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.
| 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. |
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