AGR3 encodes anterior gradient protein 3, a small secretory-pathway AGR/thioredoxin-like protein with an N-terminal signal peptide and C-terminal ER retrieval motif. AGR3 is enriched in ciliated airway epithelial cells and other epithelia, and loss-of-function evidence supports a role in calcium-dependent control of ciliary beat frequency and mucociliary clearance. AGR3 also has reported cancer-associated extracellular interactions with alpha-dystroglycan and LYPD3/C4.4a, but its precise molecular catalytic activity and physiological client proteins remain unresolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER localization is well supported for AGR3 by its signal peptide, QSEL retrieval motif, KDEL-receptor localization study, and airway epithelial cell localization evidence. Reason: ER residence is the best-supported compartment for AGR3 and is consistent with both phylogenetic transfer and direct experimental localization evidence. Supporting Evidence: PMID:18086916 Three of the 16 constructs, ERp18, Hag3, and GP7R, changed their localization from the ER to the Golgi when the putative ER-retention motif was not present PMID:25751668 Here we report that AGR3, unlike its closest homolog AGR2, is restricted to ciliated cells in the airway epithelium and is not induced by ER stress. |
| GO:0002162 dystroglycan binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: AGR3 binding to alpha-dystroglycan was reported in yeast two-hybrid screens, but the evidence is cancer/extracellular-context interaction evidence rather than the main physiological airway/ER function of AGR3. Reason: The term is specific enough to retain, and the IBA is consistent with the original AGR2/AGR3 two-hybrid evidence, but it should not be treated as the core function because the paper itself called for additional clinical-context validation. Supporting Evidence: PMID:12592373 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 PMID:12592373 Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical cancers |
| GO:0002162 dystroglycan binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA transfer of dystroglycan binding is consistent with direct AGR3/DAG1 yeast two-hybrid evidence, but it remains a non-core cancer/extracellular interaction. Reason: Keep the specific binding term as non-core: the interaction is reported, but the strongest physiological evidence for AGR3 concerns ER-localized control of airway ciliary beat regulation. Supporting Evidence: PMID:12592373 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 PMID:12592373 Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical cancers |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Automated ER localization is consistent with experimental literature and the UniProt-recognized AGR3 ER retrieval motif. Reason: ER is the principal supported cellular compartment for AGR3. Supporting Evidence: PMID:18086916 Three of the 16 constructs, ERp18, Hag3, and GP7R, changed their localization from the ER to the Golgi when the putative ER-retention motif was not present PMID:25751668 Here we report that AGR3, unlike its closest homolog AGR2, is restricted to ciliated cells in the airway epithelium and is not induced by ER stress. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: This Stitch-seq interactome annotation reports an AGR3 binary interaction but collapses it to generic protein binding, which is not informative for AGR3 functional curation. Reason: Generic protein binding should not be retained as a meaningful AGR3 function, especially for high-throughput interactome rows without a mechanistic connection to AGR3 airway or ER biology. Supporting Evidence: PMID:21516116 We describe a massively parallel interactome-mapping pipeline, Stitch-seq, that combines PCR stitching with next-generation sequencing and used it to generate a new human interactome dataset. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: The proteome-scale interactome map contributes several AGR3 binary interaction rows, but the resulting GO term protein binding is too broad to clarify AGR3 function. Reason: The annotation should not be treated as core AGR3 biology because it is a broad high-throughput interaction label without a specific biochemical or pathway interpretation. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: HuRI reports many AGR3 binary interaction partners, but generic protein binding obscures rather than explains the protein's biological role. Reason: This high-throughput interaction evidence is useful as candidate-interactor context but should not be propagated as a core or informative molecular function annotation. Supporting Evidence: PMID:32296183 Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based ER localization is consistent with direct literature showing AGR3 as an ER-resident ciliated-airway protein. Reason: The experimental cellular-component annotation matches the best-supported localization for AGR3. Supporting Evidence: PMID:18086916 Three of the 16 constructs, ERp18, Hag3, and GP7R, changed their localization from the ER to the Golgi when the putative ER-retention motif was not present PMID:25751668 Here we report that AGR3, unlike its closest homolog AGR2, is restricted to ciliated cells in the airway epithelium and is not induced by ER stress. |
| GO:0005515 protein binding | IPI PMID:12592373 hAG-2 and hAG-3, human homologues of genes involved in diffe... | MODIFY | Summary: The protein-binding annotation from PMID:12592373 reflects specific yeast-two-hybrid interactions with C4.4a/LYPD3 and alpha-dystroglycan; dystroglycan binding is the more informative existing GO term. Reason: Protein binding is too generic. Replace it with the specific supported DAG1 interaction term, while noting that the LYPD3/C4.4a interaction does not currently have an equivalently specific GO binding term in this review. Proposed replacements: dystroglycan binding Supporting Evidence: PMID:12592373 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 PMID:12592373 Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical cancers |
| GO:0002162 dystroglycan binding | IDA PMID:12592373 hAG-2 and hAG-3, human homologues of genes involved in diffe... | KEEP AS NON CORE | Summary: Direct yeast-two-hybrid evidence supports AGR3 binding to alpha-dystroglycan, but this is not AGR3's main supported physiological function. Reason: Retain the specific molecular interaction as non-core because the best functional evidence instead points to ER-localized regulation of ciliary beat frequency in airway epithelium. Supporting Evidence: PMID:12592373 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 PMID:12592373 Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical cancers |
| GO:0003351 epithelial cilium movement involved in extracellular fluid movement | ISS PMID:25751668 The Endoplasmic Reticulum Resident Protein AGR3. Required fo... | NEW | Summary: NEW annotation. Mouse Agr3 loss reduces airway ciliary beat frequency and mucociliary transport while preserving ciliary ultrastructure, supporting a conserved AGR3 role in epithelial motile-cilium function rather than ciliogenesis. Reason: This is the clearest biological-process annotation for AGR3's best-supported physiological role. It is proposed for human AGR3 by sequence/orthology-supported inference from the mouse knockout and airway epithelial evidence. Supporting Evidence: PMID:25751668 Mice lacking AGR3 are viable and develop ciliated cells with normal-appearing cilia. However, ciliary beat frequency was lower in airways from AGR3-deficient mice compared with control mice PMID:25751668 Decreased CBF was associated with impaired mucociliary clearance in AGR3-deficient airways. |
| GO:0019722 calcium-mediated signaling | ISS PMID:25751668 The Endoplasmic Reticulum Resident Protein AGR3. Required fo... | NEW | Summary: NEW annotation. AGR3 deficiency affects ciliary beat frequency in a calcium-dependent manner, supporting involvement in calcium-mediated control of airway ciliary function. Reason: This term captures the calcium-dependent mechanism reported for AGR3 more conservatively than asserting a specific calcium transporter, channel, or enzymatic activity. Supporting Evidence: PMID:25751668 AGR3 deficiency had no detectable effects on ciliary beat frequency (CBF) when airways were perfused with a calcium-free solution, suggesting that AGR3 is required for calcium-mediated regulation of ciliary function. |
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Download this section (compressed HTML)Q: Does purified AGR3 have measurable protein disulfide isomerase or other redox/foldase activity, or should the PN PDI-family projection be treated as family context only?
Q: Which ER client protein or calcium-handling pathway links AGR3 to airway epithelial ciliary beat regulation?
Q: Is extracellular AGR3/Src signaling a physiological epithelial function, a cancer-specific state, or a consequence of altered ER retention/secretion?
Experiment: Test purified AGR3, Cys71 mutants, and canonical PDI controls against standard disulfide isomerase/reductase substrates and candidate airway epithelial client proteins.
Type: biochemical activity assay
Experiment: Rescue AGR3-deficient differentiated airway epithelial cultures with wild-type AGR3, QSEL-retention mutants, and Cys71 mutants while measuring ER localization, live-cell Ca2+ dynamics, ciliary beat frequency, and mucociliary transport.
Type: structure-function rescue
Experiment: Use proximity labeling or crosslinking/coimmunoprecipitation in differentiated ciliated airway epithelium to identify AGR3-proximal ER proteins and distinguish physiological clients from high-throughput interactome candidates.
Type: client discovery
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