STC1

id: P52823
gene_symbol: STC1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Stanniocalcin-1 (STC1) is a secreted homodimeric glycoprotein hormone of the stanniocalcin family,
  originally characterized as a calcium-regulating hormone in fish and now known to function as a
  pleiotropic autocrine/paracrine regulator in mammals. STC1 stimulates renal phosphate reabsorption
  and inhibits calcium ion transport, contributing to mineral homeostasis. Recent work has identified
  STC1 as a potent inhibitor (Ki = 68 pM) of the metalloproteinase PAPP-A, thereby modulating IGF
  signaling through preventing cleavage of IGF-binding proteins. STC1 also functions as a selective
  modulator of HGF-induced angiogenic responses and inhibits transendothelial migration of
  inflammatory cells. The protein is widely expressed and is upregulated under hypoxia/stress
  conditions. In the heart, STC1 inhibits L-type calcium channels and may contribute to cardiac
  calcium homeostasis.
existing_annotations:
  - term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation inferred from phylogenetic analysis. STC1 was originally characterized as a
        calcium-regulating hormone in fish where it functions in preventing hypercalcemia [PMID:8700837].
        Human STC1 has been shown to reversibly inhibit transmembrane calcium currents through L-channels
        in cardiomyocytes, slowing endogenous beating rate and diminishing intracellular calcium rise
        with each contraction [PMID:12663264]. The role in intracellular calcium homeostasis is well
        supported by experimental evidence across the stanniocalcin family.
      action: ACCEPT
      reason: >-
        This is a core conserved function of the stanniocalcin family. Multiple studies demonstrate
        STC1's role in calcium homeostasis - it inhibits calcium uptake in fish [PMID:8700837] and
        inhibits L-channel calcium currents in mammalian cardiomyocytes [PMID:12663264]. The IBA
        annotation appropriately captures this evolutionarily conserved function.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "Recombinant hSTC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat"
        - reference_id: PMID:12663264
          supporting_text: "Addition of recombinant STC1 to the medium of cultured rat cardiomyocytes slows their endogenous beating rate and diminishes the rise in intracellular calcium with each contraction"

  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: >-
        IBA annotation for cellular component. STC1 is a secreted glycoprotein hormone, consistent
        with its localization to the extracellular space. UniProt clearly indicates "Secreted" as
        the subcellular location, and the protein has a signal peptide (residues 1-17) [PMID:8700837,
        UniProt P52823].
      action: ACCEPT
      reason: >-
        STC1 is well-established as a secreted hormone. The protein has a signal peptide and is
        released to function in autocrine/paracrine signaling. This annotation is accurate and
        represents a core aspect of STC1 biology.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "We have isolated a human cDNA clone encoding the mammalian homolog of stanniocalcin (STC), a calcium- and phosphate-regulating hormone that was first described in fishes where it functions in preventing hypercalcemia"
        - reference_id: PMID:14500721
          supporting_text: "Stanniocalcin 1 (STC1) is a secreted glycoprotein originally described as a hormone involved in calcium and phosphate homeostasis in bony fishes"

  - term:
      id: GO:0007165
      label: signal transduction
    evidence_type: IEA
    original_reference_id: GO_REF:0000108
    review:
      summary: >-
        IEA annotation based on logical inference. STC1 functions as a signaling molecule that
        modulates multiple pathways including HGF/c-met signaling [PMID:14500721] and has been
        shown to bind Notch1 to activate Notch signaling in cancer contexts [deep research].
        However, "signal transduction" is a very broad term.
      action: ACCEPT
      reason: >-
        While broad, this annotation is accurate. STC1 is a secreted hormone that acts via
        autocrine/paracrine mechanisms to regulate cellular responses. It modulates HGF-induced
        signaling and affects downstream pathways like focal adhesion kinase. As an IEA annotation,
        the breadth is acceptable given the well-documented signaling roles of STC1.
      supported_by:
        - reference_id: PMID:14500721
          supporting_text: "STC1 did not inhibit HGF-induced c-met receptor phosphorylation, but did block HGF-induced focal adhesion kinase activation"

  - term:
      id: GO:0005179
      label: hormone activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for molecular function. STC1 is classified as a hormone in UniProt and was
        originally identified as the mammalian homolog of fish stanniocalcin, a calcium-regulating
        hormone. STC1 acts via autocrine/paracrine mechanisms to regulate mineral homeostasis and
        cellular responses [PMID:8700837].
      action: ACCEPT
      reason: >-
        This accurately captures STC1's function as a hormone. The stanniocalcin family was
        originally characterized as hormonal regulators of mineral metabolism. STC1 is secreted
        and acts on target cells to modulate calcium/phosphate handling and other cellular processes.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "Human stanniocalcin: a possible hormonal regulator of mineral metabolism"

  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: >-
        IEA annotation for cellular component. This is a broader parent term of "extracellular space"
        (GO:0005615) which is already annotated with IBA evidence. Both are correct - STC1 is a
        secreted protein that localizes to the extracellular region.
      action: ACCEPT
      reason: >-
        Accurate annotation. STC1 is a secreted glycoprotein and localizes to the extracellular
        region. This IEA annotation is consistent with the more specific IBA annotation for
        extracellular space.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "Human STC (hSTC) was found to be 247 amino acids long"

  - term:
      id: GO:0001503
      label: ossification
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 has been shown to regulate growth plate
        chondrogenesis and bone development in studies using recombinant human STC1 [PMID:16377640].
        The annotation is supported by evidence that STC1 overexpression causes dwarfism in mice.
      action: KEEP_AS_NON_CORE
      reason: >-
        While STC1 does affect bone development and the annotation is accurate based on experimental
        studies, ossification is not a core function of STC1. The primary functions are mineral
        homeostasis, PAPP-A inhibition, and angiogenesis regulation. Bone effects may be secondary
        to its role in phosphate handling and IGF signaling modulation.
      supported_by:
        - reference_id: PMID:16377640
          supporting_text: "STC1 inhibits longitudinal bone growth directly at the growth plate"

  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs for cellular component. Duplicate of the IBA
        annotation above. STC1 is clearly a secreted protein localized to the extracellular space.
      action: ACCEPT
      reason: >-
        Accurate annotation supported by multiple lines of evidence. Having both IBA and IEA
        evidence for the same term is acceptable and reflects consistent annotation across
        species and methods.
      supported_by:
        - reference_id: PMID:14500721
          supporting_text: "Stanniocalcin 1 (STC1) is a secreted glycoprotein"

  - term:
      id: GO:0007566
      label: embryo implantation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 expression has been associated with
        reproductive processes and decidualization, which relates to embryo implantation.
        However, direct experimental evidence for STC1's role in embryo implantation is limited.
      action: KEEP_AS_NON_CORE
      reason: >-
        This annotation may reflect expression data or ortholog-based inference rather than
        direct functional evidence. STC1's pleiotropic nature means it is expressed in many
        tissues including reproductive organs, but embryo implantation is not considered a
        primary function based on available literature.
      supported_by:
        - reference_id: file:human/STC1/STC1-deep-research-falcon.md
          supporting_text: "STC1 is expressed in reproductive organs"

  - term:
      id: GO:0016324
      label: apical plasma membrane
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 has been detected on the apical surface
        of endothelial cells in vivo [PMID:17032941]. The annotation is consistent with STC1's
        role in regulating transendothelial migration.
      action: ACCEPT
      reason: >-
        Supported by direct detection of STC1 on the apical surface of endothelial cells.
        This localization is relevant to STC1's function in modulating inflammatory cell
        transmigration and endothelial function.
      supported_by:
        - reference_id: PMID:17032941
          supporting_text: "STC1 regulates gene expression in cultured endothelial cells and is detected on the apical surface of endothelial cells in vivo"

  - term:
      id: GO:0033280
      label: response to vitamin D
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 is involved in mineral homeostasis and
        vitamin D is a key regulator of calcium metabolism. The connection is plausible given
        STC1's role in calcium/phosphate handling, but direct evidence from the publications
        reviewed is limited.
      action: KEEP_AS_NON_CORE
      reason: >-
        While the connection between STC1 and vitamin D signaling is biologically plausible
        given their shared roles in mineral metabolism, this is not a core function based
        on available direct experimental evidence. The annotation may reflect expression
        regulation rather than direct functional involvement.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "The evidence suggests that mammalian STC, like its piscine counterpart, is a regulator of mineral homeostasis"

  - term:
      id: GO:0046697
      label: decidualization
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 is expressed in reproductive tissues
        and may have roles in uterine biology. However, direct evidence for STC1 function in
        decidualization from the primary literature reviewed is limited.
      action: KEEP_AS_NON_CORE
      reason: >-
        This annotation likely reflects expression patterns in uterine tissue rather than
        direct functional evidence. Decidualization is not a primary function of STC1 based
        on the core literature, though expression in reproductive organs is documented.
      supported_by:
        - reference_id: file:human/STC1/STC1-deep-research-falcon.md
          supporting_text: "STC1 is expressed in reproductive organs"

  - term:
      id: GO:0071320
      label: cellular response to cAMP
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 expression may be regulated by cAMP
        signaling, but direct evidence for functional involvement in cellular response to
        cAMP is limited in the literature reviewed.
      action: KEEP_AS_NON_CORE
      reason: >-
        This annotation likely reflects transcriptional regulation of STC1 by cAMP rather
        than STC1 being a mediator of cAMP responses. Not a core function based on
        available evidence.
      supported_by:
        - reference_id: file:human/STC1/STC1-deep-research-falcon.md
          supporting_text: "STC1 is induced by stress/hypoxia pathways"

  - term:
      id: GO:0071385
      label: cellular response to glucocorticoid stimulus
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 expression may be regulated by
        glucocorticoids, but this reflects transcriptional regulation rather than STC1
        being a core mediator of glucocorticoid responses.
      action: KEEP_AS_NON_CORE
      reason: >-
        This annotation likely reflects STC1 being a glucocorticoid-responsive gene rather
        than a primary mediator of glucocorticoid responses. Not a core function of STC1.
      supported_by:
        - reference_id: file:human/STC1/STC1-deep-research-falcon.md
          supporting_text: "STC1 is widely expressed in many organs"

  - term:
      id: GO:0071456
      label: cellular response to hypoxia
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: >-
        IEA annotation transferred from orthologs. STC1 is known to be induced by hypoxia
        and stress pathways. The deep research indicates STC1 is linked to hypoxia-driven
        programs and functions in stress responses [deep research]. STC1 upregulation in
        failing hearts is relevant to hypoxic stress [PMID:12663264].
      action: ACCEPT
      reason: >-
        This annotation is well-supported. STC1 is induced by hypoxia/stress and may play
        protective roles under hypoxic conditions. The protein is markedly upregulated in
        failing hearts (a hypoxic condition) and is reduced after mechanical unloading
        [PMID:12663264]. Hypoxia regulation is a documented aspect of STC1 biology.
      supported_by:
        - reference_id: PMID:12663264
          supporting_text: "STC1 protein is markedly upregulated in cardiomyocytes and arterial walls of failing hearts pre-LVAD and is strikingly reduced after LVAD treatment"
        - reference_id: file:human/STC1/STC1-deep-research-falcon.md
          supporting_text: "STC1 is linked to hypoxia-driven programs and stress responses"

  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: >-
        IPI annotation based on high-throughput interactome study (HuRI). The study identified
        STC1 interacting with MEOX2. However, "protein binding" is uninformative - it does not
        specify the functional nature of the interaction.
      action: MODIFY
      reason: >-
        "Protein binding" is too vague and uninformative. STC1 has specific and functionally
        important protein interactions - most notably it binds and inhibits PAPP-A with very
        high affinity (KD = 75 pM) [PMID:26195635]. It also forms homodimers. The annotation
        should be replaced with more specific molecular function terms.
      proposed_replacement_terms:
        - id: GO:0008191
          label: metalloendopeptidase inhibitor activity
      additional_reference_ids:
        - PMID:26195635
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: "Global insights into cellular organization and genome function require comprehensive understanding of the interactome networks"

  - term:
      id: GO:0042802
      label: identical protein binding
    evidence_type: IPI
    original_reference_id: PMID:26195635
    review:
      summary: >-
        IPI annotation from PMID:26195635 which demonstrated STC1 homodimerization. The paper
        states that STC1 is a "disulfide-bound homodimeric glycoprotein." UniProt also confirms
        "Homodimer; disulfide-linked." IntAct records STC1-STC1 interaction.
      action: ACCEPT
      reason: >-
        This annotation is well-supported by the primary literature. STC1 functions as a
        homodimer linked by disulfide bonds. This is a core structural feature of the protein.
      supported_by:
        - reference_id: PMID:26195635
          supporting_text: "Stanniocalcin-1 (STC1) is a disulfide-bound homodimeric glycoprotein"

  - term:
      id: GO:0030336
      label: negative regulation of cell migration
    evidence_type: IDA
    original_reference_id: PMID:17032941
    review:
      summary: >-
        IDA annotation based on direct experimental evidence. The study showed that STC1 inhibits
        transmigration of macrophages and T lymphocytes through endothelial cell monolayers
        [PMID:17032941]. STC1 also inhibits chemotaxis of macrophage-like cells.
      action: ACCEPT
      reason: >-
        Well-supported by direct experimental evidence. STC1 inhibits the migration of specific
        immune cell types (macrophages, T lymphocytes) across endothelial barriers. This is
        a core functional role consistent with STC1's autocrine/paracrine signaling function.
      supported_by:
        - reference_id: PMID:17032941
          supporting_text: "STC1 inhibited transmigration of macrophages and T lymphocytes through quiescent or IL-1beta-activated HUVECs but did not attenuate the transmigration of neutrophils and B lymphocytes"

  - term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    evidence_type: IDA
    original_reference_id: PMID:8700837
    review:
      summary: >-
        IDA annotation from the foundational paper characterizing human STC1. The study showed
        that recombinant hSTC inhibited calcium transport in fish gills and stimulated renal
        phosphate reabsorption in rats, indicating a role in mineral metabolism and calcium
        homeostasis [PMID:8700837].
      action: ACCEPT
      reason: >-
        This is the core conserved function of stanniocalcins - regulation of calcium homeostasis.
        The original identification of human STC1 demonstrated its ability to inhibit calcium
        transport, consistent with fish STC function. This is fundamental to STC1 biology.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "Recombinant hSTC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat"

  - term:
      id: GO:0051926
      label: negative regulation of calcium ion transport
    evidence_type: IDA
    original_reference_id: PMID:8700837
    review:
      summary: >-
        IDA annotation from the foundational paper. STC1 inhibits calcium transport - demonstrated
        by recombinant hSTC inhibiting gill calcium transport in fish [PMID:8700837]. Further
        supported by patch-clamp studies showing STC1 inhibits L-channel calcium currents in
        cardiomyocytes [PMID:12663264].
      action: ACCEPT
      reason: >-
        Well-supported core function. STC1 negatively regulates calcium transport across multiple
        experimental systems and cell types. This is the primary molecular activity underlying
        STC1's role in calcium homeostasis.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "Recombinant hSTC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat"
        - reference_id: PMID:12663264
          supporting_text: "using whole cell patch-clamp studies in cultured rat cardiomyocytes, we find that addition of STC1 to the bath causes reversible inhibition of transmembrane calcium currents through L-channels"

  - term:
      id: GO:1903403
      label: negative regulation of renal phosphate excretion
    evidence_type: IDA
    original_reference_id: PMID:8700837
    review:
      summary: >-
        IDA annotation from the foundational paper. The study demonstrated that recombinant hSTC
        "stimulated renal phosphate reabsorption in the rat" [PMID:8700837]. Stimulating
        reabsorption is equivalent to negatively regulating excretion.
      action: ACCEPT
      reason: >-
        Well-supported core function. STC1 stimulates renal phosphate reabsorption, thereby
        reducing phosphate excretion. This is part of STC1's fundamental role as a regulator
        of mineral homeostasis, specifically phosphate handling in the kidney.
      supported_by:
        - reference_id: PMID:8700837
          supporting_text: "Recombinant hSTC inhibited the gill transport of calcium when administered to fish and stimulated renal phosphate reabsorption in the rat"

  - term:
      id: GO:0001886
      label: endothelial cell morphogenesis
    evidence_type: IDA
    original_reference_id: PMID:14500721
    review:
      summary: >-
        IDA annotation from the angiogenesis study. The paper showed that STC1 is "a selective
        modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis"
        [PMID:14500721]. STC1 acts as a "stop signal" or stabilizing factor for blood vessel
        maturation.
      action: ACCEPT
      reason: >-
        Supported by direct experimental evidence showing STC1 modulates HGF-induced endothelial
        morphogenesis. This is a well-characterized function where STC1 acts to regulate the
        maturation and morphogenesis of endothelial cells during angiogenesis.
      supported_by:
        - reference_id: PMID:14500721
          supporting_text: "STC1 is a selective modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis, but not proliferation"

  - term:
      id: GO:0003421
      label: growth plate cartilage axis specification
    evidence_type: IDA
    original_reference_id: PMID:16377640
    review:
      summary: >-
        IDA annotation from the chondrogenesis study. The paper demonstrated that STC1 acts as
        a "paracrine regulator of growth plate chondrogenesis" affecting growth plate
        chondrocyte proliferation and differentiation [PMID:16377640].
      action: KEEP_AS_NON_CORE
      reason: >-
        While the annotation is supported by experimental evidence, "growth plate cartilage axis
        specification" is a very specific developmental term. The study primarily showed effects
        on chondrocyte proliferation and differentiation, which may be secondary to STC1's
        effects on phosphate transport. This is not a primary molecular function.
      supported_by:
        - reference_id: PMID:16377640
          supporting_text: "STC1 inhibits longitudinal bone growth directly at the growth plate"

  - term:
      id: GO:0035988
      label: chondrocyte proliferation
    evidence_type: IDA
    original_reference_id: PMID:16377640
    review:
      summary: >-
        IDA annotation from the chondrogenesis study. The paper directly showed that rhSTC
        "suppressed metatarsal growth, growth plate chondrocyte proliferation and
        hypertrophy/differentiation" [PMID:16377640].
      action: KEEP_AS_NON_CORE
      reason: >-
        Supported by direct experimental evidence but represents a tissue-specific effect rather
        than core function. The effects on chondrocyte proliferation appear to be mediated through
        phosphate transport modulation rather than direct regulation of proliferation pathways.
      supported_by:
        - reference_id: PMID:16377640
          supporting_text: "rhSTC suppressed metatarsal growth, growth plate chondrocyte proliferation and hypertrophy/differentiation"

  - term:
      id: GO:0044070
      label: regulation of monoatomic anion transport
    evidence_type: IDA
    original_reference_id: PMID:16377640
    review:
      summary: >-
        IDA annotation from the chondrogenesis study. The paper showed that rhSTC "increased
        phosphate uptake" in chondrocytes and that the effects were reversed by phosphonoformic
        acid, an inhibitor of phosphate transport [PMID:16377640].
      action: ACCEPT
      reason: >-
        Well-supported annotation consistent with STC1's core function in mineral ion transport.
        The study directly demonstrated that STC1 regulates phosphate (a monoatomic anion)
        transport in chondrocytes, mechanistically linking to effects on bone development.
      supported_by:
        - reference_id: PMID:16377640
          supporting_text: "In cultured chondrocytes, rhSTC increased phosphate uptake... All these effects were reversed by culturing chondrocytes with rhSTC and phosphonoformic acid, an inhibitor of phosphate transport"

  - term:
      id: GO:0060348
      label: bone development
    evidence_type: IDA
    original_reference_id: PMID:16377640
    review:
      summary: >-
        IDA annotation from the chondrogenesis study. The paper demonstrated STC1's role in
        regulating longitudinal bone growth through effects on growth plate chondrogenesis.
        STC1 overexpression in mice causes dwarfism [PMID:16377640].
      action: KEEP_AS_NON_CORE
      reason: >-
        While supported by experimental evidence, bone development effects are likely secondary
        to STC1's primary role in regulating phosphate transport and possibly IGF signaling
        (via PAPP-A inhibition). Not a core molecular function of STC1.
      supported_by:
        - reference_id: PMID:16377640
          supporting_text: "STC1 inhibits longitudinal bone growth directly at the growth plate. Such growth inhibition, likely mediated by an increased chondrocyte phosphate uptake"

  - term:
      id: GO:0090280
      label: positive regulation of calcium ion import
    evidence_type: IDA
    original_reference_id: PMID:17032941
    review:
      summary: >-
        IDA annotation from PMID:17032941. However, this annotation appears inconsistent with
        the major body of evidence showing STC1 INHIBITS calcium transport. The paper focuses
        on endothelial function and inflammatory cell migration, and the abstract states STC1
        "may involve attenuation of the intracellular calcium signal."
      action: REMOVE
      reason: >-
        This annotation appears to be erroneous. The overwhelming evidence shows STC1 INHIBITS
        calcium transport and reduces intracellular calcium levels [PMID:8700837, PMID:12663264].
        PMID:17032941 actually states STC1 attenuates intracellular calcium signals in chemotaxis.
        The annotation should be removed as it contradicts the established biology of STC1.
      supported_by:
        - reference_id: PMID:17032941
          supporting_text: "The mammalian counterpart of the fish calcium-regulating hormone stanniocalcin-1 (STC1) inhibits monocyte chemotactic protein-1- and stromal-derived factor-1alpha (SDF-1alpha)-mediated chemotaxis and diminishes chemokinesis in macrophage-like RAW264.7 and U937 cells in a manner that may involve attenuation of the intracellular calcium signal"

  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:12663264
    review:
      summary: >-
        IDA annotation from the cardiomyocyte study. The paper states "STC1 is diffusely expressed
        in cardiomyocytes, although nuclear predominance is apparent" [PMID:12663264]. Nuclear
        localization of a secreted protein is unusual but was observed in this study.
      action: ACCEPT
      reason: >-
        Supported by direct immunolocalization studies in cardiomyocytes showing nuclear
        predominance. While STC1 is primarily a secreted protein, some intracellular localization
        has been documented, possibly related to internalization mechanisms.
      supported_by:
        - reference_id: PMID:12663264
          supporting_text: "STC1 is diffusely expressed in cardiomyocytes, although nuclear predominance is apparent"

  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:12663264
    review:
      summary: >-
        IDA annotation from the cardiomyocyte study. The paper states "STC1 is diffusely expressed
        in cardiomyocytes" indicating cytoplasmic localization [PMID:12663264]. As a secreted
        protein, STC1 transits through the cytoplasm during biosynthesis.
      action: ACCEPT
      reason: >-
        Supported by immunolocalization studies. STC1 was detected diffusely in cardiomyocytes,
        consistent with cytoplasmic presence during secretory pathway transit or after
        internalization.
      supported_by:
        - reference_id: PMID:12663264
          supporting_text: "STC1 is diffusely expressed in cardiomyocytes"

  - term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    evidence_type: IDA
    original_reference_id: PMID:12663264
    review:
      summary: >-
        IDA annotation from the cardiomyocyte study. The paper directly demonstrated that STC1
        affects intracellular calcium in cardiomyocytes by inhibiting L-channel calcium currents
        and reducing intracellular calcium rise with each contraction [PMID:12663264].
      action: ACCEPT
      reason: >-
        Strong experimental evidence showing STC1 regulates intracellular calcium homeostasis
        in cardiomyocytes. This complements the IBA and earlier IDA annotations for the same
        term and represents a core function of STC1.
      supported_by:
        - reference_id: PMID:12663264
          supporting_text: "Addition of recombinant STC1 to the medium of cultured rat cardiomyocytes slows their endogenous beating rate and diminishes the rise in intracellular calcium with each contraction"

  - term:
      id: GO:0010596
      label: negative regulation of endothelial cell migration
    evidence_type: IDA
    original_reference_id: PMID:14500721
    review:
      summary: >-
        IDA annotation from the angiogenesis study. The paper showed that "STC1 is a selective
        modulator of hepatocyte growth factor (HGF)-induced endothelial migration" - specifically
        it inhibits HGF-induced migration [PMID:14500721].
      action: ACCEPT
      reason: >-
        Well-supported by direct experimental evidence. STC1 selectively inhibits HGF-induced
        endothelial cell migration (but not VEGF or bFGF-induced migration). This is a key
        function in STC1's role as an autocrine modulator of angiogenesis.
      supported_by:
        - reference_id: PMID:14500721
          supporting_text: "STC1 is a selective modulator of hepatocyte growth factor (HGF)-induced endothelial migration and morphogenesis, but not proliferation. STC1 did not inhibit proliferative or migratory responses to vascular endothelial growth factor or basic fibroblast growth factor."

  - term:
      id: GO:0086004
      label: regulation of cardiac muscle cell contraction
    evidence_type: IDA
    original_reference_id: PMID:12663264
    review:
      summary: >-
        IDA annotation from the cardiomyocyte study. The paper demonstrated that STC1 "slows
        their endogenous beating rate" in cultured cardiomyocytes through L-channel inhibition
        [PMID:12663264].
      action: ACCEPT
      reason: >-
        Supported by direct functional evidence showing STC1 regulates cardiomyocyte
        contractility by inhibiting calcium currents and slowing beating rate. This may
        be relevant to cardiac pathophysiology in heart failure.
      supported_by:
        - reference_id: PMID:12663264
          supporting_text: "Addition of recombinant STC1 to the medium of cultured rat cardiomyocytes slows their endogenous beating rate"

  # Adding missing key annotation for PAPP-A inhibition
  - term:
      id: GO:0008191
      label: metalloendopeptidase inhibitor activity
    evidence_type: IDA
    original_reference_id: PMID:26195635
    review:
      summary: >-
        New annotation based on PMID:26195635 which demonstrated that STC1 is a potent inhibitor
        of the metalloproteinase PAPP-A. STC1 binds PAPP-A with very high affinity (KD = 75 pM)
        and inhibits its proteolytic activity (Ki = 68 pM). This inhibition affects IGF signaling
        by preventing IGFBP cleavage.
      action: NEW
      reason: >-
        This represents a newly recognized and important molecular function of STC1 that should
        be annotated. STC1 is a proteinase inhibitor specific for the pappalysin family of
        metalloproteinases. This function links STC1 to IGF signaling regulation and may
        explain some of its growth-related effects.
      supported_by:
        - reference_id: PMID:26195635
          supporting_text: "We here demonstrate that STC1 is an inhibitor of the metzincin metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A)... STC1 potently (Ki = 68 pm) inhibits PAPP-A cleavage of IGFBP-4"

references:
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: STC1 role in calcium homeostasis is evolutionarily conserved across the stanniocalcin family

  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara.
    findings:
      - statement: Multiple annotations transferred from orthologous genes based on evolutionary conservation

  - id: GO_REF:0000108
    title: Automatic assignment of GO terms using logical inference, based on inter-ontology links.
    findings:
      - statement: Signal transduction annotation inferred from hormone activity

  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods.
    findings:
      - statement: Hormone activity and extracellular localization annotations from automated methods

  - id: PMID:12663264
    title: 'Stanniocalcin-1 is a naturally occurring L-channel inhibitor in cardiomyocytes: relevance to human heart failure.'
    findings:
      - statement: STC1 is upregulated in failing hearts and reduced after mechanical unloading
      - statement: STC1 inhibits L-type calcium channels in cardiomyocytes
      - statement: STC1 slows cardiomyocyte beating rate and reduces intracellular calcium transients
      - statement: STC1 shows diffuse cytoplasmic expression with nuclear predominance in cardiomyocytes

  - id: PMID:14500721
    title: Stanniocalcin 1 is an autocrine modulator of endothelial angiogenic responses to hepatocyte growth factor.
    findings:
      - statement: STC1 selectively inhibits HGF-induced endothelial migration and morphogenesis
      - statement: STC1 does not affect VEGF or bFGF-induced responses
      - statement: STC1 blocks HGF-induced focal adhesion kinase activation
      - statement: STC1 may serve as a stop signal for blood vessel maturation

  - id: PMID:16377640
    title: Stanniocalcin 1 acts as a paracrine regulator of growth plate chondrogenesis.
    findings:
      - statement: STC1 inhibits longitudinal bone growth at the growth plate
      - statement: STC1 increases phosphate uptake in chondrocytes
      - statement: Effects on growth are mediated through phosphate transport
      - statement: STC1 suppresses chondrocyte proliferation and differentiation

  - id: PMID:17032941
    title: Stanniocalcin-1 regulates endothelial gene expression and modulates transendothelial migration of leukocytes.
    findings:
      - statement: STC1 inhibits transmigration of macrophages and T lymphocytes
      - statement: STC1 does not affect neutrophil or B lymphocyte migration
      - statement: STC1 is detected on apical surface of endothelial cells in vivo
      - statement: STC1 may attenuate intracellular calcium signaling

  - id: PMID:26195635
    title: Stanniocalcin-1 Potently Inhibits the Proteolytic Activity of the Metalloproteinase Pregnancy-associated Plasma Protein-A.
    findings:
      - statement: STC1 is a potent inhibitor of PAPP-A (Ki = 68 pM)
      - statement: STC1 binds PAPP-A with high affinity (KD = 75 pM)
      - statement: STC1 forms homodimers via disulfide bonds
      - statement: STC1 antagonizes PAPP-A-mediated IGF receptor phosphorylation
      - statement: STC1 and STC2 are proteinase inhibitors specific for pappalysins

  - id: PMID:32296183
    title: A reference map of the human binary protein interactome.
    findings:
      - statement: High-throughput Y2H screening identified STC1 protein interactions
      - statement: Part of the HuRI comprehensive human interactome project

  - id: PMID:8700837
    title: 'Human stanniocalcin: a possible hormonal regulator of mineral metabolism.'
    findings:
      - statement: First characterization of human STC1
      - statement: STC1 inhibits calcium transport in fish gills
      - statement: STC1 stimulates renal phosphate reabsorption in rats
      - statement: STC1 localizes to nephron tubules in kidney

  - id: file:human/STC1/STC1-deep-research-falcon.md
    title: Deep research report on STC1
    findings:
      - statement: STC1 is a secreted dimeric glycoprotein functioning via autocrine/paracrine mechanisms
      - statement: STC1 is upregulated by hypoxia and stress pathways
      - statement: STC1 directly binds Notch1 in cancer contexts
      - statement: STC1 acts as a phagocytosis checkpoint through macrophage-centered effects
      - statement: High STC1 expression associated with poor cancer prognosis

core_functions:
  - molecular_function:
      id: GO:0005179
      label: hormone activity
    description: >-
      STC1 is a secreted glycoprotein hormone that acts via autocrine/paracrine mechanisms
      to regulate mineral homeostasis and cellular responses in target tissues.
    supported_by:
      - reference_id: PMID:8700837
        supporting_text: "Human stanniocalcin: a possible hormonal regulator of mineral metabolism"

  - molecular_function:
      id: GO:0008191
      label: metalloendopeptidase inhibitor activity
    description: >-
      Recently discovered function - STC1 potently inhibits PAPP-A metalloproteinase with
      Ki = 68 pM, thereby modulating IGF signaling by preventing IGFBP-4 cleavage.
    supported_by:
      - reference_id: PMID:26195635
        supporting_text: "STC1 potently (Ki = 68 pm) inhibits PAPP-A cleavage of IGFBP-4"

  - molecular_function:
      id: GO:0042802
      label: identical protein binding
    description: >-
      STC1 functions as a disulfide-linked homodimer, which is essential for its biological
      activity as a secreted hormone.
    supported_by:
      - reference_id: PMID:26195635
        supporting_text: "Stanniocalcin-1 (STC1) is a disulfide-bound homodimeric glycoprotein"
    directly_involved_in:
      - id: GO:0006874
        label: intracellular calcium ion homeostasis
      - id: GO:0051926
        label: negative regulation of calcium ion transport
      - id: GO:1903403
        label: negative regulation of renal phosphate excretion
    locations:
      - id: GO:0005576
        label: extracellular region

proposed_new_terms:
  - proposed_name: pappalysin inhibitor activity
    proposed_definition: >-
      Inhibition of the proteolytic activity of pappalysin family metalloproteinases (PAPP-A
      and PAPP-A2). Stanniocalcins (STC1 and STC2) specifically inhibit these enzymes but
      not other metalloproteinases or serine proteinases.
    justification: >-
      STC1 and STC2 specifically inhibit the pappalysin family of metalloproteinases
      (PAPP-A and PAPP-A2) but not other metalloproteinases or serine proteinases
      [PMID:26195635]. A more specific term would be valuable for precise annotation.
    proposed_parent:
      id: GO:0008191
      label: metalloendopeptidase inhibitor activity
    supported_by:
      - reference_id: PMID:26195635
        supporting_text: "We therefore conclude that the STCs are proteinase inhibitors, probably restricted in specificity to the pappalysin family of metzincin metalloproteinases"

suggested_questions:
  - question: >-
      What is the receptor for STC1 in mammalian tissues beyond Notch1? While Notch1 has been
      identified as a receptor in cancer contexts, the broader receptor landscape for STC1
      remains incompletely defined. Understanding the receptor(s) would clarify the signaling mechanism.

  - question: >-
      Does the PAPP-A inhibitory function of STC1 contribute to its effects on bone growth?
      STC1 overexpression causes dwarfism, and STC1 inhibits PAPP-A which regulates IGF signaling.
      It is unclear if growth effects are primarily through phosphate transport or IGF axis modulation.

suggested_experiments:
  - description: >-
      Test whether STC1 effects on chondrocyte proliferation are blocked by PAPP-A
      overexpression to determine if PAPP-A inhibition contributes to growth plate effects.
      If PAPP-A inhibition is the mechanism, excess PAPP-A should rescue STC1-mediated
      growth suppression.
    hypothesis: >-
      PAPP-A inhibition contributes to STC1-mediated growth suppression in chondrocytes

  - description: >-
      Identify the primary receptor for STC1 in endothelial cells using crosslinking
      and mass spectrometry approaches to identify endothelial cell surface receptor(s)
      mediating STC1 effects on HGF signaling and migration.
    hypothesis: >-
      STC1 has a specific cell surface receptor in endothelial cells distinct from Notch1