SPARC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0031012 extracellular matrix	IBA GO_REF:0000033	ACCEPT	Summary: Core localization supported by phylogenetic inference and extensive experimental evidence. Reason: SPARC is definitively localized to the extracellular matrix where it functions as a matricellular protein. This is a core cellular component annotation supported by phylogenetic analysis and consistent with its biological role in modulating ECM assembly and cell-matrix interactions.
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: General extracellular localization supported by phylogenetic analysis and experimental data. Reason: SPARC is a secreted protein that functions in the extracellular space. This broader localization term is appropriate and consistent with SPARC being found in extracellular matrix, basement membrane, and extracellular fluids.
GO:0048752 semicircular canal morphogenesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically-inferred role in inner ear development. Reason: This IBA annotation suggests a role in semicircular canal morphogenesis based on phylogenetic inference. While SPARC is expressed during development and tissue morphogenesis, this represents a specific developmental process rather than SPARC's core matricellular function. SPARC's role here would likely be as a modulator of ECM assembly during ear development.
GO:0050807 regulation of synapse organization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetically-inferred role in synapse organization. Reason: This IBA annotation suggests a role in regulating synapse organization based on phylogenetic inference. SPARC's counter-adhesive and ECM-modulating functions could plausibly affect synapse structure, but this is not a core biological process for SPARC and would be context-specific rather than central to its primary matricellular functions.
GO:0005509 calcium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: Core molecular function of SPARC supported by phylogenetic inference, direct biochemical evidence, and structural studies showing multiple Ca2+ binding sites. Reason: SPARC is definitively a high-affinity calcium-binding protein with 8-10 Ca2+ binding sites per molecule. The acidic N-terminal domain binds 5-8 Ca2+ with low affinity, and the C-terminal EF-hand domain binds Ca2+ with high affinity. This is a core molecular function essential for protein structure and function. Supporting Evidence: PMID:7034958 Osteonectin is a 32,000 dalton bone-specific protein that binds selectively to both hydroxyapatite and collagen. When osteonectin is bound to insolubilized type I collagen, the resultant complex binds synthetic apatite crystals and free calcium ions. PMID:9501084 The extracellular calcium-binding domain (positions 138-286) of the matrix protein BM-40 possesses a binding epitope of moderate affinity for several collagen types.
GO:0005509 calcium ion binding	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate annotation via InterPro mapping, consistent with IBA and IDA evidence. Reason: This IEA annotation based on InterPro domain recognition is consistent with the experimentally validated calcium binding function and can be retained as supporting evidence.
GO:0005604 basement membrane	IEA GO_REF:0000044	ACCEPT	Summary: Well-supported localization to basement membrane supported by UniProt subcellular location vocabulary and experimental studies. Reason: SPARC is well-documented to localize in or around basement membranes, where it modulates ECM assembly and cell-matrix interactions. UniProt annotation states "In or around the basement membrane" based on multiple experimental studies.
GO:0005615 extracellular space	IEA GO_REF:0000002	ACCEPT	Summary: Duplicate annotation consistent with IBA evidence. Reason: This IEA annotation from InterPro is consistent with experimental evidence and can be retained.
GO:0046872 metal ion binding	IEA GO_REF:0000043	MODIFY	Summary: Overly generic term when specific calcium ion binding is documented. Reason: SPARC specifically binds calcium ions (GO:0005509), which is already well-annotated. The generic "metal ion binding" term is less informative than the specific calcium ion binding annotations. SPARC also binds copper ions, but the primary and most extensively studied metal binding activity is calcium. Proposed replacements: calcium ion binding
GO:0005515 protein binding	IPI PMID:18808384 Identification of a novel protein promoting the colonization...	REMOVE	Summary: Non-informative generic annotation for interaction with bacterial protein FafA from Finegoldia magna. Reason: The generic "protein binding" term provides no functional insight. This study identifies SPARC as a binding partner for a bacterial adhesin but does not inform our understanding of SPARC's core molecular functions. This appears to be an opportunistic interaction during bacterial infection rather than a core biological activity. Supporting Evidence: PMID:18808384 Epub 2008 Sep 18. Identification of a novel protein promoting the colonization and survival of Finegoldia magna, a bacterial commensal and opportunistic pathogen.
GO:0005515 protein binding	IPI PMID:19011090 Structural basis of sequence-specific collagen recognition b...	REMOVE	Summary: Non-informative generic annotation from collagen binding study. Reason: This study demonstrated collagen binding (already captured by GO:0005518), not a distinct protein binding function. The generic "protein binding" term adds no additional functional information beyond the specific collagen binding annotations. Supporting Evidence: PMID:19011090 Structural basis of sequence-specific collagen recognition by SPARC.
GO:0005515 protein binding	IPI PMID:20926826 Interaction of recombinant myocilin with the matricellular p...	REMOVE	Summary: Non-informative generic annotation for interaction with myocilin. Reason: While the SPARC-myocilin interaction may be relevant in glaucoma pathology, the generic "protein binding" term provides no functional insight. The study does not establish this as a core molecular function of SPARC. Supporting Evidence: PMID:20926826 Print 2011 Jan. Interaction of recombinant myocilin with the matricellular protein SPARC: functional implications.
GO:0005201 extracellular matrix structural constituent	RCA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive...	REMOVE	Summary: Mischaracterization of SPARC as a structural ECM component. Reason: SPARC is definitively a matricellular protein, not a structural ECM component. Matricellular proteins modulate cell-matrix interactions and ECM assembly but do not themselves provide structural support. This annotation fundamentally misrepresents SPARC biology. The correct molecular function is as a regulatory/modulating protein, not as a structural constituent. Supporting Evidence: PMID:28327460 Epub 2017 Mar 7. Comprehensive proteomic characterization of stem cell-derived extracellular matrices.
GO:0031012 extracellular matrix	HDA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive...	ACCEPT	Summary: High-throughput proteomic identification of SPARC in ECM consistent with core localization. Reason: This HDA annotation from a proteomic study of stem cell-derived ECM is consistent with the well-established ECM localization of SPARC. Supporting Evidence: PMID:28327460 Epub 2017 Mar 7. Comprehensive proteomic characterization of stem cell-derived extracellular matrices.
GO:0005886 plasma membrane	TAS Reactome:R-HSA-9612277	ACCEPT	Summary: Plasma membrane localization is supported by experimental evidence, though this specific citation may be from a pathway context. Reason: While this Reactome annotation may have been derived from a pathway context, SPARC plasma membrane localization is supported by direct experimental evidence (IDA) showing localization to alpha-granule membranes, which are plasma membrane-derived.
GO:0005576 extracellular region	HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper...	ACCEPT	Summary: High-throughput proteomic identification in varicose vein ECM. Reason: This proteomic study of ECM remodeling in varicose veins identified SPARC, consistent with its core extracellular/ECM localization. Supporting Evidence: PMID:27068509 Apr 11. Extracellular matrix remodelling in response to venous hypertension: proteomics of human varicose veins.
GO:0001937 negative regulation of endothelial cell proliferation	IDA PMID:12867428 Cleavage of the matricellular protein SPARC by matrix metall...	ACCEPT	Summary: Direct experimental evidence for SPARC peptides inhibiting endothelial cell proliferation. Reason: This study demonstrated that MMP-3 cleavage of SPARC produces peptides (Z-2 and Z-3) that inhibit endothelial cell proliferation in a concentration-dependent manner. This anti-proliferative effect on endothelial cells is part of SPARC's anti-angiogenic activities and represents a core biological function. Supporting Evidence: PMID:12867428 In contrast, peptides Z-2 (6.1 kDa, containing Ca2+-binding EF hand-1) and Z-3 (2.2 kDa, containing neither Cu2+-binding motifs nor EF hands), inhibited cell proliferation in a concentration-dependent manner and exhibited no effects on vessel growth in the CAM.
GO:0005518 collagen binding	IDA PMID:9501084 Crystal structure and mapping by site-directed mutagenesis o...	ACCEPT	Summary: Crystal structure and mutagenesis study definitively mapping the collagen-binding epitope in SPARC with sequence-specific recognition. Reason: This is a definitive structural and functional study showing SPARC binds collagens I and IV with sequence-specific recognition of the GVMGFO motif. Five residues (R149, N156, L242, M245, E246) were identified as crucial for collagen binding. This represents a core molecular function of SPARC. Supporting Evidence: PMID:9501084 Five residues were crucial for binding, R149 and N156 in helix alphaA, and L242, M245 and E246 in a loop region connecting the two EF hands of BM-40. These residues are spatially close and form a flat ring of 15 A diameter which matches the diameter of a triple-helical collagen domain. The mutations showed similar effects on binding to collagens I and IV, indicating nearly identical binding sites on both collagens. file:human/SPARC/SPARC-deep-research-falcon.md Across 2023-2024 sources, SPARC's most reproducible molecular functions are: - Collagen/ECM binding and ECM organization.
GO:0005737 cytoplasm	IDA PMID:15389586 Spreading of embryologically distinct urothelial cells is in...	KEEP AS NON CORE	Summary: Experimental evidence for intracellular SPARC localization in cycling urothelial cells. Reason: This study demonstrated that cycling urothelial cells sequester SPARC within cytoplasm and nuclei, while differentiated cells show apical membrane localization. While this is legitimate experimental evidence, cytoplasmic localization represents trafficking/biosynthetic localization rather than the functional location where SPARC exerts its core matricellular activities. SPARC is a secreted protein with an N-terminal signal peptide. Supporting Evidence: PMID:15389586 In contrast, the basal layer of transitional epithelium in vivo and cycling cells in vitro did not exhibit this apical staining pattern, but instead sequestered the SPARC polypeptide within urothelial cytoplasm and/or nuclei, as revealed by immunohistochemical analysis.
GO:0009986 cell surface	IDA PMID:15389586 Spreading of embryologically distinct urothelial cells is in...	ACCEPT	Summary: Experimental evidence for SPARC localization at apical plasma membrane of differentiated urothelial cells. Reason: This study showed polarized localization of SPARC to apical plasma membranes of suprabasal/intermediate urothelial cells. Cell surface localization is relevant for SPARC's counter-adhesive function and interaction with cell surface receptors, though the primary functional location is the extracellular matrix. Supporting Evidence: PMID:15389586 Through the use of a monoclonal antibody that recognizes this epitope, transitional epithelium was found to restrict expression of SPARC to the suprabasal and intermediate layer. Such intracellular expression was defined by immunoreactive signals that localized to the apical plasma membranes of suprabasal and intermediate cells.
GO:0010595 positive regulation of endothelial cell migration	IDA PMID:12867428 Cleavage of the matricellular protein SPARC by matrix metall...	ACCEPT	Summary: SPARC-derived peptides stimulate endothelial cell migration in collagen gels. Reason: This study showed that MMP-3-generated SPARC peptides Z-2 and Z-3 stimulated endothelial cell migration in collagen gels, demonstrating a pro-migratory effect. This represents part of SPARC's complex, context-dependent regulation of angiogenesis where different fragments have distinct activities. Supporting Evidence: PMID:12867428 Reciprocal results were obtained in a migration assay in native collagen gels: peptide Z-1 was ineffective over a range of concentrations, whereas Z-2 or Z-3 stimulated cell migration.
GO:0016363 nuclear matrix	IDA PMID:15389586 Spreading of embryologically distinct urothelial cells is in...	KEEP AS NON CORE	Summary: Experimental evidence for SPARC in nuclear matrix, colocalized with Ki-67. Reason: The study demonstrated SPARC presence in the nuclear matrix where it colocalized with Ki-67 antigen in cycling urothelial cells. However, this represents an atypical localization for a secreted matricellular protein. Nuclear localization may reflect biosynthetic/trafficking processes rather than core function. The functional significance remains unclear. Supporting Evidence: PMID:15389586 Elution of soluble proteins and DNA from urothelial cells revealed the presence of SPARC within the nuclear matrix--and that SPARC colocalized with the nuclear matrix Ki-67 antigen.
GO:0016525 negative regulation of angiogenesis	IDA PMID:12867428 Cleavage of the matricellular protein SPARC by matrix metall...	ACCEPT	Summary: SPARC-derived peptides inhibit angiogenesis in vivo. Reason: This study demonstrated that certain SPARC peptides (Z-2, Z-3) generated by MMP-3 cleavage inhibit angiogenesis, having no effect on vessel growth in the chick chorioallantoic membrane assay. This anti-angiogenic activity represents a core biological function of SPARC, though the protein shows context-dependent pro- and anti-angiogenic effects. Supporting Evidence: PMID:12867428 In contrast, peptides Z-2 (6.1 kDa, containing Ca2+-binding EF hand-1) and Z-3 (2.2 kDa, containing neither Cu2+-binding motifs nor EF hands), inhibited cell proliferation in a concentration-dependent manner and exhibited no effects on vessel growth in the CAM.
GO:0022604 regulation of cell morphogenesis	IDA PMID:15389586 Spreading of embryologically distinct urothelial cells is in...	ACCEPT	Summary: SPARC inhibits cell spreading and promotes cell rounding in urothelial cells. Reason: This study demonstrated that recombinant SPARC inhibits spreading of freshly plated urothelial cells in a concentration- and time-dependent manner (rounding assay). This counter-adhesive effect on cell morphology is a core biological function of SPARC as a matricellular protein that disrupts focal adhesions and regulates cell shape. Supporting Evidence: PMID:15389586 rSPARC activity was demonstrated and quantified with a rounding assay whereby the spreading of freshly plated cells was inhibited by recombinant SPARC in a concentration- and time-dependent manner. Inhibition of spreading was observed in urothelial cells derived from endoderm (bladder) and mesoderm (ureter) germ layers.
GO:0005509 calcium ion binding	IDA PMID:7034958 Osteonectin, a bone-specific protein linking mineral to coll...	ACCEPT	Summary: Direct experimental demonstration of calcium binding by osteonectin in the seminal 1981 study. Reason: This is the foundational experimental evidence for SPARC calcium binding activity. The study demonstrated that osteonectin binds free calcium ions and showed this is a core molecular function. Supporting Evidence: PMID:7034958 Osteonectin is a 32,000 dalton bone-specific protein that binds selectively to both hydroxyapatite and collagen. When osteonectin is bound to insolubilized type I collagen, the resultant complex binds synthetic apatite crystals and free calcium ions.
GO:0005518 collagen binding	IDA PMID:7034958 Osteonectin, a bone-specific protein linking mineral to coll...	ACCEPT	Summary: Foundational experimental evidence demonstrating SPARC binds selectively to collagen type I. Reason: This 1981 study provided the first experimental demonstration that osteonectin/SPARC binds selectively to type I collagen, establishing collagen binding as a core molecular function. When bound to collagen, the complex also binds calcium and nucleates mineral deposition. Supporting Evidence: PMID:7034958 Osteonectin is a 32,000 dalton bone-specific protein that binds selectively to both hydroxyapatite and collagen. When osteonectin is bound to insolubilized type I collagen, the resultant complex binds synthetic apatite crystals and free calcium ions.
GO:0005737 cytoplasm	IDA PMID:11856645 Investigation of osteocalcin, osteonectin, and dentin sialop...	KEEP AS NON CORE	Summary: Cytoplasmic localization during biosynthesis in developing teeth. Reason: This study on developing human teeth detected osteonectin/SPARC in cytoplasm, consistent with biosynthetic/secretory pathway localization. As a secreted protein, SPARC transits through the cytoplasm but this is not its functional location. Supporting Evidence: PMID:11856645 Investigation of osteocalcin, osteonectin, and dentin sialophosphoprotein in developing human teeth.
GO:0005737 cytoplasm	IDA NOT PMID:1737102 Localization of platelet osteonectin at the internal face of...	ACCEPT	Summary: PMID:1737102 localized platelet osteonectin to alpha-granule membranes rather than cytoplasm. Reason: The study used immunogold labeling to localize osteonectin to the internal face of alpha-granule membranes, supporting a NOT cytoplasm annotation for this PMID. Supporting Evidence: PMID:1737102 Localization of platelet osteonectin at the internal face of the alpha-granule membranes in platelets and megakaryocytes.
GO:0005737 cytoplasm	IDA PMID:3400777 Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tiss...	KEEP AS NON CORE	Summary: Cytoplasmic staining in decidua and carcinoma tissues. Reason: This immunolocalization study in decidua and carcinoma showed cytoplasmic staining, consistent with biosynthetic/secretory pathway localization for this secreted ECM protein. Not the primary functional location. Supporting Evidence: PMID:3400777 Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane.
GO:0005739 mitochondrion	IDA NOT PMID:1737102 Localization of platelet osteonectin at the internal face of...	ACCEPT	Summary: PMID:1737102 did not detect mitochondrial localization of platelet osteonectin. Reason: This PMID reports alpha-granule membrane localization and supports a NOT mitochondrion annotation. Supporting Evidence: PMID:1737102 Localization of platelet osteonectin at the internal face of the alpha-granule membranes in platelets and megakaryocytes.
GO:0005886 plasma membrane	IDA NOT PMID:1737102 Localization of platelet osteonectin at the internal face of...	ACCEPT	Summary: PMID:1737102 localized osteonectin to alpha-granule membranes and did not report plasma membrane localization in resting platelets. Reason: The abstract indicates internal alpha-granule membrane localization and a redistribution to the surface upon activation, so GOA captures this PMID as NOT plasma membrane. Supporting Evidence: PMID:1737102 Localization of platelet osteonectin at the internal face of the alpha-granule membranes in platelets and megakaryocytes.
GO:0009986 cell surface	IDA PMID:3400777 Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tiss...	ACCEPT	Summary: Cell surface localization in decidua and carcinoma tissues. Reason: This immunolocalization study detected SPARC at cell surfaces in decidua and carcinoma. Cell surface localization is consistent with SPARC's counter-adhesive function and its ability to interact with cell surface receptors while also being deposited into the ECM. Supporting Evidence: PMID:3400777 Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues characterized by de novo formation of basement membrane.
GO:0031091 platelet alpha granule	IDA PMID:1737102 Localization of platelet osteonectin at the internal face of...	ACCEPT	Summary: Well-established localization of SPARC in platelet alpha granules. Reason: SPARC is a well-documented component of platelet alpha granules, where it is stored and released upon platelet activation. This is an established biological function of SPARC in hemostasis and wound healing. The study specifically localized osteonectin to the internal face of alpha-granule membranes. Supporting Evidence: PMID:1737102 Localization of platelet osteonectin at the internal face of the alpha-granule membranes in platelets and megakaryocytes.
GO:0031092 platelet alpha granule membrane	IDA PMID:1737102 Localization of platelet osteonectin at the internal face of...	ACCEPT	Summary: Specific localization to the internal face of platelet alpha granule membranes. Reason: This study specifically demonstrated SPARC localization at the internal face of alpha-granule membranes in platelets and megakaryocytes, representing a more specific localization than just the alpha granule lumen. This is well-supported experimental evidence. Supporting Evidence: PMID:1737102 Localization of platelet osteonectin at the internal face of the alpha-granule membranes in platelets and megakaryocytes.
GO:0031093 platelet alpha granule lumen	TAS Reactome:R-HSA-481007	ACCEPT	Summary: Reactome pathway annotation for SPARC in platelet degranulation. Reason: This Reactome annotation captures SPARC as a component released during platelet alpha granule exocytosis. This is consistent with experimental evidence showing SPARC in platelet alpha granules.
GO:0071682 endocytic vesicle lumen	TAS Reactome:R-HSA-2247513	KEEP AS NON CORE	Summary: Reactome annotation for SPARC uptake via STAB1-mediated endocytosis. Reason: This Reactome pathway describes STAB1 (stabilin-1/FEEL-1)-mediated endocytosis of SPARC. While this represents a clearance mechanism for extracellular SPARC, endocytic vesicle localization is not a core functional location but rather represents protein turnover/degradation.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2197770	ACCEPT	Summary: Reactome annotation for SPARC as STAB1 ligand. Reason: This Reactome pathway describes SPARC binding to STAB1 receptor, consistent with SPARC's extracellular localization where it can interact with cell surface receptors.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2247513	ACCEPT	Summary: Reactome annotation for STAB1-mediated endocytosis of extracellular SPARC. Reason: Consistent with SPARC's extracellular localization prior to receptor-mediated endocytosis.
GO:0005576 extracellular region	TAS Reactome:R-HSA-2424243	ACCEPT	Summary: Reactome annotation for SPARC binding to collagen, hydroxylapatite, and Ca2+. Reason: This Reactome pathway captures SPARC's core molecular interactions in the extracellular matrix, consistent with its matricellular function.
GO:0005576 extracellular region	TAS Reactome:R-HSA-481007	ACCEPT	Summary: Reactome annotation for SPARC release during platelet degranulation. Reason: Consistent with SPARC being released into the extracellular region during platelet alpha granule exocytosis.
GO:0005515 protein binding	IPI PMID:3402455 Complex formation of human thrombospondin with osteonectin.	REMOVE	Summary: Non-informative generic annotation for thrombospondin binding. Reason: While SPARC forms complexes with thrombospondin in the ECM, the generic "protein binding" term provides no functional insight. The biological significance of this interaction is unclear and does not represent a core molecular function of SPARC. Supporting Evidence: PMID:3402455 Complex formation of human thrombospondin with osteonectin.
GO:0005576 extracellular region	NAS PMID:14718574 The human plasma proteome: a nonredundant list developed by ...	ACCEPT	Summary: Non-traceable author statement identifying SPARC in human plasma proteome. Reason: SPARC is a known component of the human plasma proteome, consistent with its secreted nature and presence in blood from platelet alpha granules. This represents extracellular localization. Supporting Evidence: PMID:14718574 Epub 2004 Jan 12. The human plasma proteome: a nonredundant list developed by combination of four separate sources.
GO:0050839 cell adhesion molecule binding	NAS	NEW	Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:15389586 rSPARC activity was demonstrated and quantified with a rounding assay whereby the spreading of freshly plated cells was inhibited by recombinant SPARC in a concentration- and time-dependent manner.

Gene Description

Existing Annotations Review

Core Functions

SPARC binds to collagens I, IV, and V with sequence-specific recognition of the GVMGFO motif through five critical residues (R149, N156, L242, M245, E246) that form the collagen-binding epitope. This high-affinity interaction is central to SPARC's role in ECM organization and bone mineralization.

SPARC binds 8-10 calcium ions per molecule through two distinct mechanisms - low-affinity binding via the acidic N-terminal domain (5-8 Ca2+) and high-affinity binding via the C-terminal EF-hand domain. Calcium binding is essential for protein structure, stability, and collagen interaction.

SPARC functions as a matricellular counter-adhesive protein that disrupts focal adhesions, promotes cell rounding/deadhesion, and inhibits cell spreading. This activity regulates cell-matrix interactions and cell morphology during tissue remodeling, development, and wound healing.

References

Deep Research

Falcon

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