Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
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
Gene Ontology annotation based on curation of immunofluorescence data
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan.
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AGR2 was reported to bind C4.4a/LYPD3 and alpha-dystroglycan in yeast two-hybrid screens.
"Yeast two-hybrid cloning identified metastasis-associated GPI-anchored C4.4a protein and extracellular alpha-dystroglycan (DAG-1) as binding partners for both hAG-2 and hAG-3"
AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer.
Towards a proteome-scale map of the human protein-protein interaction network.
The protein disulfide isomerase AGR2 is essential for production of intestinal mucus.
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AGR2 is an ER-localized PDI-family factor required for intestinal MUC2 production and mucus.
"Here, we show that AGR2 is present within the ER of intestinal secretory epithelial cells and is essential for in vivo production of the intestinal mucin MUC2"
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AGR2 forms mixed disulfide bonds with MUC2 via its thioredoxin-like cysteine.
"A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing."
AGR2 gene function requires a unique endoplasmic reticulum localization motif.
Dimerization of pro-oncogenic protein Anterior Gradient 2 is required for the interaction with BiP/GRP78.
Metastasis-promoting anterior gradient 2 protein has a dimeric thioredoxin fold structure and a role in cell adhesion.
A highly sensitive targeted mass spectrometric assay for quantification of AGR2 protein in human urine and serum.
A proteome-scale map of the human interactome network.
Epidermal growth factor receptor (EGFR) signaling requires a specific endoplasmic reticulum thioredoxin for the post-translational control of receptor presentation to the cell surface.
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AGR2 binds EGFR in the ER and promotes EGFR surface delivery/signaling in cancer-cell models.
"EGFR binding to anterior gradient homolog 2 ( AGR2 ) in the endoplasmic reticulum is required for receptor delivery to the plasma membrane and thus EGFR signaling."
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This EGFR-focused study provides a competing interpretation of AGR2 substrate biology by reporting no MUC2 in its AGR2 mixed-disulfide analysis and citing a re-evaluation against MUC2 folding.
"Re-evaluation of MUC2 in a recent study also concluded that it is not a AGR2-binding protein and that AGR2 served no role in its folding."
Widespread macromolecular interaction perturbations in human genetic disorders.
Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation.
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AGR2 dimerization links ER proteostasis to secretion and inflammation.
"AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers."
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AGR2 dimers dissociate downstream of ER stress sensing rather than driving UPR — establishing the AGR2-versus-UPR-sensor directionality as sensor-driven, not AGR2-driven.
"dissociation of AGR2 homodimers as assessed by the decrease in luminescence observed for all the constructs tested"
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The IRE1 mention in this paper is the ERMIT mammalian two-hybrid bait scaffold, not a biological regulatory target — relevant for evaluating arm-specific UPR claims.
"the luminal domain of IRE1 was replaced by different bait proteins"
Leveraging the Role of the Metastatic Associated Protein Anterior Gradient Homologue 2 in Unfolded Protein Degradation: A Novel Therapeutic Biomarker for Cancer.
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The well-established AGR2/UPR-sensor directionality is sensor-driven — IRE1α and ATF6α regulate AGR2 expression, not vice versa. PERK is conspicuously absent from the AGR2 mechanistic literature.
"This was demonstrated when IREα and ATF6α were knocked down using small interfering RNA (siRNA) in HeLa cells, resulting in the decreased expression levels of the AGR2 protein"
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Mechanistic review summary of AGR2 expression regulators omits any AGR2 → IRE1/PERK regulatory direction.
"The top molecules implicated in regulating the expression of AGR2 included IRE1α, ATF6α, AKT, FOXA1/2, HIF-1, TMED2, and the frequently mutated tumor suppressor p53."
A reference map of the human binary protein interactome.
Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease.
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Human AGR2 deficiency causes goblet-cell and gel-forming mucin loss with ER stress and mucus barrier disease.
"Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress."
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Human AGR2 H117Y has reduced MUC2 binding and reduced ER-stress relief, supporting AGR2-MUC2 functional interaction despite the earlier EGFR-focused conflict.
"The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress."
Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2.
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AGR2 negatively regulates IRE1β-mediated UPR signaling in goblet-cell contexts by binding IRE1β and blocking oligomerization and endonuclease outputs.
"AGR2 binding to IRE1β disrupts IRE1β oligomerization, thereby blocking its downstream endonuclease activity."
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Loss of endogenous AGR2 activates IRE1β in goblet cells, supporting AGR2 as a threshold-setting repressor rather than an activator.
"Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1β activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1β activation."
The IRE1β-mediated unfolded protein response is repressed by the chaperone AGR2 in mucin producing cells.
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AGR2 selectively represses IRE1β luminal-domain signaling and supports a mucin-producing-cell-specific IRE1β regulatory mechanism.
"The mucin-specific chaperone AGR2 repressed IRE1 activity in cells expressing the domain-swapped IRE1β/α chimera, but had no effect on IRE1α."
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Biophysical evidence supports direct AGR2 destabilization of IRE1β luminal-domain dimers.
"In vitro, AGR2 actively de-stabilised the IRE1β luminal domain dimer and formed a reversible complex with the inactive monomer."
Manual AGR2 curation notes
Falcon deep research report for AGR2
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Falcon research supports AGR2 as an ER PDI-family mucin client-processing factor and identifies a newer negative-regulatory role for IRE1β-mediated UPR signaling.
"Across authoritative reviews and primary studies, the strongest consensus is that AGR2’s primary physiological role is as an ER proteostasis factor for mucin-producing epithelial cells"