Affinage

SPARC

SPARC · UniProt P09486

Length
303 aa
Mass
34.6 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1992 Medium

    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

    PMID:1481911

    Open questions at the time
    • Shared albumin-binding domain not mapped at residue level
    • Functional consequence for transcytosis not directly demonstrated
  2. 1998 High

    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

    PMID:9792673

    Open questions at the time
    • Binding stoichiometry and affinity to VEGF not quantified
    • Whether the same domains mediate effects on other growth factors untested
  3. 1998 Medium

    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

    PMID:9790954

    Open questions at the time
    • Kinase responsible for substrate phosphorylation not identified
    • Receptor mediating SPARC signaling not defined
  4. 1998 High

    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

    PMID:9856777

    Open questions at the time
    • Molecular link between SPARC loss and fiber differentiation failure not resolved
    • Does not establish collagen-dependence of the cataract phenotype
  5. 2000 High

    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

    PMID:10801822

    Open questions at the time
    • Does not address EF-hand role in ligand binding directly
    • ER/Golgi processing steps not visualized
  6. 2001 High

    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

    PMID:11102747 PMID:11223341

    Open questions at the time
    • Trigger that relieves αC masking in vivo unknown
    • Full-length structure including the acidic N-terminus not determined
  7. 2004 High

    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

    PMID:15044389

    Open questions at the time
    • Physiological consequence of glycoform differences in vivo untested
    • Glycosylation site responsible not pinpointed functionally
  8. 2008 High

    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

    PMID:18487610

    Open questions at the time
    • Effect on fibril architecture in vivo at the molecular level not shown
    • How delayed fibrillogenesis translates to tissue assembly unresolved
  9. 2006 Medium

    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

    PMID:16885349

    Open questions at the time
    • Receptor/signal coupling SPARC to Snail induction not defined
    • Single cell-type context
  10. 2011 High

    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

    PMID:22001347

    Open questions at the time
    • Molecular receptor mediating macrophage TNF suppression not identified
    • Direct demonstration of SPARC-collagen processing in vivo not shown
  11. 2009 Medium

    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

    PMID:23321672

    Open questions at the time
    • Direct SPARC target controlling NF-κB/AP1 not defined
    • Reconciliation with pro-inflammatory roles elsewhere not addressed
  12. 2012 Medium

    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

    PMID:22308039

    Open questions at the time
    • Direct miR-29a binding to SPARC mRNA not shown in these cells
    • Single cancer context
  13. 2013 Medium

    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

    PMID:23382286

    Open questions at the time
    • Upstream receptor coupling SPARC to p38 not identified
    • Single cell line context
  14. 2013 Medium

    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

    PMID:23467362

    Open questions at the time
    • Receptor mediating microglial responses unknown
    • Mechanism linking SPARC to proliferation control unresolved
  15. 2015 High

    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

    PMID:26420865

    Open questions at the time
    • Receptor for the C-terminal disassembly signal not identified
    • Relationship to neurexin/neuroligin binding not yet integrated
  16. 2021 High

    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

    PMID:33535026

    Open questions at the time
    • In vivo demonstration of competition at synapses not shown
    • Relation to C-terminal synapse-elimination activity not unified
  17. 2022 High

    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

    PMID:35963236

    Open questions at the time
    • Direct SPARC-TLR4 binding interface not resolved
    • Link between dampened mitochondrial respiration and ISG induction mechanistically incomplete
  18. 2023 High

    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

    PMID:37781916

    Open questions at the time
    • Receptor coupling SPARC to JNK not defined
    • Relationship to the TLR4/IRF3 program not integrated
  19. 2019 Medium

    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

    PMID:30933983

    Open questions at the time
    • Direct integrin binding not biochemically demonstrated here
    • Downstream contractile machinery target unknown
  20. 2016 Medium

    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

    PMID:38471084

    Open questions at the time
    • How a normally secreted protein accesses the cytosolic TRIM21 pathway unresolved
    • Single tumor context
  21. 2020 Medium

    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

    PMID:33067534

    Open questions at the time
    • Receptor coupling secreted SPARC to PI3K in beta cells unknown
    • Mechanism of RGS4 transcriptional control unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 2 GO:0031012 extracellular matrix 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
APOECOL1A1ITGB1ITGB4NLGNNRXNPRKAA1VEGF

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 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. DNA synthesis assay, 125I-VEGF binding/radioimmune precipitation, Western blot for ERK1/2 phosphorylation, SPARC domain peptide competition The Journal of biological chemistry High 9792673
2000 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. Ca2+ binding assays, deletion mutagenesis, mammalian cell secretion assay, thermodynamic analysis The Journal of biological chemistry High 10801822
2001 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. Protein crystallography, site-directed mutagenesis, collagen binding assays Matrix biology High 11102747 11223341
2008 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. Rotary shadowing/electron microscopy, CNBr peptide binding, synthetic triple-helical peptide binding, surface plasmon resonance, in vitro fibrillogenesis assay The Journal of biological chemistry High 18487610
2004 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. Endoglycosidase/exoglycosidase digestion, HPLC glycan analysis, surface plasmon resonance collagen binding assay Glycobiology High 15044389
1992 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. Antibody cross-reactivity assay, competitive inhibition of albumin binding, cell-based albumin binding assay The American journal of physiology Medium 1481911
1998 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. Macromolecular flux assay, phosphotyrosine Western blot/immunolocalization, pharmacologic kinase/phosphatase inhibition, substrate identification Biochemical and biophysical research communications Medium 9790954
1998 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. Targeted gene disruption (knockout mouse), slit-lamp microscopy, histology Investigative ophthalmology & visual science High 9856777
2006 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. Overexpression and siRNA knockdown, RT-PCR, Western blot, cell morphology/motility assays, invasion assay Cancer research Medium 16885349
2010 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. Yeast two-hybrid screen, co-immunoprecipitation of endogenous proteins, siRNA knockdown, Western blot for GLUT4 expression Biochemical and biophysical research communications Medium 20460104
2014 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. Reporter assays, Western blot for pathway activation, pharmacologic inhibition, murine AML models The Journal of clinical investigation Medium 24590286
2015 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. Single-cell autaptic microculture assay, domain peptide application, in vivo peptide injection with behavioral and morphological readout Proceedings of the National Academy of Sciences of the United States of America High 26420865
2013 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. SPARC-null reporter mice, in vivo lesion models, in vitro microglial proliferation assay with SPARC rescue The Journal of neuroscience Medium 23467362
2022 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. Macrophage treatment with recombinant SPARC, domain deletion constructs, pathway inhibitor experiments, adipocyte-specific conditional knockout, transcriptomic analysis Immunity High 35963236
2023 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. Inducible knockdown, adipocyte-specific conditional knockout, NLRP3 inflammasome assays, JNK pathway Western blot, metabolic phenotyping The Journal of clinical investigation High 37781916
2016 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. Co-immunoprecipitation, ubiquitylation assay, competitive binding assay, siRNA knockdown, Western blot for PI3K-AKT and EMT markers Cancer research Medium 38471084
2012 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. miRNA expression analysis, miR-29a manipulation, β4 integrin knockdown/overexpression, TOR inhibition, Matrigel invasion assay The Journal of biological chemistry Medium 22308039
2013 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. Sparc-deficient mice with chemical carcinogenesis, syngeneic transplantation models, NF-κB/AP1 reporter assays, ROS measurement The Journal of clinical investigation Medium 23321672
2016 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. Sparc knockout mouse tendon analysis, mechanical tensile testing, histology, cell cytoskeletal staining, lipid staining, gene expression analysis Scientific reports Medium 27586416
2018 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. Murine pressure overload model, immunohistochemistry, flow cytometry, time-course measurement of collagen mRNA/protein and myocardial stiffness American journal of physiology. Heart and circulatory physiology Medium 29522370
2019 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. Ex vivo cardiomyocyte shortening assay with recombinant SPARC, in vivo cardiac function measurements, co-localization by immunofluorescence PloS one Medium 30933983
2021 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. Crystal structure of hevin FS-EC, binding affinity measurements, competitive binding assays, domain analysis Structure (London, England : 1993) High 33535026
2013 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. Overexpression/co-transfection of SPARC and PTEN constructs, Western blot time-course for pathway components, cell migration assay on fibronectin Neuro-oncology Medium 23382286
2011 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. Reciprocal bone marrow chimera experiments (Sparc-/- and WT), conditional dominant-negative TGF-β receptor under CD68 promoter, cytokine measurement The American journal of pathology High 22001347
2016 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. In vivo tibial implantation/selection, ELISA for secreted BMP7, siRNA knockdown, Western blot for p38/p21, 5-azacytidine demethylation, in vivo bone tumor models The Journal of biological chemistry Medium 27422817
2011 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. Overexpression and siRNA knockdown of TP53INP1 and SPARC, RT-PCR, cell migration assay, in vivo tumor model Oncogene Medium 21339733
2020 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. siRNA knockdown, monoclonal antibody blockade, Western blot for AKT/MMP-2, invasion assay, in vivo metastasis model Journal of cellular physiology Medium 32780451
2020 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. SPARC overexpression/knockdown in Min6 cells, Western blot for RGS4, PI3K inhibitor (LY-294002) epistasis, islet secretion assay, sparc-/- mice Scientific reports Medium 33067534
2015 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. SILAC secretome comparison, SPARC immunodepletion, siRNA knockdown, Transwell-Matrigel invasion assay, orthotopic co-injection in vivo model, bioluminescence metastasis monitoring Molecular cancer Medium 25331979
2015 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. Isoform purification and characterization, integrin binding assays, siRNA knockdown, FAK/ERK/ILK/Akt Western blot, ASC migration assay Stem cells (Dayton, Ohio) Medium 26381424
2022 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. siRNA knockdown, overexpression, conditioned medium/coculture experiments, AAV-mediated knockdown in vivo, hemodynamic measurements Circulation Medium 35175782
2009 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. Sparc-/- mice with chemical carcinogenesis, syngeneic transplantation, NF-κB/AP1 activity assays, in vitro cell assays The Journal of clinical investigation Medium 23321672

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix biology : journal of the International Society for Matrix Biology 453 11223341
1994 The biology of SPARC, a protein that modulates cell-matrix interactions. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 453 8119487
2007 Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 340 17235047
1999 SPARC, a matricellular glycoprotein with important biological functions. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 298 10567433
2000 SPARC, a matricellular protein: at the crossroads of cell-matrix. Matrix biology : journal of the International Society for Matrix Biology 252 11102747
2016 SPARC/osteonectin in mineralized tissue. Matrix biology : journal of the International Society for Matrix Biology 231 26851678
1998 SPARC (BM-40, osteonectin) inhibits the mitogenic effect of vascular endothelial growth factor on microvascular endothelial cells. The Journal of biological chemistry 231 9792673
2012 Diverse biological functions of the SPARC family of proteins. The international journal of biochemistry & cell biology 215 22249026
2004 SPARC and tumor growth: where the seed meets the soil? Journal of cellular biochemistry 205 15211566
1993 Differential expression of SPARC and thrombospondin 1 in wound repair: immunolocalization and in situ hybridization. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 199 8245406
2008 SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy 196 18849185
1998 SPARC deficiency leads to early-onset cataractogenesis. Investigative ophthalmology & visual science 172 9856777
1986 Developmental and transformation-sensitive expression of the Sparc gene on mouse chromosome 11. The EMBO journal 172 3758028
2010 SPARC: a key player in the pathologies associated with obesity and diabetes. Nature reviews. Endocrinology 158 20195270
2006 SPARC represses E-cadherin and induces mesenchymal transition during melanoma development. Cancer research 143 16885349
2009 Modulation of matrix remodeling by SPARC in neoplastic progression. Seminars in cell & developmental biology 121 19958839
2014 Molecular mechanisms underlying the divergent roles of SPARC in human carcinogenesis. Carcinogenesis 119 24675529
2022 The matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging. Immunity 106 35963236
2007 Is SPARC an evolutionarily conserved collagen chaperone? Journal of dental research 103 17384023
2011 DNA methylation of SPARC and chronic low back pain. Molecular pain 102 21867537
1999 SPARC (osteonectin/BM-40). The international journal of biochemistry & cell biology 99 10641790
2013 Stromal expression of SPARC in pancreatic adenocarcinoma. Cancer metastasis reviews 95 23690170
2005 Endogenous osteonectin/SPARC/BM-40 expression inhibits MDA-MB-231 breast cancer cell metastasis. Cancer research 95 16103089
1991 Recombinant expression and properties of the human calcium-binding extracellular matrix protein BM-40. European journal of biochemistry 93 1653704
1988 Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane. The American journal of pathology 93 3400777
2016 Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone. The Journal of biological chemistry 89 27422817
2009 Cardiac extracellular matrix remodeling: fibrillar collagens and Secreted Protein Acidic and Rich in Cysteine (SPARC). Journal of molecular and cellular cardiology 86 19577572
1996 Regulation of angiogenesis by SPARC and angiostatin: implications for tumor cell biology. Seminars in cancer biology 86 8773299
1992 Antibodies to SPARC inhibit albumin binding to SPARC, gp60, and microvascular endothelium. The American journal of physiology 85 1481911
2004 Hevin/SC1, a matricellular glycoprotein and potential tumor-suppressor of the SPARC/BM-40/Osteonectin family. The international journal of biochemistry & cell biology 84 15094114
1995 Expression of SPARC in normal and fibrotic livers. Hepatology (Baltimore, Md.) 84 7875683
2011 The regulatory function of SPARC in vascular biology. Cellular and molecular life sciences : CMLS 83 21822645
2013 Loss of SPARC in bladder cancer enhances carcinogenesis and progression. The Journal of clinical investigation 79 23321672
2024 GP60 and SPARC as albumin receptors: key targeted sites for the delivery of antitumor drugs. Frontiers in pharmacology 77 38323081
2008 Mapping of SPARC/BM-40/osteonectin-binding sites on fibrillar collagens. The Journal of biological chemistry 74 18487610
2006 SPARC and Hevin expression correlate with tumour angiogenesis in hepatocellular carcinoma. The Journal of pathology 71 17029219
2014 SPARC in Tumor Pathophysiology and as a Potential Therapeutic Target. Current pharmaceutical design 67 24947586
2008 Secreted protein acidic and rich in cysteine (SPARC) in human skeletal muscle. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 67 18796407
2002 Novel functions of the matricellular proteins osteopontin and osteonectin/SPARC. Connective tissue research 67 12489175
2011 TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression. Oncogene 66 21339733
2011 Anti-cancer role of SPARC, an inhibitor of adipogenesis. Cancer treatment reviews 64 21237573
2000 Targeting angiogenesis inhibits tumor infiltration and expression of the pro-invasive protein SPARC. International journal of cancer 62 10861485
2008 SPARC is expressed by macroglia and microglia in the developing and mature nervous system. Developmental dynamics : an official publication of the American Association of Anatomists 59 18366138
2013 SPARC regulates microgliosis and functional recovery following cortical ischemia. The Journal of neuroscience : the official journal of the Society for Neuroscience 58 23467362
2011 SPARC oppositely regulates inflammation and fibrosis in bleomycin-induced lung damage. The American journal of pathology 58 22001347
2010 KLF4 inhibition of lung cancer cell invasion by suppression of SPARC expression. Cancer biology & therapy 57 20215880
1997 Cloning and expression of murine SC1, a gene product homologous to SPARC. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 55 9199668
2018 Pre-eclampsia onset and SPARC: A possible involvement in placenta development. Journal of cellular physiology 54 30426491
2014 Role of SPARC in bone remodeling and cancer-related bone metastasis. Journal of cellular biochemistry 54 24038053
2022 SPARC, a Novel Regulator of Vascular Cell Function in Pulmonary Hypertension. Circulation 53 35175782
2014 SPARC promotes leukemic cell growth and predicts acute myeloid leukemia outcome. The Journal of clinical investigation 52 24590286
2010 SPARC interacts with AMPK and regulates GLUT4 expression. Biochemical and biophysical research communications 52 20460104
2014 SPARC mediates metastatic cooperation between CSC and non-CSC prostate cancer cell subpopulations. Molecular cancer 51 25331979
2018 Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis. American journal of physiology. Heart and circulatory physiology 49 29522370
2015 SPARC triggers a cell-autonomous program of synapse elimination. Proceedings of the National Academy of Sciences of the United States of America 46 26420865
2008 Sparc protein is required for normal growth of zebrafish otoliths. Journal of the Association for Research in Otolaryngology : JARO 45 18784957
2000 Calcium affinity, cooperativity, and domain interactions of extracellular EF-hands present in BM-40. The Journal of biological chemistry 45 10801822
2004 Structural variability of BM-40/SPARC/osteonectin glycosylation: implications for collagen affinity. Glycobiology 44 15044389
2015 The role of secreted protein acidic and rich in cysteine (SPARC) in cardiac repair and fibrosis: Does expression of SPARC by macrophages influence outcomes? Journal of molecular and cellular cardiology 43 26582465
2016 Pleiotropic roles of the matricellular protein Sparc in tendon maturation and ageing. Scientific reports 41 27586416
2009 Downregulation of SPARC expression inhibits cell migration and invasion in malignant gliomas. International journal of oncology 41 19212676
2008 Increased SPARC expression in primary angle closure glaucoma iris. Molecular vision 40 18949063
2024 SPARC Stabilizes ApoE to Induce Cholesterol-Dependent Invasion and Sorafenib Resistance in Hepatocellular Carcinoma. Cancer research 39 38471084
2012 Integrin β4 regulates SPARC protein to promote invasion. The Journal of biological chemistry 38 22308039
2015 The role of SPARC expression in pancreatic cancer progression and patient survival. Scandinavian journal of gastroenterology 37 25765175
2012 Involvement of SPARC and MMP-3 in the pathogenesis of human pterygium. Investigative ophthalmology & visual science 37 22222271
2020 SPARC is a key mediator of TGF-β-induced renal cancer metastasis. Journal of cellular physiology 36 32780451
2019 SPARC is required for the maintenance of glucose homeostasis and insulin secretion in mice. Clinical science (London, England : 1979) 36 30626728
2012 SPARC and DNA methylation: possible diagnostic and therapeutic implications in gastrointestinal cancers. Cancer letters 36 22939997
2010 Downregulation of SPARC expression decreases gastric cancer cellular invasion and survival. Journal of experimental & clinical cancer research : CR 35 20525171
2013 Testican-3: a brain-specific proteoglycan member of the BM-40/SPARC/osteonectin family. Journal of neurochemistry 34 23418755
2000 Expression and characterization of SPARC in human lens and in the aqueous and vitreous humors. Experimental eye research 34 10880278
2018 SPARC and GluA1-Containing AMPA Receptors Promote Neuronal Health Following CNS Injury. Frontiers in cellular neuroscience 32 29449802
2016 SPARC-Dependent Cardiomyopathy in Drosophila. Circulation. Cardiovascular genetics 32 26839388
1998 The counteradhesive protein SPARC regulates an endothelial paracellular pathway through protein tyrosine phosphorylation. Biochemical and biophysical research communications 32 9790954
2010 Methylation of the SPARC gene promoter and its clinical implication in pancreatic cancer. Journal of experimental & clinical cancer research : CR 31 20338068
1988 Expression of SPARC/osteonectin transcript in murine embryos and gonads. Differentiation; research in biological diversity 31 3384223
2020 Regulation of SPARC family proteins in disorders of the central nervous system. Brain research bulletin 30 32417569
2021 Interplay between hevin, SPARC, and MDGAs: Modulators of neurexin-neuroligin transsynaptic bridges. Structure (London, England : 1993) 29 33535026
2000 Expression and purification of recombinant human SPARC produced by baculovirus. Molecular cell biology research communications : MCBRC 29 11032756
2023 Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity. The Journal of clinical investigation 28 37781916
2021 SPARC Overexpression Promotes Liver Cancer Cell Proliferation and Tumor Growth. Frontiers in molecular biosciences 28 34912848
2019 Extracellular SPARC increases cardiomyocyte contraction during health and disease. PloS one 28 30933983
2019 Impact of Fibroblast-Derived SPARC on Invasiveness of Colorectal Cancer Cells. Cancers 28 31554208
2014 Aberrant methylation of the SPARC gene promoter and its clinical implication in gastric cancer. Scientific reports 28 25516351
2016 Osteonectin (SPARC) Expression in Vascular Calcification: In Vitro and Ex Vivo Studies. Calcified tissue international 27 27339669
2015 Proteolytic Isoforms of SPARC Induce Adipose Stromal Cell Mobilization in Obesity. Stem cells (Dayton, Ohio) 27 26381424
2013 PTEN suppresses SPARC-induced pMAPKAPK2 and inhibits SPARC-induced Ser78 HSP27 phosphorylation in glioma. Neuro-oncology 25 23382286
2011 The matricellular protein SPARC supports follicular dendritic cell networking toward Th17 responses. Journal of autoimmunity 25 21962567
2006 The differential expression of SPARC in esophageal squamous cell carcinoma. International journal of molecular medicine 25 16685412
2023 SPARC: a potential target for functional nanomaterials and drugs. Frontiers in molecular biosciences 24 37577749
2016 The 'SPARC' of life: Analysis of the role of osteonectin/SPARC in pancreatic cancer (Review). International journal of oncology 24 26983777
2022 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. Metabolites 23 35208200
2022 Increased Sparc release from subchondral osteoblasts promotes articular chondrocyte degeneration under estrogen withdrawal. Osteoarthritis and cartilage 23 36241137
2020 SPARC promotes insulin secretion through down-regulation of RGS4 protein in pancreatic β cells. Scientific reports 23 33067534
2018 SPARC Inhibits Metabolic Plasticity in Ovarian Cancer. Cancers 23 30332737
2020 SPARC-p53: The double agents of cancer. Advances in cancer research 22 32723563
2014 SIBLINGs and SPARC families: their emerging roles in pancreatic cancer. World journal of gastroenterology 22 25356037
2020 Secreted protein acidic and rich in cysteine (SPARC) regulates thermogenesis in white and brown adipocytes. Molecular and cellular endocrinology 18 32057945
2022 Sequencing Illumina libraries at high accuracy on the ONT MinION using R2C2. Genome research 17 36351772

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