STC2

id: O76061
gene_symbol: STC2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  STC2 (Stanniocalcin-2) is a secreted glycoprotein hormone belonging to the stanniocalcin family,
  functioning as an autocrine/paracrine regulator. It localizes to the ER and Golgi apparatus
  and is secreted to the extracellular space, with secretion enhanced during ER stress. STC2 is
  robustly induced by the unfolded protein response (UPR) via the PERK-ATF4 pathway and provides
  cytoprotective effects under cellular stress. Mechanistically, STC2 acts as (1) a negative
  modulator of store-operated calcium entry (SOCE) through physical interaction with the ER
  calcium sensor STIM1, (2) an inhibitor of pappalysin metalloproteinases (PAPP-A/PAPP-A2),
  thereby reducing IGFBP proteolysis and modulating local IGF bioavailability, and (3) a
  regulator of calcium and phosphate homeostasis with anti-hypocalcemic properties. STC2 also
  forms complexes with heme oxygenase-1 (HO-1), binds heme, and functions as a heat shock
  protein. The protein forms disulfide-linked homodimers and is N-glycosylated.
existing_annotations:
- term:
    id: GO:0006874
    label: intracellular calcium ion homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      STC2 regulates intracellular calcium ion homeostasis, consistent with the stanniocalcin family's
      ancestral role in fish as calcium-regulating hormones. In mammals, STC2 is described as having
      anti-hypocalcemic action on calcium and phosphate homeostasis (UniProt). Deep research indicates
      STC2 is a negative modulator of store-operated calcium entry (SOCE) through physical interaction
      with STIM1, thereby modulating calcium homeostasis.
    action: ACCEPT
    reason: >-
      The IBA annotation is consistent with the conserved role of stanniocalcins in calcium/phosphate
      regulation and with experimental evidence showing STC2 modulates calcium signaling via SOCE/STIM1.
      This represents a core function of STC2.
    supported_by:
      - reference_id: PMID:9753616
        supporting_text: >-
          Stanniocalcin (STC) is a Ca- and phosphate-regulating hormone produced by the corpuscles of
          Stannius in bony fishes
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          STC2 is a negative modulator of store-operated calcium entry (SOCE). STC2 deficiency
          increases Ca2+ influx after ER store depletion, while overexpression attenuates SOCE. STC2
          physically interacts with the ER Ca2+ sensor STIM1, linking it to ER-plasma membrane Ca2+
          signaling
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      STC2 is a secreted glycoprotein hormone that localizes to the extracellular space. UniProt
      annotates STC2 as secreted. STC2 has an N-terminal signal peptide for ER import and is
      N-glycosylated. Secretion is enhanced during ER stress. STC2 was detected in human colostrum
      by proteomics (PMID:16502470) confirming its presence in extracellular fluids.
    action: ACCEPT
    reason: >-
      This is a core localization annotation supported by multiple lines of evidence including
      signal peptide, secretion assays, and proteomics detection in human colostrum.
    supported_by:
      - reference_id: PMID:16502470
        supporting_text: >-
          One hundred and fifty-one proteins were identified, 83 of which have not been previously
          reported in human colostrum
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          N-terminal signal peptide for ER import; N-linked glycosylation; localizes to ER/Golgi;
          secreted into media, secretion increases during ER stress
- term:
    id: GO:0005179
    label: hormone activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      STC2 is classified as a glycoprotein hormone belonging to the stanniocalcin family, which
      originated as calcium-regulating hormones in fish. UniProt annotates STC2 with the Hormone
      keyword. STC2 functions as a paracrine/autocrine regulator in mammals rather than as a
      classical circulating hormone. It regulates calcium/phosphate homeostasis and has hormone-like
      activity in modulating steroidogenesis in the ovary (PMID:15486227).
    action: ACCEPT
    reason: >-
      The hormone activity annotation is appropriate based on STC2's classification as a stanniocalcin
      family hormone, its signaling function, and its paracrine effects on target cells including
      suppression of steroidogenesis in granulosa cells.
    supported_by:
      - reference_id: PMID:15486227
        supporting_text: >-
          Stanniocalcin is a glycoprotein hormone important in the maintenance of calcium and phosphate
          homeostasis in fish. Two related mammalian stanniocalcin genes, STC1 and STC2, were found to
          be expressed in various tissues as paracrine regulators
      - reference_id: PMID:9753616
        supporting_text: >-
          Stanniocalcin (STC) is a Ca- and phosphate-regulating hormone produced by the corpuscles of
          Stannius in bony fishes
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      STC2 is a secreted protein that localizes to the extracellular region. This is a broader
      parent term of extracellular space (GO:0005615), which is also annotated with IBA evidence.
      The annotation is redundant with the more specific extracellular space term.
    action: ACCEPT
    reason: >-
      This IEA annotation to the broader term is consistent with the evidence that STC2 is a
      secreted protein. While more specific extracellular space annotation exists, this broader
      term is not incorrect.
    supported_by:
      - reference_id: PMID:16502470
        supporting_text: >-
          One hundred and fifty-one proteins were identified, 83 of which have not been previously
          reported in human colostrum
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  review:
    summary: >-
      This annotation is inferred from the hormone activity annotation via GO logical inference.
      STC2, as a hormone, would be expected to participate in signal transduction. However, the
      term is overly broad and does not capture the specific signaling mechanisms of STC2, which
      include SOCE modulation via STIM1 and PAPP-A inhibition affecting IGF bioavailability.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While STC2 does participate in signaling pathways, this broad term does not provide
      informative annotation. The specific mechanisms (calcium signaling via STIM1, IGF axis
      modulation via PAPP-A inhibition) are more meaningful. This is a logical inference from
      hormone activity that is too general.
    supported_by:
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          STC2 physically interacts with the ER Ca2+ sensor STIM1, linking it to ER-plasma membrane
          Ca2+ signaling... acts as an endogenous inhibitor of pappalysin metalloproteinases
          (PAPP-A/PAPP-A2), thereby reducing IGFBP proteolysis and modulating local IGF bioavailability
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      STC2 localizes to the endoplasmic reticulum as part of the secretory pathway. It contains an
      N-terminal signal peptide for ER import and is N-glycosylated. Immunofluorescence and subcellular
      fractionation place endogenous STC2 predominantly in the ER and Golgi. STC2 interacts with STIM1,
      an ER calcium sensor, further supporting ER localization. This IEA annotation is also supported
      by IDA evidence from PMID:22503972.
    action: ACCEPT
    reason: >-
      ER localization is well-supported by the presence of a signal peptide, N-glycosylation,
      immunofluorescence data, and the functional interaction with ER-resident STIM1.
    supported_by:
      - reference_id: PMID:22503972
        supporting_text: >-
          The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          Immunofluorescence and subcellular fractionation place endogenous STC2 predominantly in
          the ER and Golgi
- term:
    id: GO:0005794
    label: Golgi apparatus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      STC2 transits through the Golgi apparatus as part of the secretory pathway. As a secreted
      glycoprotein with N-glycosylation, STC2 would be processed in the Golgi. Subcellular
      fractionation and immunofluorescence studies place STC2 in both ER and Golgi compartments.
    action: ACCEPT
    reason: >-
      Golgi localization is expected for a secreted N-glycosylated protein and is supported by
      subcellular fractionation data from the literature.
    supported_by:
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          Immunofluorescence and subcellular fractionation place endogenous STC2 predominantly in
          the ER and Golgi
- term:
    id: GO:0007566
    label: embryo implantation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This annotation is transferred from rat ortholog (ensembl:ENSRNOP00000028146). STC2 is expressed
      in reproductive tissues and may play a role in embryo implantation based on expression patterns.
      However, direct functional evidence for STC2 involvement in embryo implantation in humans is
      limited. The annotation may reflect expression correlation rather than direct functional role.
    action: KEEP_AS_NON_CORE
    reason: >-
      While STC2 may be expressed during implantation, this is not a core function of the protein.
      The annotation is based on ortholog transfer from rat and likely reflects expression during
      decidualization rather than a direct mechanistic role in implantation.
    supported_by:
      - reference_id: PMID:15486227
        supporting_text: >-
          STC2 is expressed mainly in thecal layers... thecal cell-derived STC2 could play a
          paracrine role during follicular development
- term:
    id: GO:0033280
    label: response to vitamin D
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This annotation is transferred from rat ortholog. Given that stanniocalcins are involved in
      calcium/phosphate homeostasis and vitamin D is a key regulator of this system, STC2 expression
      may be modulated by vitamin D. However, direct evidence for STC2 responding to vitamin D in
      humans is not provided in the available literature.
    action: KEEP_AS_NON_CORE
    reason: >-
      This is likely a peripheral response rather than a core function. STC2's role in calcium
      homeostasis makes vitamin D responsiveness plausible, but this represents a regulatory input
      rather than a core molecular function of the protein.
    supported_by:
      - reference_id: PMID:9753616
        supporting_text: >-
          Stanniocalcin (STC) is a Ca- and phosphate-regulating hormone produced by the corpuscles
          of Stannius in bony fishes
- term:
    id: GO:0043434
    label: response to peptide hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This annotation is transferred from rat ortholog. STC2 expression is regulated by gonadotropins
      (FSH/LH) in the ovary - pregnant mare serum gonadotropin increases STC2 expression while human
      chorionic gonadotropin suppresses it (PMID:15486227). This represents regulation of STC2
      expression by peptide hormones.
    action: KEEP_AS_NON_CORE
    reason: >-
      The annotation captures a regulatory response to gonadotropins that modulates STC2 expression,
      particularly in reproductive tissues. This is a peripheral function reflecting tissue-specific
      regulation rather than a core molecular function of STC2.
    supported_by:
      - reference_id: PMID:15486227
        supporting_text: >-
          Treatment of immature rats with pregnant mare serum gonadotropin increased STC2 transcripts,
          whereas subsequent treatment with human chorionic gonadotropin suppressed STC2 expression
- term:
    id: GO:0046697
    label: decidualization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      This annotation is transferred from rat ortholog. STC2 is expressed in reproductive tissues
      and may be involved in decidualization based on expression patterns. This is consistent with
      STC2's role as a paracrine factor in ovarian tissues. However, direct mechanistic evidence for
      STC2 function in decidualization is limited.
    action: KEEP_AS_NON_CORE
    reason: >-
      Decidualization is a tissue-specific process where STC2 may be expressed but is not the core
      function of the protein. This annotation likely reflects expression correlation in reproductive
      tissues rather than a direct functional role.
    supported_by:
      - reference_id: PMID:15486227
        supporting_text: >-
          thecal cell-derived STC2 could play a paracrine role during follicular development
- term:
    id: GO:0071456
    label: cellular response to hypoxia
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: >-
      STC2 is induced by various cellular stresses including hypoxia. This is consistent with STC2
      being a UPR target gene induced via the PERK-ATF4 pathway, as hypoxia causes ER stress. STC2
      provides cytoprotective effects under stress conditions including hypoxia.
    action: ACCEPT
    reason: >-
      Hypoxia response is part of STC2's broader stress response function. STC2 is robustly induced
      by ER stressors and provides cytoprotection, making this annotation consistent with its
      characterized function as a stress-responsive protein.
    supported_by:
      - reference_id: PMID:22503972
        supporting_text: >-
          STC2 has been demonstrated to be induced by different kinds of stress and display
          cytoprotective activity
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          UPR-inducible via PERK-ATF4 (and CHOP context); upregulated by tunicamycin, thapsigargin,
          hypoxia and oxidative stress
- term:
    id: GO:0005788
    label: endoplasmic reticulum lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8952289
  review:
    summary: >-
      STC2 localizes to the ER lumen as part of the secretory pathway. This annotation from Reactome
      reflects STC2 being a substrate of FAM20C, an extracellular/Golgi kinase that phosphorylates
      secreted proteins. STC2 is phosphorylated at Ser-250, Ser-251, and Thr-254 by FAM20C (UniProt).
      The ER lumen localization is consistent with STC2 having a signal peptide and transiting
      through the ER-Golgi secretory pathway.
    action: ACCEPT
    reason: >-
      ER lumen localization is appropriate for a secreted glycoprotein with a signal peptide. STC2
      is processed in the ER lumen before Golgi transit and secretion.
    supported_by:
      - reference_id: Reactome:R-HSA-8952289
        supporting_text: >-
          FAM20C phosphorylates FAM20C substrates... extracellular kinase that can phosphorylate a
          broad range of secreted protein
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          STC2 contains an N-terminal signal peptide for ER import, is N-glycosylated, and forms
          part of the secretory pathway
- term:
    id: GO:0019899
    label: enzyme binding
  evidence_type: IDA
  original_reference_id: PMID:22503972
  review:
    summary: >-
      STC2 binds to heme oxygenase-1 (HO-1), which is an enzyme that degrades heme. The interaction
      was discovered by yeast two-hybrid screening and validated by co-immunoprecipitation and
      immunofluorescence. The binding site was mapped to amino acids 181-200 of STC2. The complex
      may function as a eukaryotic stressosome involved in heme degradation.
    action: ACCEPT
    reason: >-
      The enzyme binding annotation is correct as STC2 binds HO-1, an enzyme. This represents a
      validated protein-protein interaction with functional significance in the stress response.
      A more specific term such as heme oxygenase binding does not exist in GO.
    supported_by:
      - reference_id: PMID:22503972
        supporting_text: >-
          Using yeast two-hybrid screening we identified HO1 as a binding partner of STC2. The
          interaction was validated by in vivo co-immunoprecipitation and immunofluorescence. The
          binding site for HO1 was located to amino acids 181-200 of STC2
- term:
    id: GO:0020037
    label: heme binding
  evidence_type: IDA
  original_reference_id: PMID:22503972
  review:
    summary: >-
      STC2 binds hemin via a consensus heme regulatory motif. This was demonstrated experimentally
      and suggests STC2 may function in heme metabolism as part of a stressosome complex with HO-1
      that degrades heme. This is a newly characterized function of STC2.
    action: ACCEPT
    reason: >-
      Direct experimental evidence demonstrates STC2 binds hemin through a heme regulatory motif.
      This is a validated molecular function of STC2.
    supported_by:
      - reference_id: PMID:22503972
        supporting_text: >-
          We also found that STC2 binds hemin via a consensus heme regulatory motif
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:22503972
  review:
    summary: >-
      STC2 localizes to the endoplasmic reticulum as demonstrated by immunofluorescence in
      PMID:22503972. This is consistent with STC2 having a signal peptide for ER import and
      being a secreted glycoprotein that transits through the ER. This annotation duplicates
      the IEA annotation for the same term but with stronger experimental evidence.
    action: ACCEPT
    reason: >-
      Direct experimental evidence from immunofluorescence confirms ER localization of STC2.
      This is a core localization for this secreted protein.
    supported_by:
      - reference_id: PMID:22503972
        supporting_text: >-
          The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IDA
  original_reference_id: PMID:9753616
  review:
    summary: >-
      STC2 inhibits the promoter activity of the Na-phosphate cotransporter (NaPi-3) gene. Culture
      medium from STC2-transfected CHO cells inhibited NaPi-3 promoter activity. This demonstrates
      STC2 can negatively regulate gene expression, likely through its effects on phosphate
      homeostasis signaling.
    action: ACCEPT
    reason: >-
      Direct experimental evidence shows STC2 inhibits NaPi-3 promoter activity, demonstrating
      negative regulation of gene expression. This is mechanistically linked to STC2's role in
      phosphate homeostasis.
    supported_by:
      - reference_id: PMID:9753616
        supporting_text: >-
          The culture medium of STC2-transfected CHO cells inhibited the promoter activity of
          Na-phosphate cotransporter (NaPi-3)
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IDA
  original_reference_id: PMID:15486227
  review:
    summary: >-
      STC2 forms homodimers. Recombinant human and fish STC2 proteins were found to be
      N-glycosylated homodimers. UniProt also annotates STC2 as a disulfide-linked homodimer.
      This is a core structural property of stanniocalcins.
    action: ACCEPT
    reason: >-
      Homodimerization is a well-established property of STC2 supported by biochemical
      characterization of recombinant protein. The disulfide-linked homodimer is the
      functional form of the protein.
    supported_by:
      - reference_id: PMID:15486227
        supporting_text: >-
          recombinant human and fish STC2 proteins were generated and found to be N-glycosylated
          homodimers
- term:
    id: GO:0046885
    label: regulation of hormone biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:9753616
  review:
    summary: >-
      STC2 regulates hormone biosynthesis in the ovary. Treatment of granulosa cells with STC2
      suppressed FSH-induced progesterone production by inhibiting CYP11A and 3beta-hydroxysteroid
      dehydrogenase expression (PMID:15486227). This represents a paracrine regulatory function
      of STC2 in steroidogenesis.
    action: ACCEPT
    reason: >-
      STC2 regulates steroid hormone biosynthesis by suppressing progesterone production in
      granulosa cells through inhibition of steroidogenic enzyme expression. This is a validated
      paracrine function of STC2.
    supported_by:
      - reference_id: PMID:15486227
        supporting_text: >-
          treatment with human or fish STC2 suppressed FSH-induced progesterone, but not estradiol
          or cAMP, production. The STC2 suppression of progesterone production was associated with
          the inhibition of FSH-induced CYP11A and 3beta-hydroxysteroid dehydrogenase expression
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22503972
  review:
    summary: >-
      STC2 localizes to the perinuclear region of the cytoplasm as shown by immunofluorescence.
      This is consistent with ER/Golgi localization since these organelles are concentrated in
      the perinuclear region. The localization was validated by immunofluorescence studies of
      STC2 and its interaction partner HO-1.
    action: ACCEPT
    reason: >-
      Immunofluorescence evidence supports perinuclear localization, which is consistent with
      the ER/Golgi localization expected for a secreted protein with a signal peptide.
    supported_by:
      - reference_id: PMID:22503972
        supporting_text: >-
          The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence
- term:
    id: GO:0005615
    label: extracellular space
  evidence_type: HDA
  original_reference_id: PMID:16502470
  review:
    summary: >-
      STC2 was detected in the extracellular space (human colostrum) by proteomics analysis. This
      high-throughput study identified STC2 among 151 proteins in the aqueous phase of human
      colostrum, confirming its secreted nature and presence in biological fluids.
    action: ACCEPT
    reason: >-
      Proteomic detection of STC2 in human colostrum provides direct evidence for its presence
      in the extracellular space. This is consistent with STC2 being a secreted glycoprotein.
    supported_by:
      - reference_id: PMID:16502470
        supporting_text: >-
          One hundred and fifty-one proteins were identified, 83 of which have not been previously
          reported in human colostrum, or milk
- term:
    id: GO:0008191
    label: metalloendopeptidase inhibitor activity
  evidence_type: IDA
  original_reference_id: file:human/STC2/STC2-deep-research-falcon.md
  review:
    summary: >-
      STC2 acts as an endogenous inhibitor of pappalysin metalloproteinases (PAPP-A and PAPP-A2).
      By inhibiting these metalloendopeptidases, STC2 reduces IGFBP proteolysis and thereby
      modulates local IGF bioavailability. This represents a well-established mechanism of STC2
      action supported by biochemical and genetic studies.
    action: NEW
    reason: >-
      This molecular function is not currently annotated in GO for STC2 but is well-supported
      by deep research literature. PAPP-A and PAPP-A2 are metalloendopeptidases, and STC2
      inhibition of their activity is a core function linking STC2 to growth regulation
      via the IGF axis.
    supported_by:
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          Mammalian STC2 acts as an endogenous inhibitor of pappalysin metalloproteinases
          (PAPP-A/PAPP-A2), thereby reducing IGFBP proteolysis and modulating local insulin-like
          growth factor (IGF) bioavailability
references:
- id: file:human/STC2/STC2-deep-research-falcon.md
  title: Deep research review of STC2 function
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology
    links
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15486227
  title: Identification of a stanniocalcin paralog, stanniocalcin-2, in fish and the
    paracrine actions of stanniocalcin-2 in the mammalian ovary.
  findings: []
- id: PMID:16502470
  title: 'Human colostrum: identification of minor proteins in the aqueous phase by
    proteomics.'
  findings: []
- id: PMID:22503972
  title: Stanniocalcin 2, forms a complex with heme oxygenase 1, binds hemin and is
    a heat shock protein.
  findings: []
- id: PMID:9753616
  title: Molecular cloning of a second human stanniocalcin homologue (STC2).
  findings: []
- id: Reactome:R-HSA-8952289
  title: FAM20C phosphorylates FAM20C substrates
  findings: []
core_functions:
  - molecular_function:
      id: GO:0005179
      label: hormone activity
    description: >-
      STC2 is a secreted glycoprotein hormone belonging to the stanniocalcin family. It functions
      as an autocrine/paracrine regulator with anti-hypocalcemic action on calcium and phosphate
      homeostasis. STC2 regulates target cell function including suppression of steroidogenesis
      in granulosa cells.
    locations:
      - id: GO:0005576
        label: extracellular region
    directly_involved_in:
      - id: GO:0006874
        label: intracellular calcium ion homeostasis
  - molecular_function:
      id: GO:0008191
      label: metalloendopeptidase inhibitor activity
    description: >-
      STC2 acts as an endogenous inhibitor of pappalysin metalloproteinases (PAPP-A and PAPP-A2),
      thereby reducing IGFBP proteolysis and modulating local insulin-like growth factor (IGF)
      bioavailability. This is a key mechanism linking STC2 to growth regulation.
    locations:
      - id: GO:0005576
        label: extracellular region
    supported_by:
      - reference_id: file:human/STC2/STC2-deep-research-falcon.md
        supporting_text: >-
          Mammalian STC2 acts as an endogenous inhibitor of pappalysin metalloproteinases
          (PAPP-A/PAPP-A2), thereby reducing IGFBP proteolysis and modulating local insulin-like
          growth factor (IGF) bioavailability
  - molecular_function:
      id: GO:0020037
      label: heme binding
    description: >-
      STC2 binds hemin via a consensus heme regulatory motif. This was demonstrated experimentally
      and suggests STC2 may function in heme metabolism as part of a stressosome complex with HO-1.
    locations:
      - id: GO:0005783
        label: endoplasmic reticulum
  - molecular_function:
      id: GO:0042803
      label: protein homodimerization activity
    description: >-
      STC2 forms disulfide-linked homodimers. This is the functional form of the protein required
      for its hormone activity.