SPARC

id: P09486
gene_symbol: SPARC
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'SPARC (Secreted Protein Acidic and Rich in Cysteine), also known as
  osteonectin or BM-40, is a 303-amino acid matricellular glycoprotein that modulates
  cell-matrix interactions rather than providing direct structural support. SPARC
  exhibits modular architecture comprising an acidic N-terminal domain (Ca2+ binding),
  a central follistatin-like domain with a Kazal-like protease inhibitor motif, and
  a C-terminal extracellular calcium-binding (EC) domain containing two EF-hand motifs.
  The protein binds 8-10 Ca2+ ions per molecule with both high-affinity (EF-hand)
  and low-affinity (acidic domain) sites. SPARC is a high-affinity collagen-binding
  protein with sequence-specific recognition of the GVMGFO motif in collagens I, IV,
  and V. Its primary biological role is as a counter-adhesive factor that disrupts
  focal adhesions and promotes cell rounding/deadhesion, paradoxically regulating
  cell-matrix interactions through context-dependent effects on cell adhesion, migration,
  and ECM assembly. SPARC also functions in regulating angiogenesis (both pro- and
  anti-angiogenic depending on context), bone mineralization by linking hydroxyapatite
  to collagen, and tissue remodeling during wound healing and development. The protein
  is highly expressed in tissues undergoing morphogenesis, remodeling, and repair.
  Recessive mutations in SPARC cause osteogenesis imperfecta type 17 (OI17), highlighting
  its essential role in collagen secretion and bone matrix organization.'
existing_annotations:
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core localization supported by phylogenetic inference and extensive
      experimental evidence.
    action: ACCEPT
    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.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: General extracellular localization supported by phylogenetic 
      analysis and experimental data.
    action: ACCEPT
    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.
- term:
    id: GO:0048752
    label: semicircular canal morphogenesis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetically-inferred role in inner ear development.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0050807
    label: regulation of synapse organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Phylogenetically-inferred role in synapse organization.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Core molecular function of SPARC supported by phylogenetic 
      inference, direct biochemical evidence, and structural studies showing 
      multiple Ca2+ binding sites.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7034958
      supporting_text: "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."
    - reference_id: PMID:9501084
      supporting_text: "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."
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate annotation via InterPro mapping, consistent with IBA and 
      IDA evidence.
    action: ACCEPT
    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.
- term:
    id: GO:0005604
    label: basement membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Well-supported localization to basement membrane supported by 
      UniProt subcellular location vocabulary and experimental studies.
    action: ACCEPT
    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.
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Duplicate annotation consistent with IBA evidence.
    action: ACCEPT
    reason: This IEA annotation from InterPro is consistent with experimental 
      evidence and can be retained.
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Overly generic term when specific calcium ion binding is 
      documented.
    action: MODIFY
    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_replacement_terms:
    - id: GO:0005509
      label: calcium ion binding
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18808384
  review:
    summary: Non-informative generic annotation for interaction with bacterial 
      protein FafA from Finegoldia magna.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:18808384
      supporting_text: Epub 2008 Sep 18. Identification of a novel protein 
        promoting the colonization and survival of Finegoldia magna, a bacterial
        commensal and opportunistic pathogen.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19011090
  review:
    summary: Non-informative generic annotation from collagen binding study.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:19011090
      supporting_text: Structural basis of sequence-specific collagen 
        recognition by SPARC.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20926826
  review:
    summary: Non-informative generic annotation for interaction with myocilin.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:20926826
      supporting_text: 'Print 2011 Jan. Interaction of recombinant myocilin with the
        matricellular protein SPARC: functional implications.'
- term:
    id: GO:0005201
    label: extracellular matrix structural constituent
  evidence_type: RCA
  original_reference_id: PMID:28327460
  review:
    summary: Mischaracterization of SPARC as a structural ECM component.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:28327460
      supporting_text: Epub 2017 Mar 7. Comprehensive proteomic characterization
        of stem cell-derived extracellular matrices.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: HDA
  original_reference_id: PMID:28327460
  review:
    summary: High-throughput proteomic identification of SPARC in ECM consistent
      with core localization.
    action: ACCEPT
    reason: This HDA annotation from a proteomic study of stem cell-derived ECM 
      is consistent with the well-established ECM localization of SPARC.
    supported_by:
    - reference_id: PMID:28327460
      supporting_text: Epub 2017 Mar 7. Comprehensive proteomic characterization
        of stem cell-derived extracellular matrices.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9612277
  review:
    summary: Plasma membrane localization is supported by experimental evidence,
      though this specific citation may be from a pathway context.
    action: ACCEPT
    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.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: HDA
  original_reference_id: PMID:27068509
  review:
    summary: High-throughput proteomic identification in varicose vein ECM.
    action: ACCEPT
    reason: This proteomic study of ECM remodeling in varicose veins identified 
      SPARC, consistent with its core extracellular/ECM localization.
    supported_by:
    - reference_id: PMID:27068509
      supporting_text: 'Apr 11. Extracellular matrix remodelling in response to venous
        hypertension: proteomics of human varicose veins.'
- term:
    id: GO:0001937
    label: negative regulation of endothelial cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:12867428
  review:
    summary: Direct experimental evidence for SPARC peptides inhibiting 
      endothelial cell proliferation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12867428
      supporting_text: "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."
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IDA
  original_reference_id: PMID:9501084
  review:
    summary: Crystal structure and mutagenesis study definitively mapping the 
      collagen-binding epitope in SPARC with sequence-specific recognition.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:9501084
      supporting_text: "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."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15389586
  review:
    summary: Experimental evidence for intracellular SPARC localization in 
      cycling urothelial cells.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:15389586
      supporting_text: "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."
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:15389586
  review:
    summary: Experimental evidence for SPARC localization at apical plasma 
      membrane of differentiated urothelial cells.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15389586
      supporting_text: "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."
- term:
    id: GO:0010595
    label: positive regulation of endothelial cell migration
  evidence_type: IDA
  original_reference_id: PMID:12867428
  review:
    summary: SPARC-derived peptides stimulate endothelial cell migration in 
      collagen gels.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12867428
      supporting_text: "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."
- term:
    id: GO:0016363
    label: nuclear matrix
  evidence_type: IDA
  original_reference_id: PMID:15389586
  review:
    summary: Experimental evidence for SPARC in nuclear matrix, colocalized with
      Ki-67.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:15389586
      supporting_text: "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."
- term:
    id: GO:0016525
    label: negative regulation of angiogenesis
  evidence_type: IDA
  original_reference_id: PMID:12867428
  review:
    summary: SPARC-derived peptides inhibit angiogenesis in vivo.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:12867428
      supporting_text: "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."
- term:
    id: GO:0022604
    label: regulation of cell morphogenesis
  evidence_type: IDA
  original_reference_id: PMID:15389586
  review:
    summary: SPARC inhibits cell spreading and promotes cell rounding in 
      urothelial cells.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:15389586
      supporting_text: "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."
- term:
    id: GO:0005509
    label: calcium ion binding
  evidence_type: IDA
  original_reference_id: PMID:7034958
  review:
    summary: Direct experimental demonstration of calcium binding by osteonectin
      in the seminal 1981 study.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7034958
      supporting_text: "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."
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IDA
  original_reference_id: PMID:7034958
  review:
    summary: Foundational experimental evidence demonstrating SPARC binds 
      selectively to collagen type I.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:7034958
      supporting_text: "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."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:11856645
  review:
    summary: Cytoplasmic localization during biosynthesis in developing teeth.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:11856645
      supporting_text: Investigation of osteocalcin, osteonectin, and dentin 
        sialophosphoprotein in developing human teeth.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:1737102
  negated: true
  review:
    summary: PMID:1737102 localized platelet osteonectin to alpha-granule 
      membranes rather than cytoplasm.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1737102
      supporting_text: Localization of platelet osteonectin at the internal face
        of the alpha-granule membranes in platelets and megakaryocytes.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:3400777
  review:
    summary: Cytoplasmic staining in decidua and carcinoma tissues.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:3400777
      supporting_text: Osteonectin/SPARC/BM-40 in human decidua and carcinoma, 
        tissues characterized by de novo formation of basement membrane.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:1737102
  negated: true
  review:
    summary: PMID:1737102 did not detect mitochondrial localization of platelet 
      osteonectin.
    action: ACCEPT
    reason: This PMID reports alpha-granule membrane localization and supports a
      NOT mitochondrion annotation.
    supported_by:
    - reference_id: PMID:1737102
      supporting_text: Localization of platelet osteonectin at the internal face
        of the alpha-granule membranes in platelets and megakaryocytes.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:1737102
  negated: true
  review:
    summary: PMID:1737102 localized osteonectin to alpha-granule membranes and 
      did not report plasma membrane localization in resting platelets.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1737102
      supporting_text: Localization of platelet osteonectin at the internal face
        of the alpha-granule membranes in platelets and megakaryocytes.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IDA
  original_reference_id: PMID:3400777
  review:
    summary: Cell surface localization in decidua and carcinoma tissues.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:3400777
      supporting_text: Osteonectin/SPARC/BM-40 in human decidua and carcinoma, 
        tissues characterized by de novo formation of basement membrane.
- term:
    id: GO:0031091
    label: platelet alpha granule
  evidence_type: IDA
  original_reference_id: PMID:1737102
  review:
    summary: Well-established localization of SPARC in platelet alpha granules.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1737102
      supporting_text: Localization of platelet osteonectin at the internal face
        of the alpha-granule membranes in platelets and megakaryocytes.
- term:
    id: GO:0031092
    label: platelet alpha granule membrane
  evidence_type: IDA
  original_reference_id: PMID:1737102
  review:
    summary: Specific localization to the internal face of platelet alpha 
      granule membranes.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1737102
      supporting_text: Localization of platelet osteonectin at the internal face
        of the alpha-granule membranes in platelets and megakaryocytes.
- term:
    id: GO:0031093
    label: platelet alpha granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: Reactome pathway annotation for SPARC in platelet degranulation.
    action: ACCEPT
    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.
- term:
    id: GO:0071682
    label: endocytic vesicle lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2247513
  review:
    summary: Reactome annotation for SPARC uptake via STAB1-mediated 
      endocytosis.
    action: KEEP_AS_NON_CORE
    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.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2197770
  review:
    summary: Reactome annotation for SPARC as STAB1 ligand.
    action: ACCEPT
    reason: This Reactome pathway describes SPARC binding to STAB1 receptor, 
      consistent with SPARC's extracellular localization where it can interact 
      with cell surface receptors.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2247513
  review:
    summary: Reactome annotation for STAB1-mediated endocytosis of extracellular
      SPARC.
    action: ACCEPT
    reason: Consistent with SPARC's extracellular localization prior to 
      receptor-mediated endocytosis.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2424243
  review:
    summary: Reactome annotation for SPARC binding to collagen, hydroxylapatite,
      and Ca2+.
    action: ACCEPT
    reason: This Reactome pathway captures SPARC's core molecular interactions 
      in the extracellular matrix, consistent with its matricellular function.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-481007
  review:
    summary: Reactome annotation for SPARC release during platelet 
      degranulation.
    action: ACCEPT
    reason: Consistent with SPARC being released into the extracellular region 
      during platelet alpha granule exocytosis.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:3402455
  review:
    summary: Non-informative generic annotation for thrombospondin binding.
    action: REMOVE
    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.
    supported_by:
    - reference_id: PMID:3402455
      supporting_text: Complex formation of human thrombospondin with 
        osteonectin.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: NAS
  original_reference_id: PMID:14718574
  review:
    summary: Non-traceable author statement identifying SPARC in human plasma 
      proteome.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:14718574
      supporting_text: 'Epub 2004 Jan 12. The human plasma proteome: a nonredundant
        list developed by combination of four separate sources.'
- term:
    id: GO:0050839
    label: cell adhesion molecule binding
  evidence_type: NAS
  review:
    summary: Added to align core_functions with existing annotations.
    action: NEW
    reason: Core function term not present in existing_annotations.
    supported_by:
    - reference_id: PMID:15389586
      supporting_text: "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."
core_functions:
- description: 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.
  molecular_function:
    id: GO:0005518
    label: collagen binding
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:9501084
    supporting_text: "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."
  - reference_id: PMID:19011090
    supporting_text: "SPARC recognizes the GVMGFO motifs of the middle and trailing
      collagen chains, burying a total of 720 A(2) of solvent-accessible collagen
      surface."
- description: 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.
  molecular_function:
    id: GO:0005509
    label: calcium ion binding
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:7034958
    supporting_text: "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."
- description: 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.
  molecular_function:
    id: GO:0050839
    label: cell adhesion molecule binding
  directly_involved_in:
  - id: GO:0022604
    label: regulation of cell morphogenesis
  locations:
  - id: GO:0005576
    label: extracellular region
  supported_by:
  - reference_id: PMID:15389586
    supporting_text: "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."
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with 
    GO terms.
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular 
    Location vocabulary mapping, accompanied by conservative changes to GO terms
    applied by UniProt.
  findings: []
- id: PMID:11856645
  title: Investigation of osteocalcin, osteonectin, and dentin 
    sialophosphoprotein in developing human teeth.
  findings: []
- id: PMID:12867428
  title: Cleavage of the matricellular protein SPARC by matrix metalloproteinase
    3 produces polypeptides that influence angiogenesis.
  findings: []
- id: PMID:14718574
  title: 'The human plasma proteome: a nonredundant list developed by combination
    of four separate sources.'
  findings: []
- id: PMID:15389586
  title: Spreading of embryologically distinct urothelial cells is inhibited by 
    SPARC.
  findings: []
- id: PMID:1737102
  title: Localization of platelet osteonectin at the internal face of the 
    alpha-granule membranes in platelets and megakaryocytes.
  findings: []
- id: PMID:18808384
  title: Identification of a novel protein promoting the colonization and 
    survival of Finegoldia magna, a bacterial commensal and opportunistic 
    pathogen.
  findings: []
- id: PMID:19011090
  title: Structural basis of sequence-specific collagen recognition by SPARC.
  findings: []
- id: PMID:20926826
  title: 'Interaction of recombinant myocilin with the matricellular protein SPARC:
    functional implications.'
  findings: []
- id: PMID:27068509
  title: 'Extracellular matrix remodelling in response to venous hypertension: proteomics
    of human varicose veins.'
  findings: []
- id: PMID:28327460
  title: Comprehensive proteomic characterization of stem cell-derived 
    extracellular matrices.
  findings: []
- id: PMID:3400777
  title: Osteonectin/SPARC/BM-40 in human decidua and carcinoma, tissues 
    characterized by de novo formation of basement membrane.
  findings: []
- id: PMID:3402455
  title: Complex formation of human thrombospondin with osteonectin.
  findings: []
- id: PMID:7034958
  title: Osteonectin, a bone-specific protein linking mineral to collagen.
  findings: []
- id: PMID:9501084
  title: Crystal structure and mapping by site-directed mutagenesis of the 
    collagen-binding epitope of an activated form of BM-40/SPARC/osteonectin.
  findings: []
- id: Reactome:R-HSA-2197770
  title: STAB1 (FEEL-1) binds ligands
  findings: []
- id: Reactome:R-HSA-2247513
  title: STAB1:ligand is endocytosed
  findings: []
- id: Reactome:R-HSA-2424243
  title: SPARC binds Collagen type I fibril, hydroxylapatite and Ca2+
  findings: []
- id: Reactome:R-HSA-481007
  title: Exocytosis of platelet alpha granule contents
  findings: []
- id: Reactome:R-HSA-9612277
  title: SPARC gene transcription is stimulated by ERBB4s80
  findings: []