Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Activation of an estrogen/estrogen receptor signaling by BIG3 through its inhibitory effect on nuclear transport of PHB2/REA in breast cancer.
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Endogenous BIG3 is detected in the cytoplasm of human breast carcinoma tissue by immunohistochemistry, and is absent from normal breast, heart, lung and liver.
"showed its strong staining in the cytoplasm of two different histological subtypes of breast cancer"
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BIG3 retains PHB2 in the cytoplasm, preventing its oestradiol-driven nuclear translocation and thereby increasing ERalpha transcriptional activity.
"BIG3 trapped PHB2/REA in the cytoplasm and inhibited its nuclear translocation, and caused enhancement of ERα transcriptional activity"
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A direct BIG3-ERalpha interaction was looked for and not found, so the ERalpha effect is downstream of PHB2 rather than a direct activity of BIG3.
"we investigated the possibility of a direct interaction between BIG3 and ERα, but failed to indicate their interaction (data not shown)"
Brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) is predicted to interact with its partner through an ARM-type α-helical structure.
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Alignment of BIG3 against characterised Sec7 domains shows it lacks the conserved Sec7 motif and the glutamate essential for exchange activity.
"they showed that BIG3 lacked the conserved motif and critically, the essential glutamate residue"
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The loss of the catalytic motif is shared by BIG3 orthologues, so it is a clade-level feature rather than a human-specific artefact.
"This region is conserved among the BIG3 orthologues, all of which lack the functional motif."
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The PHB2-binding region of BIG3 was delimited experimentally to residues 86-434.
"a series of co-immunoprecipitation assays identified residues 86-434 to be responsible for the binding of BIG3 to PHB2"
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Alanine substitution of Q165, D169 and Q173 within the predicted binding helix strongly reduces PHB2 binding, mapping the interface to specific side chains.
"with alanine reduced the binding affinity to PHB2 dramatically"
BIG3 inhibits insulin granule biogenesis and insulin secretion.
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BIG3 localises to insulin- and clathrin-positive trans-Golgi network compartments in insulin-secreting cells.
"BIG3 is predominantly localized to insulin- and clathrin-positive trans-Golgi network (TGN) compartments."
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Loss of BIG3 raises insulin content, granule number and stimulated secretion, identifying BIG3 as a negative regulator of granule biogenesis.
"BIG3-deficient insulin-secreting cells display increased insulin content and granule number and elevated insulin secretion upon stimulation."
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The authors' overall conclusion is that BIG3 restrains insulin granule biogenesis and secretion and contributes to systemic glucose homeostasis.
"these results demonstrate that BIG3 negatively modulates insulin granule biogenesis and insulin secretion and participates in the regulation of systemic glucose homeostasis"
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The authors state that BIG3's Sec7 domain carries a non-functional catalytic motif.
"It is worth noting that the single known functional domain in BIG3 by sequence analysis, the Sec7 domain, has a non-functional catalytic motif"
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The authors propose, as an explicitly untested hypothesis, that BIG3 acts as a competitive dead Arf-GEF; this is a model, not a result, and no annotation here rests on it.
"one of our hypotheses is that BIG3 acts as a competitive non-functional Arf-GEF, thereby negatively modulating granule production"
Detection of insulin granule exocytosis by an electrophysiology method with high temporal resolution reveals enlarged insulin granule pool in BIG3-knockout mice.
Increased biogenesis of glucagon-containing secretory granules and glucagon secretion in BIG3-knockout mice.
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BIG3 is expressed in pancreatic alpha cells as well as beta cells, and not in delta cells.
"BIG3 is highly expressed in pancreatic alpha-cells in addition to beta-cells, but is absent in delta-cells."
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Depleting BIG3 from alpha cells increases glucagon production and secretion, mirroring its effect on insulin in beta cells.
"Depletion of BIG3 in alpha-cells leads to elevated glucagon production and secretion."
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The phenotype is reproduced in whole animals under hypoglycaemic challenge.
"Consistently, BIG3-knockout (BKO) mice display increased glucagon release under hypoglycemic conditions."
A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.
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Endogenous BIG3 and PP1C-alpha interact in human ERalpha-positive breast cancer cell lines.
"We detected an endogenous interaction between BIG3 and PP1Cα in the ERα-positive breast cancer cell lines MCF-7 and KPL-3C, which highly express both proteins"
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BIG3 inhibits PP1C-alpha catalytic activity, and the inhibition requires BIG3's RVxF docking motif, since the motif-deleted mutant neither binds nor inhibits.
"This showed that the introduction of WT-BIG3 inhibited endogenous PP1Cα activity in a dose-dependent manner, while ΔPP1Cα-BIG3 did not"
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Endogenous BIG3 interacts with protein kinase A in human breast cancer cells.
"We found that endogenous BIG3 interacts with PKA in breast cancer cells"
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The PKA-binding determinant is two predicted RII-binding domains; the subunit specificity is in silico, whereas the interaction itself was measured.
"BIG3 contains two potential RII-binding domains (RIIBDs) that bind to the RII subunit of PKA"
BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells.
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BIG3 blocks oestradiol-dependent nuclear import of PHB2, acting through the karyopherin-alpha import receptors.
"Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells."
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The mechanism is occlusion of the KPNA-binding surface of PHB2 by BIG3, rather than a generic cytoplasmic tether.
"These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells."
Targeting BIG3-PHB2 interaction to overcome tamoxifen resistance in breast cancer cells.
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Disrupting the BIG3-PHB2 complex with the ERAP peptide releases PHB2 to bind ERalpha, confirming that sequestration by BIG3 is what normally prevents it.
"Intrinsic PHB2 released from BIG3 by ERAP directly binds to both nuclear- and membrane-associated ERα"
Therapeutic advances in BIG3-PHB2 inhibition targeting the crosstalk between estrogen and growth factors in breast cancer.
The survival and proliferation of osteosarcoma cells are dependent on the mitochondrial BIG3-PHB2 complex formation.
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In osteosarcoma cell lines the BIG3-PHB2 complex is mainly mitochondrial, which the authors explicitly contrast with its cytoplasmic distribution in breast cancer cells.
"BIG3-PHB2 complexes were localized mainly in mitochondria in OS cells, unlike in estrogen-dependent breast cancer cells."
Brefeldin A-inhibited guanine nucleotide exchange protein 3 is localized in lysosomes and regulates GABA signaling in hippocampal neurons.
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In hippocampal neurons BIG3 is mainly lysosomal, and its loss selectively impairs inhibitory synaptic transmission.
"In hippocampal neurons, BIG3 is mainly localized in lysosomes, and its depletion selectively impairs inhibitory synaptic transmission."
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The group that characterised BIG3 restates that its SEC7 domain carries a non-functional catalytic motif.
"we recently identified BIG3 as a novel ARF GEF protein with a non-functional catalytic motif in the SEC7 domain"
Stapled BIG3 helical peptide ERAP potentiates anti-tumour activity for breast cancer therapeutics.
Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions.
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A small molecule that disrupts the BIG3-PHB2 interaction reproduces the effect of the ERAP peptide, independently supporting sequestration as the mechanism.
"Xanthohumol suppresses oestrogen-signalling in breast cancer through the inhibition of BIG3-PHB2 interactions"
Arfgef3 knockout ameliorates ischemia reperfusion-induced acute kidney injury via mitochondrial dysfunction alleviation in mice.
Biophysical characterization of the breast cancer-related BIG3-PHB2 interaction: Effect of non-conserved loop region of BIG3 on the structure and the interaction.
BIG-3, a novel WD-40 repeat protein, is expressed in the developing growth plate and accelerates chondrocyte differentiation in vitro.
The effects of BIG-3 on osteoblast differentiation are not dependent upon endogenously produced BMPs.
Cloning and characterization of a novel WD-40 repeat protein that dramatically accelerates osteoblastic differentiation.
Overexpression of Brefeldin A-inhibited Guanine Nucleotide-exchange Protein 3 in Patients with Extramammary Paget's Disease.
Yeast Ysl2p, homologous to Sec7 domain guanine nucleotide exchange factors, functions in endocytosis and maintenance of vacuole integrity and interacts with the Arf-Like small GTPase Arl1p.
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The sole non-IBA support for yeast MON2/Ysl2p's own GO:0005085 annotation reports it as a Sec7-family homologue with a potential, not a measured, exchange activity.
"We provide multiple genetic and biochemical evidence for an interaction between Ysl12p and the Arf-like protein Arl1p, consistent with a potential function as an Arf guanine nucleotide exchange factor (GEF)."
ARFGEF3 (BIG3) - computed evidence for the GO review