STC2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0006874 intracellular calcium ion homeostasis	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:9753616 Stanniocalcin (STC) is a Ca- and phosphate-regulating hormone produced by the corpuscles of Stannius in bony fishes file:human/STC2/STC2-deep-research-falcon.md 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
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	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. Reason: This is a core localization annotation supported by multiple lines of evidence including signal peptide, secretion assays, and proteomics detection in human colostrum. Supporting Evidence: PMID:16502470 One hundred and fifty-one proteins were identified, 83 of which have not been previously reported in human colostrum file:human/STC2/STC2-deep-research-falcon.md N-terminal signal peptide for ER import; N-linked glycosylation; localizes to ER/Golgi; secreted into media, secretion increases during ER stress
GO:0005179 hormone activity	IEA GO_REF:0000120	ACCEPT	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). 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. Supporting Evidence: PMID:15486227 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 PMID:9753616 Stanniocalcin (STC) is a Ca- and phosphate-regulating hormone produced by the corpuscles of Stannius in bony fishes
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	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. 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. Supporting Evidence: PMID:16502470 One hundred and fifty-one proteins were identified, 83 of which have not been previously reported in human colostrum
GO:0007165 signal transduction	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/STC2/STC2-deep-research-falcon.md 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
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000107	ACCEPT	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. 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. Supporting Evidence: PMID:22503972 The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence file:human/STC2/STC2-deep-research-falcon.md Immunofluorescence and subcellular fractionation place endogenous STC2 predominantly in the ER and Golgi
GO:0005794 Golgi apparatus	IEA GO_REF:0000107	ACCEPT	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. Reason: Golgi localization is expected for a secreted N-glycosylated protein and is supported by subcellular fractionation data from the literature. Supporting Evidence: file:human/STC2/STC2-deep-research-falcon.md Immunofluorescence and subcellular fractionation place endogenous STC2 predominantly in the ER and Golgi
GO:0007566 embryo implantation	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15486227 STC2 is expressed mainly in thecal layers... thecal cell-derived STC2 could play a paracrine role during follicular development
GO:0033280 response to vitamin D	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:9753616 Stanniocalcin (STC) is a Ca- and phosphate-regulating hormone produced by the corpuscles of Stannius in bony fishes
GO:0043434 response to peptide hormone	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15486227 Treatment of immature rats with pregnant mare serum gonadotropin increased STC2 transcripts, whereas subsequent treatment with human chorionic gonadotropin suppressed STC2 expression
GO:0046697 decidualization	IEA GO_REF:0000107	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:15486227 thecal cell-derived STC2 could play a paracrine role during follicular development
GO:0071456 cellular response to hypoxia	IEA GO_REF:0000107	ACCEPT	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. 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. Supporting Evidence: PMID:22503972 STC2 has been demonstrated to be induced by different kinds of stress and display cytoprotective activity file:human/STC2/STC2-deep-research-falcon.md UPR-inducible via PERK-ATF4 (and CHOP context); upregulated by tunicamycin, thapsigargin, hypoxia and oxidative stress
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-8952289	ACCEPT	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. 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. Supporting Evidence: Reactome:R-HSA-8952289 FAM20C phosphorylates FAM20C substrates... extracellular kinase that can phosphorylate a broad range of secreted protein file:human/STC2/STC2-deep-research-falcon.md STC2 contains an N-terminal signal peptide for ER import, is N-glycosylated, and forms part of the secretory pathway
GO:0019899 enzyme binding	IDA PMID:22503972 Stanniocalcin 2, forms a complex with heme oxygenase 1, bind...	ACCEPT	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. 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. Supporting Evidence: PMID:22503972 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
GO:0020037 heme binding	IDA PMID:22503972 Stanniocalcin 2, forms a complex with heme oxygenase 1, bind...	ACCEPT	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. Reason: Direct experimental evidence demonstrates STC2 binds hemin through a heme regulatory motif. This is a validated molecular function of STC2. Supporting Evidence: PMID:22503972 We also found that STC2 binds hemin via a consensus heme regulatory motif
GO:0005783 endoplasmic reticulum	IDA PMID:22503972 Stanniocalcin 2, forms a complex with heme oxygenase 1, bind...	ACCEPT	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. Reason: Direct experimental evidence from immunofluorescence confirms ER localization of STC2. This is a core localization for this secreted protein. Supporting Evidence: PMID:22503972 The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence
GO:0010629 negative regulation of gene expression	IDA PMID:9753616 Molecular cloning of a second human stanniocalcin homologue ...	ACCEPT	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. 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. Supporting Evidence: PMID:9753616 The culture medium of STC2-transfected CHO cells inhibited the promoter activity of Na-phosphate cotransporter (NaPi-3)
GO:0042803 protein homodimerization activity	IDA PMID:15486227 Identification of a stanniocalcin paralog, stanniocalcin-2, ...	ACCEPT	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. 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. Supporting Evidence: PMID:15486227 recombinant human and fish STC2 proteins were generated and found to be N-glycosylated homodimers
GO:0046885 regulation of hormone biosynthetic process	IDA PMID:9753616 Molecular cloning of a second human stanniocalcin homologue ...	ACCEPT	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. 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. Supporting Evidence: PMID:15486227 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
GO:0048471 perinuclear region of cytoplasm	IDA PMID:22503972 Stanniocalcin 2, forms a complex with heme oxygenase 1, bind...	ACCEPT	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. Reason: Immunofluorescence evidence supports perinuclear localization, which is consistent with the ER/Golgi localization expected for a secreted protein with a signal peptide. Supporting Evidence: PMID:22503972 The interaction was validated by in vivo co-immunoprecipitation and immunofluorescence
GO:0005615 extracellular space	HDA PMID:16502470 Human colostrum: identification of minor proteins in the aqu...	ACCEPT	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. 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. Supporting Evidence: PMID:16502470 One hundred and fifty-one proteins were identified, 83 of which have not been previously reported in human colostrum, or milk
GO:0008191 metalloendopeptidase inhibitor activity	IDA file:human/STC2/STC2-deep-research-falcon.md	NEW	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. 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. Supporting Evidence: file:human/STC2/STC2-deep-research-falcon.md 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

Gene Description

Existing Annotations Review

Core Functions

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.

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.

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.

STC2 forms disulfide-linked homodimers. This is the functional form of the protein required for its hormone activity.

References

Deep Research

Falcon

📄 View Raw YAML