IGFBP3

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0031994 insulin-like growth factor I binding	IBA GO_REF:0000033	ACCEPT	Summary: insulin-like growth factor I binding is a core IGFBP3 molecular function; the literature consistently identifies high-affinity IGF-I/IGF-II binding as the dominant biochemical activity. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0031995 insulin-like growth factor II binding	IBA GO_REF:0000033	ACCEPT	Summary: insulin-like growth factor II binding is a core IGFBP3 molecular function; the literature consistently identifies high-affinity IGF-I/IGF-II binding as the dominant biochemical activity. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005615 extracellular space	IBA GO_REF:0000033	ACCEPT	Summary: extracellular space is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0001968 fibronectin binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Fibronectin binding is retained as a non-core transferred annotation, but the Falcon evidence set did not retrieve strong direct IGFBP3-specific support for fibronectin binding. This should not be treated as refuted; it is simply less established than IGF and hyaluronan binding. Reason: Direct support for fibronectin binding was not established in this review, but the term is not demonstrably false.
GO:0043567 regulation of insulin-like growth factor receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	Summary: IGFBP3 regulates IGF receptor signaling by sequestering IGF ligands and through IGF-independent signaling crosstalk, so this process annotation is supported. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK.
GO:0005520 insulin-like growth factor binding	IEA GO_REF:0000120	ACCEPT	Summary: insulin-like growth factor binding is a core IGFBP3 molecular function; the literature consistently identifies high-affinity IGF-I/IGF-II binding as the dominant biochemical activity. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	IEA GO_REF:0000120	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Nuclear localization is supported but represents a context-dependent IGF-independent compartment rather than the canonical extracellular IGF-binding role. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md Multiple sources support nuclear localization of IGFBP-3. Classic mechanistic evidence indicates IGFBP-3 contains a basic C-terminal nuclear localization signal (NLS) and undergoes NLS-dependent, importin-mediated nuclear translocation. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A central IGF-independent nuclear mechanism is the interaction of nuclear IGFBP-3 with retinoid X receptor alpha (RXRα). Classic evidence describes RXR as an IGFBP-3 partner identified by yeast two-hybrid screening and positions this interaction as a conceptual “paradigm shift” for IGFBP actions in transcription and apoptosis.
GO:0006915 apoptotic process	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: apoptotic process is retained as a context-dependent IGF-independent apoptotic role, including nuclear receptor and cell-death receptor mechanisms, but it is not the canonical core molecular function. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md A central IGF-independent nuclear mechanism is the interaction of nuclear IGFBP-3 with retinoid X receptor alpha (RXRα). Classic evidence describes RXR as an IGFBP-3 partner identified by yeast two-hybrid screening and positions this interaction as a conceptual “paradigm shift” for IGFBP actions in transcription and apoptosis. file:human/IGFBP3/IGFBP3-uniprot.txt apoptotic effects mediated by its receptor TMEM219/IGFBP-3R
GO:0014912 negative regulation of smooth muscle cell migration	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: negative regulation of smooth muscle cell migration is consistent with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these are downstream context-specific effects rather than the core ligand-binding activity. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0019838 growth factor binding	IEA GO_REF:0000043	MODIFY	Summary: Growth factor binding is true but less informative than the specific insulin-like growth factor binding annotations already present. Reason: Use the specific IGF binding term for this protein family. Proposed replacements: insulin-like growth factor binding Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0031994 insulin-like growth factor I binding	IEA GO_REF:0000117	ACCEPT	Summary: insulin-like growth factor I binding is a core IGFBP3 molecular function; the literature consistently identifies high-affinity IGF-I/IGF-II binding as the dominant biochemical activity. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0042567 insulin-like growth factor ternary complex	IEA GO_REF:0000117	ACCEPT	Summary: insulin-like growth factor ternary complex is supported by IGFBP3 formation of binary IGF:IGFBP complexes and ALS-containing ternary complexes in circulation. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0048662 negative regulation of smooth muscle cell proliferation	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: negative regulation of smooth muscle cell proliferation is consistent with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these are downstream context-specific effects rather than the core ligand-binding activity. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0005515 protein binding	IPI PMID:20353938 Identification of a novel cell death receptor mediating IGFB...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:20353938 2010 Mar 30. Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0005515 protein binding	IPI PMID:23178489 The role of insulin-like growth factor binding protein-3 in ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:23178489 The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0005515 protein binding	IPI PMID:30184438 Interaction of Insulin-Like Growth Factor-Binding Protein 3 ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:30184438 Epub 2018 Sep 17. Interaction of Insulin-Like Growth Factor-Binding Protein 3 With Hyaluronan and Its Regulation by Humanin and CD44. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0001649 osteoblast differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: osteoblast differentiation is retained as a context-specific differentiation phenotype downstream of IGFBP3 signaling rather than the core biochemical function. Supporting Evidence: file:human/IGFBP3/IGFBP3-uniprot.txt including proliferation, differentiation, and apoptosis in a cell-type specific manner
GO:0001968 fibronectin binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Fibronectin binding is retained as a non-core transferred annotation, but the Falcon evidence set did not retrieve strong direct IGFBP3-specific support for fibronectin binding. This should not be treated as refuted; it is simply less established than IGF and hyaluronan binding. Reason: Direct support for fibronectin binding was not established in this review, but the term is not demonstrably false.
GO:0005615 extracellular space	IEA GO_REF:0000107	ACCEPT	Summary: extracellular space is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-381466	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005515 protein binding	IPI PMID:26216267 Humanin Peptide Binds to Insulin-Like Growth Factor-Binding ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:26216267 Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0005788 endoplasmic reticulum lumen	TAS Reactome:R-HSA-8952289	KEEP AS NON CORE	Summary: Endoplasmic reticulum lumen localization is plausible for a secreted precursor and FAM20C substrate, but it is not the main functional site of mature IGFBP3. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids.
GO:0042567 insulin-like growth factor ternary complex	IDA PMID:9497324 Insulin-like growth factor (IGF)-binding protein 5 forms an ...	ACCEPT	Summary: insulin-like growth factor ternary complex is supported by IGFBP3 formation of binary IGF:IGFBP complexes and ALS-containing ternary complexes in circulation. Supporting Evidence: PMID:9497324 Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-381435	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-381446	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-381461	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-381496	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-381500	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800035	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800044	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0008285 negative regulation of cell population proliferation	IGI PMID:19258508 NKX3.1 activates expression of insulin-like growth factor bi...	KEEP AS NON CORE	Summary: negative regulation of cell population proliferation is consistent with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these are downstream context-specific effects rather than the core ligand-binding activity. Supporting Evidence: PMID:19258508 Epub 2009 Mar 3. NKX3.1 activates expression of insulin-like growth factor binding protein-3 to mediate insulin-like growth factor-I signaling and cell proliferation. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0014912 negative regulation of smooth muscle cell migration	IDA PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal ...	KEEP AS NON CORE	Summary: negative regulation of smooth muscle cell migration is consistent with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these are downstream context-specific effects rather than the core ligand-binding activity. Supporting Evidence: PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0016942 insulin-like growth factor binding protein complex	IC PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal ...	ACCEPT	Summary: insulin-like growth factor binding protein complex is supported by IGFBP3 formation of binary IGF:IGFBP complexes and ALS-containing ternary complexes in circulation. Supporting Evidence: PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0031994 insulin-like growth factor I binding	IPI PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal ...	ACCEPT	Summary: insulin-like growth factor I binding is a core IGFBP3 molecular function; the literature consistently identifies high-affinity IGF-I/IGF-II binding as the dominant biochemical activity. Supporting Evidence: PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0048662 negative regulation of smooth muscle cell proliferation	IDA PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal ...	KEEP AS NON CORE	Summary: negative regulation of smooth muscle cell proliferation is consistent with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these are downstream context-specific effects rather than the core ligand-binding activity. Supporting Evidence: PMID:10766744 Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0005615 extracellular space	IDA PMID:17119061 Ethnic disparity in the relationship between obesity and pla...	ACCEPT	Summary: Extracellular space localization is accepted because IGFBP3 is a secreted/circulating IGF-binding protein; however, PMID:17119061 is an epidemiological plasma IGF cohort study, so the original IDA evidence/citation is weak for direct localization evidence. Reason: Accepted based on the broader secreted-protein evidence while noting the source GOA citation quality issue. Supporting Evidence: PMID:17119061 Ethnic disparity in the relationship between obesity and plasma insulin-like growth factors: the multiethnic cohort. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0001933 negative regulation of protein phosphorylation	IDA PMID:17591901 The requirement of pax6 for postnatal eye development: evide...	UNDECIDED	Summary: UNDECIDED: the source GOA annotation cites PMID:17591901, but that PMID is a PAX6 postnatal eye-development paper rather than an IGFBP3 phosphorylation/signaling study. This appears to be an erroneous PMID assignment in GOA, so the annotation cannot be accepted or cleanly modified from the cited evidence. Reason: The cited publication does not support an IGFBP3 annotation; this should be flagged for source-database review. Supporting Evidence: PMID:17591901 The requirement of pax6 for postnatal eye development: evidence from experimental mouse chimeras. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0005634 nucleus	IDA PMID:17434920 Contribution of the orphan nuclear receptor Nur77 to the apo...	KEEP AS NON CORE	Summary: Nuclear localization is supported but represents a context-dependent IGF-independent compartment rather than the canonical extracellular IGF-binding role. Supporting Evidence: PMID:17434920 Apr 13. Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3. file:human/IGFBP3/IGFBP3-deep-research-falcon.md Multiple sources support nuclear localization of IGFBP-3. Classic mechanistic evidence indicates IGFBP-3 contains a basic C-terminal nuclear localization signal (NLS) and undergoes NLS-dependent, importin-mediated nuclear translocation. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A central IGF-independent nuclear mechanism is the interaction of nuclear IGFBP-3 with retinoid X receptor alpha (RXRα). Classic evidence describes RXR as an IGFBP-3 partner identified by yeast two-hybrid screening and positions this interaction as a conceptual “paradigm shift” for IGFBP actions in transcription and apoptosis.
GO:0006468 protein phosphorylation	IDA PMID:17434920 Contribution of the orphan nuclear receptor Nur77 to the apo...	MODIFY	Summary: IGFBP3 is not a protein kinase and does not catalyze protein phosphorylation. The supported biology is indirect regulation of phosphorylation/signaling downstream of IGF1R and related pathways. Reason: Replace a misleading phosphorylation-process annotation with the supported negative regulation of protein phosphorylation/signaling. Proposed replacements: negative regulation of protein phosphorylation Supporting Evidence: PMID:17434920 Apr 13. Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK.
GO:0005515 protein binding	IPI PMID:14561895 Interaction between the Alzheimer's survival peptide humanin...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:14561895 Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0005515 protein binding	IPI PMID:9388210 Inhibition of insulin receptor activation by insulin-like gr...	MARK AS OVER ANNOTATED	Summary: Generic protein binding is over-broad for IGFBP3. More informative annotations are IGF binding, hyaluronan binding, ternary complex formation, and specific receptor/importin/nuclear receptor interactions. Reason: Avoid retaining generic protein binding when specific molecular interactions are available. Supporting Evidence: PMID:9388210 Inhibition of insulin receptor activation by insulin-like growth factor binding proteins. file:human/IGFBP3/IGFBP3-deep-research-falcon.md The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.
GO:0005520 insulin-like growth factor binding	NAS PMID:12599210 Role of insulin-like growth factor binding protein-3 (IGFBP-...	ACCEPT	Summary: insulin-like growth factor binding is a core IGFBP3 molecular function; the literature consistently identifies high-affinity IGF-I/IGF-II binding as the dominant biochemical activity. Supporting Evidence: PMID:12599210 Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0008160 protein tyrosine phosphatase activator activity	IDA PMID:11940579 Insulin-like growth factor-binding protein-3 activates a pho...	KEEP AS NON CORE	Summary: Protein tyrosine phosphatase activator activity is retained as a non-core IGF-independent signaling mechanism from older experimental evidence, while newer synthesis emphasizes PP2A-mediated dephosphorylation of IGF pathway mediators. Supporting Evidence: PMID:11940579 2002 Apr 8. Insulin-like growth factor-binding protein-3 activates a phosphotyrosine phosphatase. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK.
GO:0009968 negative regulation of signal transduction	NAS PMID:11940579 Insulin-like growth factor-binding protein-3 activates a pho...	ACCEPT	Summary: Negative regulation of signal transduction is supported by IGFBP3 suppression of IGF/IGF1R pathway mediators and by hyaluronan-CD44 signaling blockade; this captures a core signaling output of IGFBP3 ligand binding in extracellular contexts. Supporting Evidence: PMID:11940579 2002 Apr 8. Insulin-like growth factor-binding protein-3 activates a phosphotyrosine phosphatase. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling.
GO:0043065 positive regulation of apoptotic process	IMP PMID:11971816 Insulin-like growth factor binding protein-3 mediates tumor ...	KEEP AS NON CORE	Summary: positive regulation of apoptotic process is retained as a context-dependent IGF-independent apoptotic role, including nuclear receptor and cell-death receptor mechanisms, but it is not the canonical core molecular function. Supporting Evidence: PMID:11971816 Insulin-like growth factor binding protein-3 mediates tumor necrosis factor-alpha-induced apoptosis: role of Bcl-2 phosphorylation. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A central IGF-independent nuclear mechanism is the interaction of nuclear IGFBP-3 with retinoid X receptor alpha (RXRα). Classic evidence describes RXR as an IGFBP-3 partner identified by yeast two-hybrid screening and positions this interaction as a conceptual “paradigm shift” for IGFBP actions in transcription and apoptosis. file:human/IGFBP3/IGFBP3-uniprot.txt apoptotic effects mediated by its receptor TMEM219/IGFBP-3R
GO:0045663 positive regulation of myoblast differentiation	IDA PMID:12599210 Role of insulin-like growth factor binding protein-3 (IGFBP-...	KEEP AS NON CORE	Summary: positive regulation of myoblast differentiation is retained as a context-specific differentiation phenotype downstream of IGFBP3 signaling rather than the core biochemical function. Supporting Evidence: PMID:12599210 Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts. file:human/IGFBP3/IGFBP3-uniprot.txt including proliferation, differentiation, and apoptosis in a cell-type specific manner
GO:0046872 metal ion binding	NAS PMID:14576163 Insulin-like growth factor-independent effects mediated by a...	KEEP AS NON CORE	Summary: The C-terminal metal-binding domain evidence is retained as a non-core IGF-independent feature. Supporting Evidence: PMID:14576163 Oct 22. Insulin-like growth factor-independent effects mediated by a C-terminal metal-binding domain of insulin-like growth factor binding protein-3.
GO:0005576 extracellular region	NAS PMID:14718574 The human plasma proteome: a nonredundant list developed by ...	ACCEPT	Summary: extracellular region is supported by IGFBP3 secretion and its extracellular/circulating IGF complex functions. Supporting Evidence: PMID:14718574 Epub 2004 Jan 12. The human plasma proteome: a nonredundant list developed by combination of four separate sources. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. file:human/IGFBP3/IGFBP3-deep-research-falcon.md A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF.
GO:0005540 hyaluronic acid binding	IDA PMID:30184438 Interaction of Insulin-Like Growth Factor-Binding Protein 3 ...	NEW	Summary: IGFBP3 hyaluronic acid binding is directly supported by PMID:30184438, which characterizes HA binding to IGFBP3 and the 215-232 C-terminal peptide and its regulation by humanin/CD44. Reason: Specific HA binding is supported by primary experimental evidence and is absent from current GOA. Supporting Evidence: PMID:30184438 Here, we characterized the binding affinities of the IGFBP-3 protein and peptide (215-KKGFYKKKQCRPSKGRKR-232) to HA and to humanin and found that HA binds with a weaker affinity to this region than does humanin. file:human/IGFBP3/IGFBP3-deep-research-falcon.md IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling.

Core Functions

High-affinity binding of IGF-I and IGF-II to regulate IGF receptor signaling and stabilize circulating IGF complexes.

Molecular Function:

insulin-like growth factor binding

Directly Involved In:

regulation of insulin-like growth factor receptor signaling pathway

Cellular Locations:

extracellular region

In Complex:

insulin-like growth factor ternary complex

Supporting Evidence:

file:human/IGFBP3/IGFBP3-deep-research-falcon.md
IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R** and modulating IGF1R signaling.
file:human/IGFBP3/IGFBP3-deep-research-falcon.md
A key systemic concept is that IGFBP-3 is the **most abundant circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing circulating IGF.
file:human/IGFBP3/IGFBP3-deep-research-falcon.md
IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal peptide** and a **264-aa mature chain**, consistent with secretion into extracellular fluids.

Hyaluronan binding that modulates extracellular HA-CD44 signaling in a phosphorylation-sensitive manner.

Molecular Function:

hyaluronic acid binding

Directly Involved In:

negative regulation of signal transduction

Cellular Locations:

extracellular region

Supporting Evidence:

file:human/IGFBP3/IGFBP3-deep-research-falcon.md
IGFBP-3 binds HA via a mapped basic C-terminal motif (aa **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks HA engagement of **CD44**, suppressing HA–CD44 signaling.

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:10766744

Substitutions for hydrophobic amino acids in the N-terminal domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions.

PMID:11940579

Insulin-like growth factor-binding protein-3 activates a phosphotyrosine phosphatase. Effects on the insulin-like growth factor signaling pathway.

PMID:11971816

Insulin-like growth factor binding protein-3 mediates tumor necrosis factor-alpha-induced apoptosis: role of Bcl-2 phosphorylation.

PMID:12599210

Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts.

PMID:14561895

Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis.

PMID:14576163

Insulin-like growth factor-independent effects mediated by a C-terminal metal-binding domain of insulin-like growth factor binding protein-3.

PMID:14718574

The human plasma proteome: a nonredundant list developed by combination of four separate sources.

PMID:17119061

Ethnic disparity in the relationship between obesity and plasma insulin-like growth factors: the multiethnic cohort.

PMID:17434920

Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of IGFBP-3.

PMID:17591901

The requirement of pax6 for postnatal eye development: evidence from experimental mouse chimeras.

PMID:19258508

NKX3.1 activates expression of insulin-like growth factor binding protein-3 to mediate insulin-like growth factor-I signaling and cell proliferation.

PMID:20353938

Identification of a novel cell death receptor mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer.

PMID:23178489

The role of insulin-like growth factor binding protein-3 in the breast cancer cell response to DNA-damaging agents.

PMID:26216267

Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β.

PMID:30184438

Interaction of Insulin-Like Growth Factor-Binding Protein 3 With Hyaluronan and Its Regulation by Humanin and CD44.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:9388210

Inhibition of insulin receptor activation by insulin-like growth factor binding proteins.

PMID:9497324

Insulin-like growth factor (IGF)-binding protein 5 forms an alternative ternary complex with IGFs and the acid-labile subunit.

Reactome:R-HSA-381435

Matrix metalloproteinase proteolyzes IGF:IGFBP3:ALS

Reactome:R-HSA-381446

Thrombin proteolyzes IGF:IGFBP3:ALS

Reactome:R-HSA-381461

Plasmin proteolyzes IGF:IGFBP-3:ALS

Reactome:R-HSA-381466

Prostate-specific Antigen proteolyzes IGF:IGFBP3:ALS

Reactome:R-HSA-381496

Formation of the IGF:IGFBP3:ALS complex

Reactome:R-HSA-381500

Cathepsin G proteolyzes IGF:IGFBP3:ALS

Reactome:R-HSA-6800035

IGFBP3 binds TMEM219

Reactome:R-HSA-6800044

TP53 stimulates IGFBP3 expression

Reactome:R-HSA-8952289

FAM20C phosphorylates FAM20C substrates

file:human/IGFBP3/IGFBP3-deep-research-falcon.md

Falcon deep research synthesis for IGFBP3

file:human/IGFBP3/IGFBP3-uniprot.txt

UniProt record for IGFBP3

Deep Research

Falcon

(IGFBP3-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 44 citations 2026-05-11T21:32:42.427554

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Human IGFBP3 (UniProt P17936) — Functional Annotation and Translational Relevance

0. Target verification (critical disambiguation)

The literature retrieved and analyzed explicitly maps human insulin-like growth factor-binding protein 3 (IGFBP-3; gene IGFBP3) to UniProt accession P17936, confirming that the target in this report matches the UniProt-provided identity. In particular, Mofid et al. state that the Homo sapiens IGFBP-3 amino-acid sequence (P17936) was retrieved from UniProt, and Price et al. list IGFBP-3 among studied proteins with UniProt accession P17936. (mofid2018insilicointeraction pages 1-3, price2020humaninblocksaggregation pages 1-2)

1. Key concepts and definitions (current understanding)

1.1 Canonical (IGF-dependent) function: high-affinity IGF sequestration and IGF1R modulation

IGFBP-3 is one of six “high-affinity” insulin-like growth factor binding proteins (IGFBPs) whose canonical cellular role is to bind IGF-1 and IGF-2 with high affinity, thereby impeding access to IGF1R and modulating IGF1R signaling. This canonical role can be context-dependent (inhibitory vs sometimes permissive/enhancing) and is regulated by post-translational modifications and proteolysis. (baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 2-2)

Structure-function evidence supports this concept: IGFBP-3 is modular (N-domain, linker, C-domain), and cooperative contributions from the N- and C-termini enable high-affinity IGF binding; binding can sterically hinder IGF-1 receptor interaction. (mofid2018insilicointeraction pages 8-10, mofid2018insilicointeraction pages 11-11)

1.2 Endocrine concept: circulating IGF stabilization and ternary complex formation

A key systemic concept is that IGFBP-3 is the most abundant circulating IGFBP and supports endocrine IGF signaling by stabilizing IGFs in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the acid-labile subunit (ALS) to form a ~150 kDa ternary complex, increasing circulating IGF. (sechrist2025pathologicsignalingand pages 2-4)

1.3 IGF-independent signaling paradigm

A major modern view is that IGFBPs—including IGFBP-3—have substantial IGF-independent actions. These include interactions with cell-surface receptors (e.g., integrins; TGFβ-family receptor systems), intracellular partners, and nuclear mechanisms that modulate survival, migration, senescence, and DNA damage responses. (baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 2-2)

2. Protein features and localization: where IGFBP-3 acts

2.1 Secreted precursor and extracellular compartment

IGFBP-3 is a secreted precursor protein. A retrieved analysis describes IGFBP-3 as a 291-aa protein comprising a 27-aa signal peptide and a 264-aa mature chain, consistent with secretion into extracellular fluids. (mofid2018insilicointeraction pages 1-3)

In extracellular contexts, IGFBP-3 participates in circulating IGF complexes (including ALS-containing complexes) and can bind extracellular matrix (ECM)-related ligands such as hyaluronan (HA) (see below). (sechrist2025pathologicsignalingand pages 2-4, coleman2023phosphorylationofigfbp3 pages 5-7)

2.2 Nuclear localization and intracellular trafficking (importin-β; energy dependence)

Multiple sources support nuclear localization of IGFBP-3. Classic mechanistic evidence indicates IGFBP-3 contains a basic C-terminal nuclear localization signal (NLS) and undergoes NLS-dependent, importin-mediated nuclear translocation. (lee2002nucleareffectsunexpected pages 3-4)

A detailed mechanistic review reports that extracellular/full-length IGFBP-3 can enter the nucleus via direct interaction with importin-β (not requiring importin-α), and that nuclear import is blocked by anti–importin-β, reduced by GTP-γS, and requires an ATP-generating system—indicating dependence on the Ran/energy-dependent nuclear import machinery. (shrivastav2020insulinlikegrowthfactor pages 7-8)

3. Pathways and mechanisms (recent and authoritative synthesis prioritized)

3.1 IGFBP-3–LRP1 (TGFβR-V)–PP2A axis: IGF-independent suppression of IGF1R pathway mediators

A 2023 Endocrine Reviews synthesis describes an IGF-independent mechanism in which IGFBP-3 engages TGFβ receptor type V (LRP1) to activate PP2A (a serine/threonine phosphatase). PP2A can associate with IGF1R via RACK1, and downregulates key IGF1R pathway mediators including Akt and Ras/MAPK. This provides a mechanistic route by which IGFBP-3 can inhibit proliferative signaling beyond simple IGF sequestration. (baxter2023signalingpathwaysof pages 3-4, baxter2023signalingpathwaysof pages 4-5)

3.2 2023 mechanistic advance: CK2 phosphorylation switches IGFBP-3–HA interactions to enable HA–CD44 pro-survival signaling in NSCLC

A 2023 primary study (Cells) provides a detailed, testable mechanism linking a post-translational modification of IGFBP-3 to ECM-mediated oncogenic signaling and chemotherapy response.

Key findings:
- Casein kinase 2 (CK2) phosphorylates IGFBP-3 at S167 and S175. (coleman2023phosphorylationofigfbp3 pages 5-7)
- CK2 phosphorylation reduces IGFBP-3 binding to hyaluronan (HA): maximal HA binding of phosphorylated IGFBP-3 is ~30% of non-phosphorylated IGFBP-3, and cell-surface association decreases by ~50%. (coleman2023phosphorylationofigfbp3 pages 5-7)
- IGFBP-3 binds HA via a mapped basic C-terminal motif (aa 215–232, sequence KKGFYKKKQCRPSKGRKR), and this interaction blocks HA engagement of CD44, suppressing HA–CD44 signaling. (coleman2023phosphorylationofigfbp3 pages 2-4, coleman2023phosphorylationofigfbp3 pages 5-7)
- When phosphorylated, IGFBP-3’s reduced HA binding permits HA–CD44 signaling, which is linked to activation of the PI3K → AKT → NFκB axis and reduced p53 activity, promoting survival and cisplatin resistance. (coleman2023phosphorylationofigfbp3 pages 1-2, coleman2023phosphorylationofigfbp3 pages 19-21)

Quantitative drug-response results (A549 vs H1299):
- CK2 inhibitor TBB IC50: 8 ± 1.5 µM (A549) and 7 ± 1.3 µM (H1299). (coleman2023phosphorylationofigfbp3 pages 5-7)
- Cisplatin IC50: 9 ± 1.5 µM (A549) and 26 ± 4 µM (H1299). (coleman2023phosphorylationofigfbp3 pages 5-7)
- TBB + cisplatin caused ~4-fold viability decrease vs ~2-fold for either alone (reported qualitatively as fold differences in viability). (coleman2023phosphorylationofigfbp3 pages 5-7)

Figure-level visual evidence supporting these results is available in the paper’s figures showing IC50 measurements and reduced HA binding upon phosphorylation. (coleman2023phosphorylationofigfbp3 media 0143ad9b, coleman2023phosphorylationofigfbp3 media 21878636)

3.3 Nuclear receptor pathway: RXRα/RAR interactions and transcriptional/apoptotic outputs

A central IGF-independent nuclear mechanism is the interaction of nuclear IGFBP-3 with retinoid X receptor alpha (RXRα). Classic evidence describes RXR as an IGFBP-3 partner identified by yeast two-hybrid screening and positions this interaction as a conceptual “paradigm shift” for IGFBP actions in transcription and apoptosis. (lee2002nucleareffectsunexpected pages 3-4)

A 2023 Endocrine Reviews synthesis further states that IGFBP-3 binds RXRα to promote RXR-specific transcription and that RXRα is required for IGFBP-3-dependent apoptosis in some models; IGFBP-3 also binds RAR and inhibits RAR signaling, and can interact with other RXRα-binding nuclear receptors. (baxter2023signalingpathwaysof pages 9-9)

4. Recent developments (prioritizing 2023–2024 sources)

1) System-level mechanistic integration (2023 Endocrine Reviews): The field’s current high-authority synthesis emphasizes that IGFBPs (including IGFBP-3) act as multifunctional signaling modulators via post-translational modification, proteolysis, receptor crosstalk (integrins, TGFβ-family systems), and nuclear mechanisms (class II nuclear receptors; DNA damage repair). (baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 2-2)

2) Post-translational modification controlling ECM signaling and drug resistance (2023 Cells): CK2 phosphorylation of IGFBP-3 at S167/S175 functionally “re-wires” HA binding and HA–CD44 signaling, providing a mechanistic rationale for combined pathway inhibition (CK2/CD44/PI3K/AKT/NFκB) to improve cisplatin sensitivity in NSCLC models. (coleman2023phosphorylationofigfbp3 pages 1-2, coleman2023phosphorylationofigfbp3 pages 5-7)

3) Nuclear import and receptor crosstalk highlighted in 2023 synthesis: Nuclear IGFBP-3 is described as predominantly nuclear in some contexts, and its importin-β interaction can be inhibited by humanin—suggesting a regulatable import mechanism connecting stress peptides and IGFBP-3 nuclear action. (baxter2023signalingpathwaysof pages 9-9)

5. Current applications and real-world implementations

5.1 Clinical/translational biomarker: serum IGFBP-3 in cancer diagnosis and prognosis

A concrete example of real-world implementation is serum IGFBP-3 measurement by ELISA followed by ROC analysis and prognostic modeling.

In esophagogastric junction adenocarcinoma (EJA), a 2022 study used serum IGFBP-3 to support diagnosis and prognosis:
- Cohort: 320 participants, split into training (112 controls; 102 EJA, incl. 24 early-stage) and validation (56 controls; 50 EJA, incl. 12 early-stage). (ding2022seruminsulinlikegrowth pages 1-3)
- Diagnostic performance:
- Training AUC 0.819 (specificity 90.18%, sensitivity 43.14%)
- Validation AUC 0.804 (specificity 87.50%, sensitivity 42.00%). (ding2022seruminsulinlikegrowth pages 1-3)
- Early-stage EJA performance:
- Training AUC 0.822 (specificity 90.18%, sensitivity 45.83%)
- Validation AUC 0.811 (specificity 84.48%, sensitivity 50.00%). (ding2022seruminsulinlikegrowth pages 1-3)
- Prognosis: IGFBP-3 remained an independent factor in multivariable Cox analysis (HR = 0.468, P=0.005), and a nomogram including IGFBP-3 improved C-index (0.625 vs 0.735). (ding2022seruminsulinlikegrowth pages 1-3)

These findings illustrate current real-world use patterns: IGFBP-3 is most commonly implemented as a blood biomarker (ELISA or proteomics panel component) rather than a direct drug target in routine care. (ding2022seruminsulinlikegrowth pages 1-3, baxter2023signalingpathwaysof pages 1-2)

5.2 Translational targeting opportunities: pathway-based interventions instead of direct IGFBP-3 drugs

Expert synthesis notes that IGFBPs have been proposed as therapeutic targets, but their ubiquity in circulation and cell contexts creates practical challenges. (baxter2023signalingpathwaysof pages 1-2)

Nevertheless, the NSCLC mechanism indicates actionable strategies: blocking CK2-mediated phosphorylation or HA–CD44 signaling (and downstream PI3K/AKT/NFκB) may counteract IGFBP-3–associated chemoresistance mechanisms. (coleman2023phosphorylationofigfbp3 pages 1-2, coleman2023phosphorylationofigfbp3 pages 19-21)

6. Expert opinions and interpretive analysis (authoritative synthesis)

A leading expert review (Endocrine Reviews, 2023) frames IGFBP-3 biology as an archetype of multifunctional extracellular proteins that can:
- inhibit IGF1R activation by IGF sequestration,
- regulate receptor signaling via phosphatase activation and receptor cross-talk,
- act in the nucleus by modulating nuclear hormone receptor activity and DNA damage responses,
- and have immune/senescence implications, creating both therapeutic opportunities and complexity. (baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 3-4)

The emerging consensus is therefore not a single “primary function” in all contexts, but a dominant primary biochemical activity—high-affinity IGF binding—that acts as a scaffold for diverse regulated functions controlled by proteolysis and phosphorylation, and by compartment switching between extracellular matrix, membrane microdomains, cytosol, and nucleus. (baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 3-4, coleman2023phosphorylationofigfbp3 pages 5-7)

7. Recent statistics and data (selected highlights)

Key quantitative values extracted from recent studies are consolidated in the table below.

Category	Claim / feature	Details / quantitative result	Evidence type	Key source (year; DOI URL)	Citation
Identity	Correct target verified as human IGFBP3 / UniProt P17936	Explicit mapping reported as Homo sapiens IGFBP-3 (P17936); separate primary study also lists IGFBP-3 = UniProt P17936	computational / primary	Mofid et al., 2018, https://doi.org/10.4103/1735-5362.235160; Price et al., 2020, https://doi.org/10.1021/acs.biochem.0c00274	(mofid2018insilicointeraction pages 1-3, price2020humaninblocksaggregation pages 1-2)
Core feature	Secreted precursor architecture	IGFBP-3 reported as 291 aa total, comprising a 27-aa signal peptide and 264-aa mature chain, consistent with a secreted precursor	computational	Mofid et al., 2018, https://doi.org/10.4103/1735-5362.235160	(mofid2018insilicointeraction pages 1-3)
Core feature	Domain organization	Modular N-domain, linker domain, C-domain; linker is a hotspot for phosphorylation/proteolysis, N- and C-termini cooperate in high-affinity IGF binding	review / computational	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008; Mofid et al., 2018, https://doi.org/10.4103/1735-5362.235160	(baxter2023signalingpathwaysof pages 1-2, mofid2018insilicointeraction pages 8-10, sechrist2025pathologicsignalingand pages 1-2, mofid2018insilicointeraction pages 11-11)
Core feature	Major circulating role	IGFBP-3 is the most abundant circulating IGFBP and stabilizes IGFs in blood, including formation of binary complexes and ALS-containing ternary complexes (~150 kDa)	review	Sechrist et al., 2025, https://doi.org/10.3390/ijms262110248	(sechrist2025pathologicsignalingand pages 2-4)
Key binding partners	Canonical ligand binding	Binds IGF-1/IGF-2 with high affinity to modulate IGF bioavailability and receptor access; sterically hinders IGF-1 interaction with IGF1R	review / computational	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008; Mofid et al., 2018, https://doi.org/10.4103/1735-5362.235160	(baxter2023signalingpathwaysof pages 1-2, mofid2018insilicointeraction pages 8-10, baxter2023signalingpathwaysof pages 3-4)
Key binding partners	Noncanonical partners	Documented partners/pathway nodes include LRP1/TGFβR-V, PP2A, RACK1, integrins, hyaluronan (HA), CD44, importin-β, RXRα/RAR, and histone H3	review / primary	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008; Coleman et al., 2023, https://doi.org/10.3390/cells12030405; Bhardwaj et al., 2021, https://doi.org/10.3390/ijms22010407	(baxter2023signalingpathwaysof pages 3-4, coleman2023phosphorylationofigfbp3 pages 2-4, shrivastav2020insulinlikegrowthfactor pages 7-8, baxter2023signalingpathwaysof pages 9-9)
Mechanism / pathway	IGF sequestration and IGF1R modulation	Canonical action is to impede access of IGF-1/2 to IGF1R; IGFBP-3 can also inhibit IGF1R signaling through phosphatase-mediated mechanisms	review	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008	(baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 3-4)
Mechanism / pathway	LRP1 / PP2A / RACK1 signaling	IGFBP-3 acting via TGFβ receptor type V / LRP1 activates PP2A; PP2A associates with IGF1R via RACK1 and suppresses signaling, with modulation by β-integrin ligation	review	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008	(baxter2023signalingpathwaysof pages 3-4, baxter2023signalingpathwaysof pages 4-5)
Mechanism / pathway	HA-CD44 survival signaling	IGFBP-3 binds HA and can block HA-CD44 signaling; when IGFBP-3 is phosphorylated by CK2, HA binding falls and PI3K-AKT-NFκB survival signaling proceeds with reduced p53 activity	primary cell study	Coleman et al., 2023, https://doi.org/10.3390/cells12030405	(coleman2023phosphorylationofigfbp3 pages 1-2, coleman2023phosphorylationofigfbp3 pages 19-21, coleman2023phosphorylationofigfbp3 pages 2-4, coleman2023phosphorylationofigfbp3 pages 5-7)
Mechanism / pathway	HA-binding region	HA-binding motif mapped to an 18-aa basic C-terminal region (aa 215–232: KKGFYKKKQCRPSKGRKR)	primary cell study	Coleman et al., 2023, https://doi.org/10.3390/cells12030405	(coleman2023phosphorylationofigfbp3 pages 2-4, coleman2023phosphorylationofigfbp3 pages 5-7)
Mechanism / pathway	CK2 phosphorylation sites	CK2 phosphorylates IGFBP-3 at S167 and S175; phosphorylation leaves IGF-1 binding intact but blocks ALS interaction and strongly reduces HA/cell-surface association	primary cell study	Coleman et al., 2023, https://doi.org/10.3390/cells12030405	(coleman2023phosphorylationofigfbp3 pages 5-7)
Quantitative mechanism	Effect of phosphorylation on HA binding	Maximal HA binding of phosphorylated IGFBP-3 ≈30% of non-phosphorylated IGFBP-3; cell-surface association reduced by ~50%	primary cell study	Coleman et al., 2023, https://doi.org/10.3390/cells12030405	(coleman2023phosphorylationofigfbp3 pages 5-7)
Mechanism / pathway	Proteolytic regulation	Proteolysis lowers IGF–IGFBP affinity, releasing IGFs and increasing bioactive ligand; the linker domain is a major proteolysis-sensitive regulatory region	review	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008	(baxter2023signalingpathwaysof pages 2-2, sechrist2025pathologicsignalingand pages 2-4, sechrist2025pathologicsignalingand pages 1-2, baxter2023signalingpathwaysof pages 3-4)
Mechanism / pathway	Nuclear import	IGFBP-3 contains a basic C-terminal/bipartite NLS and can undergo importin-β-dependent nuclear translocation; import is blocked by anti-importin-β and requires ATP/GTP	review	Shrivastav et al., 2020, https://doi.org/10.3389/fcell.2020.00286; Lee & Cohen, 2002, https://doi.org/10.1677/joe.0.1750033	(lee2002nucleareffectsunexpected pages 3-4, shrivastav2020insulinlikegrowthfactor pages 7-8, shrivastav2020insulinlikegrowthfactor pages 2-4)
Mechanism / pathway	Nuclear receptor interactions	Nuclear IGFBP-3 binds RXRα and RAR, promotes RXR-specific transcription, inhibits RAR signaling, and RXRα is reported as required for IGFBP-3-dependent apoptosis in some models	review	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008; Lee & Cohen, 2002, https://doi.org/10.1677/joe.0.1750033	(baxter2023signalingpathwaysof pages 9-9, lee2002nucleareffectsunexpected pages 1-3)
Mechanism / pathway	IGF-independent apoptosis / senescence	IGFBP-3 can trigger IGF-independent apoptosis and senescence-related programs; mutants with little or no IGF binding can still induce apoptosis	review / primary	Lee & Cohen, 2002, https://doi.org/10.1677/joe.0.1750033; Kwon et al., 2023, https://doi.org/10.1038/s41598-023-35291-5	(lee2002nucleareffectsunexpected pages 3-4, skorupa2018igfbp3inducedby pages 19-23)
Quantitative mechanism	Senescence phenotype in breast cancer cells	In MCF-7 cells, induced IGFBP-3 increased SA-β-gal-positive cells 3.4-fold over control and reduced telomerase activity by lowering hTR/hTERT	primary cell study	Kwon et al., 2023, https://doi.org/10.1038/s41598-023-35291-5	(skorupa2018igfbp3inducedby pages 19-23)
Human biomarker	EJA diagnostic performance	In esophagogastric junction adenocarcinoma (EJA), serum IGFBP-3 AUC was 0.819 (training) and 0.804 (validation); specificity/sensitivity 90.18%/43.14% and 87.50%/42.00%	human cohort	Ding et al., 2022, https://doi.org/10.1007/s12672-022-00591-1	(ding2022seruminsulinlikegrowth pages 1-3)
Human biomarker	Early-stage EJA diagnostic performance	For early-stage EJA, AUC was 0.822 (training) and 0.811 (validation); specificity/sensitivity 90.18%/45.83% and 84.48%/50.00%	human cohort	Ding et al., 2022, https://doi.org/10.1007/s12672-022-00591-1	(ding2022seruminsulinlikegrowth pages 1-3)
Human biomarker	EJA prognosis	Lower serum IGFBP-3 associated with worse survival; multivariable Cox analysis: HR = 0.468, P = 0.005. Nomogram including IGFBP-3 improved C-index from 0.625 to 0.735 (P = 0.001) vs TNM alone	human cohort	Ding et al., 2022, https://doi.org/10.1007/s12672-022-00591-1	(ding2022seruminsulinlikegrowth pages 1-3)
Human biomarker	EJA serum concentrations	Mean serum IGFBP-3 was lower in controls vs EJA comparisons: training 1664 ng/mL (controls) vs 1138 ng/mL (EJA) / 1121 ng/mL (early-stage EJA); validation 1632 ng/mL vs 1142 ng/mL / 1124 ng/mL	human cohort	Ding et al., 2022, https://doi.org/10.1007/s12672-022-00591-1	(ding2022seruminsulinlikegrowth pages 3-5)
Human biomarker	Prostate cancer risk association	Collaborative analysis of 20 prospective studies (up to 17,009 cases, including 2,332 aggressive cases) found higher circulating IGFBP-3 associated with overall prostate cancer risk: OR per 1 SD = 1.08 (95% CI 1.04–1.11); association attenuated after IGF-I adjustment	human cohort	Watts et al., 2023, https://doi.org/10.1093/ije/dyac124	(watts2023circulatinginsulinlikegrowth pages 13-14)
Quantitative mechanism	NSCLC drug-response metrics	TBB IC50: 8 ± 1.5 µM (A549), 7 ± 1.3 µM (H1299); cisplatin IC50: 9 ± 1.5 µM (A549), 26 ± 4 µM (H1299); combined TBB + cisplatin caused ~4-fold viability decrease vs ~2-fold for either alone	primary cell study	Coleman et al., 2023, https://doi.org/10.3390/cells12030405	(coleman2023phosphorylationofigfbp3 pages 5-7)
Translational relevance	Real-world implementation	Current real-world use is mainly as a circulating biomarker/analyte in clinical or translational studies (e.g., cancer risk/prognosis panels), while therapeutic interest centers on modulating IGFBP-3 signaling or downstream pathways rather than established approved IGFBP-3-targeted drugs	review / human cohort	Baxter, 2023, https://doi.org/10.1210/endrev/bnad008; Ding et al., 2022, https://doi.org/10.1007/s12672-022-00591-1	(baxter2023signalingpathwaysof pages 1-2, ding2022seruminsulinlikegrowth pages 1-3)

Table: This table condenses verified identity, core biology, major signaling mechanisms, and representative quantitative biomarker findings for human IGFBP3/UniProt P17936. It is useful as a compact evidence map linking functional annotation to recent translational and clinical data.

8. Limitations of this evidence set

Some important “IGFBP-3 standard biology” points (e.g., precise structural domain boundaries from crystallography) are not directly extractable from the retrieved full-text set; however, mechanisms and numeric results are strongly supported by the 2023 Endocrine Reviews synthesis and 2023 mechanistic primary data. (baxter2023signalingpathwaysof pages 1-2, coleman2023phosphorylationofigfbp3 pages 5-7)
Biomarker evidence here is anchored by a robust 2022 clinical study in EJA and mechanistic 2023 cell-line data; additional 2023–2024 cohort biomarker studies likely exist across diseases, but were not all retrievable within the current tool results. (ding2022seruminsulinlikegrowth pages 1-3)

Key cited sources (with dates and URLs)

Baxter RC. Endocrine Reviews (Mar 2023). “Signaling Pathways of the Insulin-like Growth Factor Binding Proteins.” https://doi.org/10.1210/endrev/bnad008 (baxter2023signalingpathwaysof pages 1-2, baxter2023signalingpathwaysof pages 3-4, baxter2023signalingpathwaysof pages 9-9)
Coleman K-l et al. Cells (Jan 2023). “Phosphorylation of IGFBP-3 by Casein Kinase 2 Blocks Its Interaction with Hyaluronan…” https://doi.org/10.3390/cells12030405 (coleman2023phosphorylationofigfbp3 pages 1-2, coleman2023phosphorylationofigfbp3 pages 5-7, coleman2023phosphorylationofigfbp3 media 0143ad9b, coleman2023phosphorylationofigfbp3 media 21878636)
Ding T-Y et al. Discover Oncology (Nov 2022). “Serum IGFBP3 as a diagnostic and prognostic biomarker in esophagogastric junction adenocarcinoma.” https://doi.org/10.1007/s12672-022-00591-1 (ding2022seruminsulinlikegrowth pages 1-3)
Shrivastav SV et al. Frontiers in Cell and Developmental Biology (May 2020). “IGFBP-3: IGF-independent effects within the cell.” https://doi.org/10.3389/fcell.2020.00286 (shrivastav2020insulinlikegrowthfactor pages 7-8)
Lee K-W, Cohen P. Journal of Endocrinology (Oct 2002). “Nuclear effects: unexpected intracellular actions of IGFBP-3.” https://doi.org/10.1677/joe.0.1750033 (lee2002nucleareffectsunexpected pages 3-4)
Mofid MR et al. Research in Pharmaceutical Sciences (Jul 2018). “In silico interaction of IGFBP-3 with IGF-1.” https://doi.org/10.4103/1735-5362.235160 (mofid2018insilicointeraction pages 1-3)

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(lee2002nucleareffectsunexpected pages 1-3): KW Lee and P Cohen. Nuclear effects: unexpected intracellular actions of insulin-like growth factor binding protein-3. Journal of Endocrinology, 175:33-40, Oct 2002. URL: https://doi.org/10.1677/joe.0.1750033, doi:10.1677/joe.0.1750033. This article has 127 citations and is from a peer-reviewed journal.
(skorupa2018igfbp3inducedby pages 19-23): Jennifer A. Skorupa. Igfbp-3 induced by ribotoxic stress is not secreted prior to nuclear localization in mammary epithelial cells. ArXiv, Jan 2018. URL: https://doi.org/10.7282/t3d50r5w, doi:10.7282/t3d50r5w. This article has 0 citations.
(ding2022seruminsulinlikegrowth pages 3-5): Tian-Yan Ding, Yu-Hui Peng, Chao-Qun Hong, Bin-Liang Huang, Can-Tong Liu, Yun Luo, Ling-Yu Chu, Biao Zhang, Xin-Hao Li, Qi-Qi Qu, Yi-Wei Xu, and Fang-Cai Wu. Serum insulin-like growth factor binding protein 3 as a promising diagnostic and prognostic biomarker in esophagogastric junction adenocarcinoma. Discover. Oncology, Nov 2022. URL: https://doi.org/10.1007/s12672-022-00591-1, doi:10.1007/s12672-022-00591-1. This article has 5 citations.
(watts2023circulatinginsulinlikegrowth pages 13-14): Eleanor L Watts, Aurora Perez-Cornago, Georgina K Fensom, Karl Smith-Byrne, Urwah Noor, Colm D Andrews, Marc J Gunter, Michael V Holmes, Richard M Martin, Konstantinos K Tsilidis, Demetrius Albanes, Aurelio Barricarte, H Bas Bueno-de-Mesquita, Barbara A Cohn, Melanie Deschasaux-Tanguy, Niki L Dimou, Luigi Ferrucci, Leon Flicker, Neal D Freedman, Graham G Giles, Edward L Giovannucci, Christopher A Haiman, Graham J Hankey, Jeffrey M P Holly, Jiaqi Huang, Wen-Yi Huang, Lauren M Hurwitz, Rudolf Kaaks, Tatsuhiko Kubo, Loic Le Marchand, Robert J MacInnis, Satu Männistö, E Jeffrey Metter, Kazuya Mikami, Lorelei A Mucci, Anja Olsen, Kotaro Ozasa, Domenico Palli, Kathryn L Penney, Elizabeth A Platz, Michael N Pollak, Monique J Roobol, Catherine A Schaefer, Jeannette M Schenk, Pär Stattin, Akiko Tamakoshi, Elin Thysell, Chiaojung Jillian Tsai, Mathilde Touvier, Stephen K Van Den Eeden, Elisabete Weiderpass, Stephanie J Weinstein, Lynne R Wilkens, Bu B Yeap, Rosalind A Eeles, Christopher A Haiman, Zsofia Kote-Jarai, Fredrick R Schumacher, Sara Benlloch, Ali Amin Al Olama, Kenneth R Muir, Sonja I Berndt, David V Conti, Fredrik Wiklund, Stephen Chanock, Ying Wang, Catherine M Tangen, Jyotsna Batra, Judith A Clements, Naomi E Allen, Timothy J Key, and Ruth C Travis. Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and mendelian randomization analysis. International Journal of Epidemiology, 52:71-86, Jun 2023. URL: https://doi.org/10.1093/ije/dyac124, doi:10.1093/ije/dyac124. This article has 60 citations and is from a highest quality peer-reviewed journal.

Citations

sechrist2025pathologicsignalingand pages 2-4
mofid2018insilicointeraction pages 1-3
lee2002nucleareffectsunexpected pages 3-4
shrivastav2020insulinlikegrowthfactor pages 7-8
baxter2023signalingpathwaysof pages 9-9
ding2022seruminsulinlikegrowth pages 1-3
baxter2023signalingpathwaysof pages 1-2
ding2022seruminsulinlikegrowth pages 3-5
watts2023circulatinginsulinlikegrowth pages 13-14
price2020humaninblocksaggregation pages 1-2
baxter2023signalingpathwaysof pages 2-2
mofid2018insilicointeraction pages 8-10
mofid2018insilicointeraction pages 11-11
baxter2023signalingpathwaysof pages 3-4
baxter2023signalingpathwaysof pages 4-5
sechrist2025pathologicsignalingand pages 1-2
shrivastav2020insulinlikegrowthfactor pages 2-4
lee2002nucleareffectsunexpected pages 1-3
https://doi.org/10.4103/1735-5362.235160;
https://doi.org/10.1021/acs.biochem.0c00274
https://doi.org/10.4103/1735-5362.235160
https://doi.org/10.1210/endrev/bnad008;
https://doi.org/10.3390/ijms262110248
https://doi.org/10.3390/cells12030405;
https://doi.org/10.3390/ijms22010407
https://doi.org/10.1210/endrev/bnad008
https://doi.org/10.3390/cells12030405
https://doi.org/10.3389/fcell.2020.00286;
https://doi.org/10.1677/joe.0.1750033
https://doi.org/10.1677/joe.0.1750033;
https://doi.org/10.1038/s41598-023-35291-5
https://doi.org/10.1007/s12672-022-00591-1
https://doi.org/10.1093/ije/dyac124
https://doi.org/10.3389/fcell.2020.00286
https://doi.org/10.4103/1735-5362.235160,
https://doi.org/10.1021/acs.biochem.0c00274,
https://doi.org/10.1210/endrev/bnad008,
https://doi.org/10.3390/ijms262110248,
https://doi.org/10.3390/cells12030405,
https://doi.org/10.1677/joe.0.1750033,
https://doi.org/10.3389/fcell.2020.00286,
https://doi.org/10.1007/s12672-022-00591-1,
https://doi.org/10.7282/t3d50r5w,
https://doi.org/10.1093/ije/dyac124,

📄 View Raw YAML

id: P17936
gene_symbol: IGFBP3
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'IGFBP3 encodes a secreted insulin-like growth factor binding protein whose dominant
  biochemical activity is high-affinity binding of IGF-I and IGF-II, thereby regulating IGF
  receptor signaling and circulating IGF stability through binary and ALS-containing ternary
  complexes. It also has context-dependent IGF-independent roles involving nuclear import,
  RXR/RAR signaling, phosphatase-mediated suppression of IGF pathway mediators, apoptosis,
  and hyaluronan-CD44 signaling.'
existing_annotations:
  - term:
      id: GO:0031994
      label: insulin-like growth factor I binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: insulin-like growth factor I binding is a core IGFBP3 molecular function;
        the literature consistently identifies high-affinity IGF-I/IGF-II binding as the
        dominant biochemical activity.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0031995
      label: insulin-like growth factor II binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: insulin-like growth factor II binding is a core IGFBP3 molecular
        function; the literature consistently identifies high-affinity IGF-I/IGF-II
        binding as the dominant biochemical activity.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: extracellular space is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0001968
      label: fibronectin binding
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: Fibronectin binding is retained as a non-core transferred annotation, but
        the Falcon evidence set did not retrieve strong direct IGFBP3-specific support
        for fibronectin binding. This should not be treated as refuted; it is simply
        less established than IGF and hyaluronan binding.
      action: KEEP_AS_NON_CORE
      reason: Direct support for fibronectin binding was not established in this review,
        but the term is not demonstrably false.
  - term:
      id: GO:0043567
      label: regulation of insulin-like growth factor receptor signaling pathway
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: IGFBP3 regulates IGF receptor signaling by sequestering IGF ligands and
        through IGF-independent signaling crosstalk, so this process annotation is
        supported.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
  - term:
      id: GO:0005520
      label: insulin-like growth factor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: insulin-like growth factor binding is a core IGFBP3 molecular function;
        the literature consistently identifies high-affinity IGF-I/IGF-II binding as the
        dominant biochemical activity.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: Nuclear localization is supported but represents a context-dependent
        IGF-independent compartment rather than the canonical extracellular IGF-binding
        role.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: Multiple sources support nuclear localization of IGFBP-3.
            Classic mechanistic evidence indicates IGFBP-3 contains a **basic C-terminal
            nuclear localization signal (NLS)** and undergoes **NLS-dependent,
            importin-mediated nuclear translocation**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A central IGF-independent nuclear mechanism is the
            interaction of nuclear IGFBP-3 with **retinoid X receptor alpha (RXRα)**.
            Classic evidence describes RXR as an IGFBP-3 partner identified by yeast
            two-hybrid screening and positions this interaction as a conceptual
            “paradigm shift” for IGFBP actions in transcription and apoptosis.
  - term:
      id: GO:0006915
      label: apoptotic process
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: apoptotic process is retained as a context-dependent IGF-independent
        apoptotic role, including nuclear receptor and cell-death receptor mechanisms,
        but it is not the canonical core molecular function.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A central IGF-independent nuclear mechanism is the
            interaction of nuclear IGFBP-3 with **retinoid X receptor alpha (RXRα)**.
            Classic evidence describes RXR as an IGFBP-3 partner identified by yeast
            two-hybrid screening and positions this interaction as a conceptual
            “paradigm shift” for IGFBP actions in transcription and apoptosis.
        - reference_id: file:human/IGFBP3/IGFBP3-uniprot.txt
          supporting_text: apoptotic effects mediated by its receptor TMEM219/IGFBP-3R
  - term:
      id: GO:0014912
      label: negative regulation of smooth muscle cell migration
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: negative regulation of smooth muscle cell migration is consistent with
        IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these
        are downstream context-specific effects rather than the core ligand-binding
        activity.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0019838
      label: growth factor binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: Growth factor binding is true but less informative than the specific
        insulin-like growth factor binding annotations already present.
      action: MODIFY
      reason: Use the specific IGF binding term for this protein family.
      proposed_replacement_terms:
        - id: GO:0005520
          label: insulin-like growth factor binding
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0031994
      label: insulin-like growth factor I binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: insulin-like growth factor I binding is a core IGFBP3 molecular function;
        the literature consistently identifies high-affinity IGF-I/IGF-II binding as the
        dominant biochemical activity.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0042567
      label: insulin-like growth factor ternary complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: insulin-like growth factor ternary complex is supported by IGFBP3
        formation of binary IGF:IGFBP complexes and ALS-containing ternary complexes in
        circulation.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0048662
      label: negative regulation of smooth muscle cell proliferation
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: negative regulation of smooth muscle cell proliferation is consistent
        with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but
        these are downstream context-specific effects rather than the core
        ligand-binding activity.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20353938
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:20353938
          supporting_text: 2010 Mar 30. Identification of a novel cell death receptor
            mediating IGFBP-3-induced anti-tumor effects in breast and prostate cancer.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23178489
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:23178489
          supporting_text: The role of insulin-like growth factor binding protein-3 in
            the breast cancer cell response to DNA-damaging agents.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30184438
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:30184438
          supporting_text: Epub 2018 Sep 17. Interaction of Insulin-Like Growth
            Factor-Binding Protein 3 With Hyaluronan and Its Regulation by Humanin and
            CD44.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of Neurodegenerative
            Disease Proteins and Uncovers Widespread Protein Aggregation in Affected
            Brains.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0001649
      label: osteoblast differentiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: osteoblast differentiation is retained as a context-specific
        differentiation phenotype downstream of IGFBP3 signaling rather than the core
        biochemical function.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-uniprot.txt
          supporting_text: including proliferation, differentiation, and apoptosis in a
            cell-type specific manner
  - term:
      id: GO:0001968
      label: fibronectin binding
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: Fibronectin binding is retained as a non-core transferred annotation, but
        the Falcon evidence set did not retrieve strong direct IGFBP3-specific support
        for fibronectin binding. This should not be treated as refuted; it is simply
        less established than IGF and hyaluronan binding.
      action: KEEP_AS_NON_CORE
      reason: Direct support for fibronectin binding was not established in this review,
        but the term is not demonstrably false.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: extracellular space is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-381466
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26216267
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:26216267
          supporting_text: Humanin Peptide Binds to Insulin-Like Growth Factor-Binding
            Protein 3 (IGFBP3) and Regulates Its Interaction with Importin-β.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0005788
      label: endoplasmic reticulum lumen
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-8952289
    review:
      summary: Endoplasmic reticulum lumen localization is plausible for a secreted
        precursor and FAM20C substrate, but it is not the main functional site of mature
        IGFBP3.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
  - term:
      id: GO:0042567
      label: insulin-like growth factor ternary complex
    evidence_type: IDA
    original_reference_id: PMID:9497324
    review:
      summary: insulin-like growth factor ternary complex is supported by IGFBP3
        formation of binary IGF:IGFBP complexes and ALS-containing ternary complexes in
        circulation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:9497324
          supporting_text: Insulin-like growth factor (IGF)-binding protein 5 forms an
            alternative ternary complex with IGFs and the acid-labile subunit.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-381435
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-381446
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-381461
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-381496
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-381500
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800035
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-6800044
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      supported_by:
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0008285
      label: negative regulation of cell population proliferation
    evidence_type: IGI
    original_reference_id: PMID:19258508
    review:
      summary: negative regulation of cell population proliferation is consistent with
        IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these
        are downstream context-specific effects rather than the core ligand-binding
        activity.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:19258508
          supporting_text: Epub 2009 Mar 3. NKX3.1 activates expression of insulin-like
            growth factor binding protein-3 to mediate insulin-like growth factor-I
            signaling and cell proliferation.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0014912
      label: negative regulation of smooth muscle cell migration
    evidence_type: IDA
    original_reference_id: PMID:10766744
    review:
      summary: negative regulation of smooth muscle cell migration is consistent with
        IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but these
        are downstream context-specific effects rather than the core ligand-binding
        activity.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:10766744
          supporting_text: Substitutions for hydrophobic amino acids in the N-terminal
            domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their
            biologic actions.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0016942
      label: insulin-like growth factor binding protein complex
    evidence_type: IC
    original_reference_id: PMID:10766744
    review:
      summary: insulin-like growth factor binding protein complex is supported by IGFBP3
        formation of binary IGF:IGFBP complexes and ALS-containing ternary complexes in
        circulation.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:10766744
          supporting_text: Substitutions for hydrophobic amino acids in the N-terminal
            domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their
            biologic actions.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0031994
      label: insulin-like growth factor I binding
    evidence_type: IPI
    original_reference_id: PMID:10766744
    review:
      summary: insulin-like growth factor I binding is a core IGFBP3 molecular function;
        the literature consistently identifies high-affinity IGF-I/IGF-II binding as the
        dominant biochemical activity.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:10766744
          supporting_text: Substitutions for hydrophobic amino acids in the N-terminal
            domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their
            biologic actions.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0048662
      label: negative regulation of smooth muscle cell proliferation
    evidence_type: IDA
    original_reference_id: PMID:10766744
    review:
      summary: negative regulation of smooth muscle cell proliferation is consistent
        with IGFBP3 modulation of IGF/IGF1R and IGF-independent signaling outputs, but
        these are downstream context-specific effects rather than the core
        ligand-binding activity.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:10766744
          supporting_text: Substitutions for hydrophobic amino acids in the N-terminal
            domains of IGFBP-3 and -5 markedly reduce IGF-I binding and alter their
            biologic actions.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0005615
      label: extracellular space
    evidence_type: IDA
    original_reference_id: PMID:17119061
    review:
      summary: Extracellular space localization is accepted because IGFBP3 is a
        secreted/circulating IGF-binding protein; however, PMID:17119061 is an
        epidemiological plasma IGF cohort study, so the original IDA evidence/citation
        is weak for direct localization evidence.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:17119061
          supporting_text: 'Ethnic disparity in the relationship between obesity and plasma
            insulin-like growth factors: the multiethnic cohort.'
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
      reason: Accepted based on the broader secreted-protein evidence while noting the
        source GOA citation quality issue.
  - term:
      id: GO:0001933
      label: negative regulation of protein phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:17591901
    review:
      summary: 'UNDECIDED: the source GOA annotation cites PMID:17591901, but that PMID is
        a PAX6 postnatal eye-development paper rather than an IGFBP3 phosphorylation/signaling
        study. This appears to be an erroneous PMID assignment in GOA, so the annotation cannot
        be accepted or cleanly modified from the cited evidence.'
      action: UNDECIDED
      supported_by:
        - reference_id: PMID:17591901
          supporting_text: 'The requirement of pax6 for postnatal eye development: evidence
            from experimental mouse chimeras.'
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
      reason: The cited publication does not support an IGFBP3 annotation; this should
        be flagged for source-database review.
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:17434920
    review:
      summary: Nuclear localization is supported but represents a context-dependent
        IGF-independent compartment rather than the canonical extracellular IGF-binding
        role.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:17434920
          supporting_text: Apr 13. Contribution of the orphan nuclear receptor Nur77 to
            the apoptotic action of IGFBP-3.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: Multiple sources support nuclear localization of IGFBP-3.
            Classic mechanistic evidence indicates IGFBP-3 contains a **basic C-terminal
            nuclear localization signal (NLS)** and undergoes **NLS-dependent,
            importin-mediated nuclear translocation**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A central IGF-independent nuclear mechanism is the
            interaction of nuclear IGFBP-3 with **retinoid X receptor alpha (RXRα)**.
            Classic evidence describes RXR as an IGFBP-3 partner identified by yeast
            two-hybrid screening and positions this interaction as a conceptual
            “paradigm shift” for IGFBP actions in transcription and apoptosis.
  - term:
      id: GO:0006468
      label: protein phosphorylation
    evidence_type: IDA
    original_reference_id: PMID:17434920
    review:
      summary: IGFBP3 is not a protein kinase and does not catalyze protein
        phosphorylation. The supported biology is indirect regulation of
        phosphorylation/signaling downstream of IGF1R and related pathways.
      action: MODIFY
      reason: Replace a misleading phosphorylation-process annotation with the supported
        negative regulation of protein phosphorylation/signaling.
      proposed_replacement_terms:
        - id: GO:0001933
          label: negative regulation of protein phosphorylation
      supported_by:
        - reference_id: PMID:17434920
          supporting_text: Apr 13. Contribution of the orphan nuclear receptor Nur77 to
            the apoptotic action of IGFBP-3.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:14561895
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:14561895
          supporting_text: Interaction between the Alzheimer's survival peptide humanin
            and insulin-like growth factor-binding protein 3 regulates cell survival and
            apoptosis.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:9388210
    review:
      summary: Generic protein binding is over-broad for IGFBP3. More informative
        annotations are IGF binding, hyaluronan binding, ternary complex formation, and
        specific receptor/importin/nuclear receptor interactions.
      action: MARK_AS_OVER_ANNOTATED
      reason: Avoid retaining generic protein binding when specific molecular
        interactions are available.
      supported_by:
        - reference_id: PMID:9388210
          supporting_text: Inhibition of insulin receptor activation by insulin-like
            growth factor binding proteins.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: The emerging consensus is therefore not a single “primary
            function” in all contexts, but a dominant primary biochemical
            activity—**high-affinity IGF binding**—that acts as a scaffold for diverse
            regulated functions controlled by **proteolysis** and **phosphorylation**,
            and by compartment switching between extracellular matrix, membrane
            microdomains, cytosol, and nucleus.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
  - term:
      id: GO:0005520
      label: insulin-like growth factor binding
    evidence_type: NAS
    original_reference_id: PMID:12599210
    review:
      summary: insulin-like growth factor binding is a core IGFBP3 molecular function;
        the literature consistently identifies high-affinity IGF-I/IGF-II binding as the
        dominant biochemical activity.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:12599210
          supporting_text: Role of insulin-like growth factor binding protein-3
            (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0008160
      label: protein tyrosine phosphatase activator activity
    evidence_type: IDA
    original_reference_id: PMID:11940579
    review:
      summary: Protein tyrosine phosphatase activator activity is retained as a non-core
        IGF-independent signaling mechanism from older experimental evidence, while
        newer synthesis emphasizes PP2A-mediated dephosphorylation of IGF pathway
        mediators.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:11940579
          supporting_text: 2002 Apr 8. Insulin-like growth factor-binding protein-3
            activates a phosphotyrosine phosphatase.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
  - term:
      id: GO:0009968
      label: negative regulation of signal transduction
    evidence_type: NAS
    original_reference_id: PMID:11940579
    review:
      summary: Negative regulation of signal transduction is supported by IGFBP3
        suppression of IGF/IGF1R pathway mediators and by hyaluronan-CD44 signaling
        blockade; this captures a core signaling output of IGFBP3 ligand binding in
        extracellular contexts.
      action: ACCEPT
      supported_by:
        - reference_id: PMID:11940579
          supporting_text: 2002 Apr 8. Insulin-like growth factor-binding protein-3
            activates a phosphotyrosine phosphatase.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A 2023 Endocrine Reviews synthesis describes an
            IGF-independent mechanism in which IGFBP-3 engages **TGFβ receptor type V
            (LRP1)** to activate **PP2A** (a serine/threonine phosphatase). PP2A can
            associate with IGF1R via **RACK1**, and downregulates key IGF1R pathway
            mediators including **Akt** and **Ras/MAPK**.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
            factor binding proteins (IGFBPs) whose canonical cellular role is to bind
            **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
            and modulating IGF1R signaling.
  - term:
      id: GO:0043065
      label: positive regulation of apoptotic process
    evidence_type: IMP
    original_reference_id: PMID:11971816
    review:
      summary: positive regulation of apoptotic process is retained as a
        context-dependent IGF-independent apoptotic role, including nuclear receptor and
        cell-death receptor mechanisms, but it is not the canonical core molecular
        function.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:11971816
          supporting_text: 'Insulin-like growth factor binding protein-3 mediates tumor necrosis
            factor-alpha-induced apoptosis: role of Bcl-2 phosphorylation.'
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A central IGF-independent nuclear mechanism is the
            interaction of nuclear IGFBP-3 with **retinoid X receptor alpha (RXRα)**.
            Classic evidence describes RXR as an IGFBP-3 partner identified by yeast
            two-hybrid screening and positions this interaction as a conceptual
            “paradigm shift” for IGFBP actions in transcription and apoptosis.
        - reference_id: file:human/IGFBP3/IGFBP3-uniprot.txt
          supporting_text: apoptotic effects mediated by its receptor TMEM219/IGFBP-3R
  - term:
      id: GO:0045663
      label: positive regulation of myoblast differentiation
    evidence_type: IDA
    original_reference_id: PMID:12599210
    review:
      summary: positive regulation of myoblast differentiation is retained as a
        context-specific differentiation phenotype downstream of IGFBP3 signaling rather
        than the core biochemical function.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:12599210
          supporting_text: Role of insulin-like growth factor binding protein-3
            (IGFBP-3) in the differentiation of primary human adult skeletal myoblasts.
        - reference_id: file:human/IGFBP3/IGFBP3-uniprot.txt
          supporting_text: including proliferation, differentiation, and apoptosis in a
            cell-type specific manner
  - term:
      id: GO:0046872
      label: metal ion binding
    evidence_type: NAS
    original_reference_id: PMID:14576163
    review:
      summary: The C-terminal metal-binding domain evidence is retained as a non-core
        IGF-independent feature.
      action: KEEP_AS_NON_CORE
      supported_by:
        - reference_id: PMID:14576163
          supporting_text: Oct 22. Insulin-like growth factor-independent effects
            mediated by a C-terminal metal-binding domain of insulin-like growth factor
            binding protein-3.
  - term:
      id: GO:0005576
      label: extracellular region
    evidence_type: NAS
    original_reference_id: PMID:14718574
    review:
      summary: extracellular region is supported by IGFBP3 secretion and its
        extracellular/circulating IGF complex functions.
      action: ACCEPT
      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.'
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
            describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
            peptide** and a **264-aa mature chain**, consistent with secretion into
            extracellular fluids.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
            circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
            in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
            acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
            circulating IGF.
  - term:
      id: GO:0005540
      label: hyaluronic acid binding
    evidence_type: IDA
    original_reference_id: PMID:30184438
    review:
      summary: IGFBP3 hyaluronic acid binding is directly supported by PMID:30184438,
        which characterizes HA binding to IGFBP3 and the 215-232 C-terminal peptide and
        its regulation by humanin/CD44.
      action: NEW
      reason: Specific HA binding is supported by primary experimental evidence and is
        absent from current GOA.
      supported_by:
        - reference_id: PMID:30184438
          supporting_text: Here, we characterized the binding affinities of the IGFBP-3
            protein and peptide (215-KKGFYKKKQCRPSKGRKR-232) to HA and to humanin and
            found that HA binds with a weaker affinity to this region than does humanin.
        - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
          supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
            **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks
            HA engagement of **CD44**, suppressing HA–CD44 signaling.
references:
  - 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: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation data to
      orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:10766744
    title: Substitutions for hydrophobic amino acids in the N-terminal domains of
      IGFBP-3 and -5 markedly reduce IGF-I binding and alter their biologic actions.
    findings: []
  - id: PMID:11940579
    title: Insulin-like growth factor-binding protein-3 activates a phosphotyrosine
      phosphatase. Effects on the insulin-like growth factor signaling pathway.
    findings: []
  - id: PMID:11971816
    title: 'Insulin-like growth factor binding protein-3 mediates tumor necrosis factor-alpha-induced
      apoptosis: role of Bcl-2 phosphorylation.'
    findings: []
  - id: PMID:12599210
    title: Role of insulin-like growth factor binding protein-3 (IGFBP-3) in the
      differentiation of primary human adult skeletal myoblasts.
    findings: []
  - id: PMID:14561895
    title: Interaction between the Alzheimer's survival peptide humanin and insulin-like
      growth factor-binding protein 3 regulates cell survival and apoptosis.
    findings: []
  - id: PMID:14576163
    title: Insulin-like growth factor-independent effects mediated by a C-terminal
      metal-binding domain of insulin-like growth factor binding protein-3.
    findings: []
  - id: PMID:14718574
    title: 'The human plasma proteome: a nonredundant list developed by combination of four
      separate sources.'
    findings: []
  - id: PMID:17119061
    title: 'Ethnic disparity in the relationship between obesity and plasma insulin-like growth
      factors: the multiethnic cohort.'
    findings: []
  - id: PMID:17434920
    title: Contribution of the orphan nuclear receptor Nur77 to the apoptotic action of
      IGFBP-3.
    findings: []
  - id: PMID:17591901
    title: 'The requirement of pax6 for postnatal eye development: evidence from experimental
      mouse chimeras.'
    findings: []
  - id: PMID:19258508
    title: NKX3.1 activates expression of insulin-like growth factor binding protein-3
      to mediate insulin-like growth factor-I signaling and cell proliferation.
    findings: []
  - id: PMID:20353938
    title: Identification of a novel cell death receptor mediating IGFBP-3-induced
      anti-tumor effects in breast and prostate cancer.
    findings: []
  - id: PMID:23178489
    title: The role of insulin-like growth factor binding protein-3 in the breast cancer
      cell response to DNA-damaging agents.
    findings: []
  - id: PMID:26216267
    title: Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3
      (IGFBP3) and Regulates Its Interaction with Importin-β.
    findings: []
  - id: PMID:30184438
    title: Interaction of Insulin-Like Growth Factor-Binding Protein 3 With Hyaluronan
      and Its Regulation by Humanin and CD44.
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
      and Uncovers Widespread Protein Aggregation in Affected Brains.
    findings: []
  - id: PMID:9388210
    title: Inhibition of insulin receptor activation by insulin-like growth factor
      binding proteins.
    findings: []
  - id: PMID:9497324
    title: Insulin-like growth factor (IGF)-binding protein 5 forms an alternative
      ternary complex with IGFs and the acid-labile subunit.
    findings: []
  - id: Reactome:R-HSA-381435
    title: Matrix metalloproteinase proteolyzes IGF:IGFBP3:ALS
    findings: []
  - id: Reactome:R-HSA-381446
    title: Thrombin proteolyzes IGF:IGFBP3:ALS
    findings: []
  - id: Reactome:R-HSA-381461
    title: Plasmin proteolyzes IGF:IGFBP-3:ALS
    findings: []
  - id: Reactome:R-HSA-381466
    title: 'Prostate-specific Antigen proteolyzes IGF:IGFBP3:ALS '
    findings: []
  - id: Reactome:R-HSA-381496
    title: Formation of the IGF:IGFBP3:ALS complex
    findings: []
  - id: Reactome:R-HSA-381500
    title: Cathepsin G proteolyzes IGF:IGFBP3:ALS
    findings: []
  - id: Reactome:R-HSA-6800035
    title: IGFBP3 binds TMEM219
    findings: []
  - id: Reactome:R-HSA-6800044
    title: TP53 stimulates IGFBP3 expression
    findings: []
  - id: Reactome:R-HSA-8952289
    title: FAM20C phosphorylates FAM20C substrates
    findings: []
  - id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
    title: Falcon deep research synthesis for IGFBP3
    findings: []
  - id: file:human/IGFBP3/IGFBP3-uniprot.txt
    title: UniProt record for IGFBP3
    findings: []
core_functions:
  - description: High-affinity binding of IGF-I and IGF-II to regulate IGF receptor
      signaling and stabilize circulating IGF complexes.
    molecular_function:
      id: GO:0005520
      label: insulin-like growth factor binding
    directly_involved_in:
      - id: GO:0043567
        label: regulation of insulin-like growth factor receptor signaling pathway
    locations:
      - id: GO:0005576
        label: extracellular region
    in_complex:
      id: GO:0042567
      label: insulin-like growth factor ternary complex
    supported_by:
      - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
        supporting_text: IGFBP-3 is one of six “high-affinity” insulin-like growth
          factor binding proteins (IGFBPs) whose canonical cellular role is to bind
          **IGF-1 and IGF-2** with high affinity, thereby **impeding access to IGF1R**
          and modulating IGF1R signaling.
      - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
        supporting_text: A key systemic concept is that IGFBP-3 is the **most abundant
          circulating IGFBP** and supports endocrine IGF signaling by stabilizing IGFs
          in blood. IGFBP-3 forms binary IGF:IGFBP complexes and can bind the
          acid-labile subunit (ALS) to form a **~150 kDa ternary complex**, increasing
          circulating IGF.
      - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
        supporting_text: IGFBP-3 is a secreted precursor protein. A retrieved analysis
          describes IGFBP-3 as a **291-aa** protein comprising a **27-aa signal
          peptide** and a **264-aa mature chain**, consistent with secretion into
          extracellular fluids.
  - description: Hyaluronan binding that modulates extracellular HA-CD44 signaling in a
      phosphorylation-sensitive manner.
    molecular_function:
      id: GO:0005540
      label: hyaluronic acid binding
    directly_involved_in:
      - id: GO:0009968
        label: negative regulation of signal transduction
    locations:
      - id: GO:0005576
        label: extracellular region
    supported_by:
      - reference_id: file:human/IGFBP3/IGFBP3-deep-research-falcon.md
        supporting_text: IGFBP-3 binds HA via a mapped basic C-terminal motif (aa
          **215–232**, sequence **KKGFYKKKQCRPSKGRKR**), and this interaction blocks HA
          engagement of **CD44**, suppressing HA–CD44 signaling.
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []

Gene Description

Existing Annotations Review

Core Functions

High-affinity binding of IGF-I and IGF-II to regulate IGF receptor signaling and stabilize circulating IGF complexes.

Hyaluronan binding that modulates extracellular HA-CD44 signaling in a phosphorylation-sensitive manner.

References

Deep Research

Falcon

Research Report: Human IGFBP3 (UniProt P17936) — Functional Annotation and Translational Relevance

0. Target verification (critical disambiguation)

1. Key concepts and definitions (current understanding)

1.1 Canonical (IGF-dependent) function: high-affinity IGF sequestration and IGF1R modulation

1.2 Endocrine concept: circulating IGF stabilization and ternary complex formation

1.3 IGF-independent signaling paradigm

2. Protein features and localization: where IGFBP-3 acts

2.1 Secreted precursor and extracellular compartment

2.2 Nuclear localization and intracellular trafficking (importin-β; energy dependence)

3. Pathways and mechanisms (recent and authoritative synthesis prioritized)

3.1 IGFBP-3–LRP1 (TGFβR-V)–PP2A axis: IGF-independent suppression of IGF1R pathway mediators

3.2 2023 mechanistic advance: CK2 phosphorylation switches IGFBP-3–HA interactions to enable HA–CD44 pro-survival signaling in NSCLC

3.3 Nuclear receptor pathway: RXRα/RAR interactions and transcriptional/apoptotic outputs

4. Recent developments (prioritizing 2023–2024 sources)

5. Current applications and real-world implementations

5.1 Clinical/translational biomarker: serum IGFBP-3 in cancer diagnosis and prognosis

5.2 Translational targeting opportunities: pathway-based interventions instead of direct IGFBP-3 drugs

6. Expert opinions and interpretive analysis (authoritative synthesis)

7. Recent statistics and data (selected highlights)

8. Limitations of this evidence set

Key cited sources (with dates and URLs)

Citations

📄 View Raw YAML