationship to the TLR4/IRF3 program not integrated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a direct inotropic role for extracellular SPARC acting through integrin-\\u03b21/ILK on the cardiomyocyte membrane.\",\n      \"evidence\": \"Ex vivo cardiomyocyte shortening with recombinant SPARC, in vivo function and integrin/ILK co-localization\",\n      \"pmids\": [\"30933983\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct integrin binding not biochemically demonstrated here\", \"Downstream contractile machinery target unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an intracellular role for SPARC in stabilizing ApoE by competitively blocking TRIM21-mediated ubiquitylation, driving cholesterol-dependent PI3K-AKT signaling and EMT.\",\n      \"evidence\": \"Reciprocal Co-IP, competitive binding and ubiquitylation assays with siRNA in HCC cells\",\n      \"pmids\": [\"38471084\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a normally secreted protein accesses the cytosolic TRIM21 pathway unresolved\", \"Single tumor context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a beta-cell role for SPARC promoting glucose-stimulated insulin secretion by PI3K-dependent down-regulation of the M3 receptor inhibitor RGS4.\",\n      \"evidence\": \"Overexpression/knockdown in Min6, PI3K inhibitor epistasis, islet secretion assays and Sparc-/- mice\",\n      \"pmids\": [\"33067534\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor coupling secreted SPARC to PI3K in beta cells unknown\", \"Mechanism of RGS4 transcriptional control unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor(s) transducing secreted SPARC signaling across its many contexts and how a single protein reconciles pro- versus anti-inflammatory and tumor-suppressive versus pro-invasive roles remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying receptor identified despite integrin, TLR4 and synaptic-organizer interactions reported\", \"Domain- and isoform-specific activities not integrated into one structural model\", \"Context-dependent opposing phenotypes not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 21, 15]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 2, 18]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [0, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 11, 28]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [3, 29]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [20, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [3, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 14, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 20, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [26, 22, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VEGF\", \"COL1A1\", \"NRXN\", \"NLGN\", \"ITGB1\", \"APOE\", \"PRKAA1\", \"ITGB4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}