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.
|
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
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.
AGR3 in this report refers specifically to the human protein Anterior gradient protein 3, also annotated as PDIA18 (protein disulfide isomerase family A member 18), corresponding to UniProt accession Q8TD06. It is a small (~166 aa) single-domain thioredoxin/PDI-family protein with a noncanonical CXXS-like active-site region and a C‑terminal ER retention signal (QSEL), consistent across structural, airway-epithelium, and review literature describing AGR3 (bonser2015theendoplasmicreticulum pages 1-5, boisteau2022anteriorgradientproteins pages 6-10, nguyen2018crystalstructureof pages 1-2).
AGR3 is part of the anterior gradient (AGR) family (AGR1/AGR2/AGR3), a subset of protein disulfide isomerase (PDI)-related proteins typically associated with the secretory pathway and the endoplasmic reticulum (ER). Reviews position AGR proteins as PDI-like factors involved in secretory and transmembrane protein biogenesis in the ER (boisteau2022anteriorgradientproteins pages 1-6, boisteau2022anteriorgradientproteins pages 6-10).
A key concept for AGR3 is that, unlike canonical PDIs that catalyze thiol–disulfide exchange via a CXXC motif, AGR3 contains a noncanonical motif that lacks the second catalytic cysteine, implying atypical or reduced classical thiol–disulfide exchange capability (nguyen2018crystalstructureof pages 1-2, nguyen2018crystalstructureof pages 5-6).
The AGR3 crystal structure literature explicitly emphasizes divergence from the canonical catalytic PDI motif and interprets this as evidence that AGR3 is unlikely to function as a typical thiol–disulfide exchange enzyme in oxidative protein folding (nguyen2018crystalstructureof pages 1-2). Thus, AGR3 is best conceptualized as a PDI-family/thioredoxin-fold protein whose primary biological roles may include selective protein–protein interactions, chaperone-like behavior, or specialized quality-control functions, rather than broad-spectrum disulfide isomerization.
AGR3 is described as a single-domain thioredoxin/PDI-like protein that is routed into the secretory pathway by an N‑terminal signal peptide and contains a nonstandard ER-retention sequence QSEL (nguyen2018crystalstructureof pages 1-2, boisteau2022anteriorgradientproteins pages 6-10).
Crystal structure work reports that AGR3 lacks the canonical WCXXC/CXXC active-site motif and instead contains DCYQS at the equivalent position (nguyen2018crystalstructureof pages 1-2). Structural analysis places this motif in helix 2 and identifies Cys71 as solvent-exposed and observed in a reduced (not oxidized) state in the crystal (nguyen2018crystalstructureof pages 3-5).
Mechanistically, the missing second cysteine (relative to CXXC PDIs) and the presence of an adjacent acidic residue predicted to modulate cysteine pKa support the interpretation that AGR3 has reduced/altered thiolate reactivity and therefore may not efficiently catalyze classical disulfide exchange reactions characteristic of canonical PDIs (nguyen2018crystalstructureof pages 5-6, nguyen2018crystalstructureof pages 1-2). Nonetheless, the exposed cysteine and nearby structural elements (e.g., a cis-proline near the motif) are consistent with a role in substrate binding or specialized redox interactions (nguyen2018crystalstructureof pages 3-5).
In the AGR3 crystal asymmetric unit, two molecules associate, but the authors report that biochemical/PISA analyses provide no evidence for a stable dimer in solution and that AGR3 lacks a component of the salt bridge found in AGR2 dimers (nguyen2018crystalstructureof pages 3-5). This indicates that stable dimerization is not strongly supported for AGR3 under the conditions tested, although transient or context-dependent interactions remain possible.
A core, well-supported feature of AGR3 is its ER localization in ciliated airway epithelial cells.
Bonser et al. report ER localization by immunostaining/colocalization: 99.5% of AGR3 signal colocalized with ER markers (GRP78/GRP94), and AGR3 staining was largely distinct from AGR2 (97.7% in regions distinct from AGR2), reinforcing that AGR3 is an ER-resident protein with cell-type specificity in the airway epithelium (bonser2015theendoplasmicreticulum pages 5-10).
AGR3 expression increases sharply during airway epithelial differentiation: AGR3 mRNA increased ~1000‑fold from day 7 to day 21 in differentiated airway epithelial cultures (bonser2015theendoplasmicreticulum pages 10-13). In contrast to AGR2, AGR3 is not induced by ER stress: tunicamycin increased AGR2 mRNA ~13‑fold but did not increase AGR3 mRNA (bonser2015theendoplasmicreticulum pages 5-10). Reviews similarly describe AGR3 expression as independent of ER stress (boisteau2022anteriorgradientproteins pages 1-6, boisteau2022anteriorgradientproteins pages 6-10).
The strongest mechanistic functional evidence for AGR3 comes from mouse genetics and airway physiology. Agr3 knockout mice (Agr3−/−) were viable and had normal ciliary ultrastructure (normal “9+2” arrangement and dynein arms), indicating AGR3 is not required for ciliogenesis per se (bonser2015theendoplasmicreticulum pages 10-13).
However, Agr3−/− tracheal cilia exhibited a clear functional defect:
- Baseline ciliary beat frequency (CBF) was reduced by ~20% vs controls in 1 mM extracellular Ca2+ (bonser2015theendoplasmicreticulum pages 10-13).
- After extracellular ATP stimulation, CBF was ~35% lower in Agr3−/− tracheas (bonser2015theendoplasmicreticulum pages 10-13).
- Mucociliary particle transport speed was reduced by 35% in Agr3−/− tracheas, supporting impaired mucociliary clearance (bonser2015theendoplasmicreticulum pages 10-13).
These data define AGR3’s best-supported physiological role as regulation of ciliary motility and mucociliary clearance, rather than structural assembly of cilia.
Bonser et al. provide evidence that the ciliary phenotype is calcium-dependent:
- The genotype difference in CBF disappeared in calcium-free solution (bonser2015theendoplasmicreticulum pages 10-13).
- Cultured tracheal epithelial cells from Agr3−/− mice had lower intracellular Ca2+ than wild-type (139.7 ± 98.2 nM vs 362.1 ± 55.0 nM, n=6, p<0.001) (bonser2015theendoplasmicreticulum pages 10-13).
Thus, AGR3 appears to influence intracellular Ca2+ homeostasis/signaling in ciliated cells in a way that impacts ciliary beat regulation.
Reviews summarize that AGR3 has been detected beyond the ER context in cancer, including reports of cell membrane association and extracellular AGR3 (eAGR3), and that AGR3 expression in breast cancer correlates with estrogen receptor status (boisteau2022anteriorgradientproteins pages 6-10). These observations motivate mechanistic studies of extracellular AGR3.
A key primary study demonstrated that breast cancer cells secrete AGR3 and that extracellular AGR3 has functional activity. In ER-positive breast cancer cell lines (MCF‑7, T‑47D), AGR3 was found in conditioned media at nanomolar concentrations (obacz2019extracellularagr3regulates pages 2-4). The same study reports higher serum eAGR3 in breast cancer patients vs healthy controls (no absolute concentration values were present in the retrieved excerpt) (obacz2019extracellularagr3regulates pages 6-8).
Functionally, recombinant eAGR3 (commonly 5 ng/mL, tested across ~0.5–50 ng/mL) increased migration in wound-healing assays and increased resistance to detachment in adhesion-related assays (obacz2019extracellularagr3regulates pages 4-6, obacz2019extracellularagr3regulates pages 2-4).
Mechanistically, the study provides both pharmacologic and genetic evidence that eAGR3 acts via Src kinase signaling:
- eAGR3 increased tyrosine phosphorylation and increased c‑Src phosphorylation; Src phosphorylation was blocked by dasatinib (obacz2019extracellularagr3regulates pages 4-6).
- Dasatinib (1 µM in migration assays) significantly reduced migration in both control and eAGR3-stimulated cells (obacz2019extracellularagr3regulates pages 4-6).
- A kinase-dead/dominant-negative Src mutant (K298R) abolished the migratory response to eAGR3, while wild-type Src did not (obacz2019extracellularagr3regulates pages 4-6).
The authors additionally note that dasatinib did not fully abolish the eAGR3 migration effect, suggesting additional pathways may contribute (obacz2019extracellularagr3regulates pages 6-8).
Given the magnitude of effects on CBF and mucociliary transport in Agr3−/− models, AGR3 is a plausible mechanistic node for disorders where mucociliary clearance is compromised, though the provided evidence does not include direct AGR3-targeted therapies (bonser2015theendoplasmicreticulum pages 10-13).
Patient serum elevation of eAGR3 relative to healthy controls suggests a potential liquid-biopsy biomarker direction, but the retrieved evidence excerpt does not provide performance metrics (AUC, sensitivity/specificity) or absolute concentration ranges needed for clinical evaluation (obacz2019extracellularagr3regulates pages 6-8).
Searches prioritized to 2023–2024 AGR3/PDIA18 did not yield additional AGR3-focused primary literature within the accessible corpus for this run; the most recent authoritative synthesis available here is a 2022 review, while the strongest primary mechanistic studies remain 2015 (airway) and 2019 (extracellular Src signaling) (boisteau2022anteriorgradientproteins pages 6-10, bonser2015theendoplasmicreticulum pages 10-13, obacz2019extracellularagr3regulates pages 4-6). Therefore, this report emphasizes high-confidence mechanistic findings from these studies and explicitly avoids extrapolating beyond available evidence.
| Topic | Key findings | Evidence type | Primary source (first author, journal) | Publication date (month year) | URL | Notes/limitations |
|---|---|---|---|---|---|---|
| Identity | Human AGR3 corresponds to UniProt Q8TD06 / PDIA18, an AGR-family, PDI-like protein encoded on chromosome 7p21.1; reported as a 166-aa protein of ~19.2 kDa (boisteau2022anteriorgradientproteins pages 6-10, bonser2015theendoplasmicreticulum pages 1-5) | Review synthesis of gene/protein annotation; primary experimental background | Boisteau, Oncogene; Bonser, Am J Respir Cell Mol Biol | Sep 2022; Oct 2015 | https://doi.org/10.1038/s41388-022-02452-1 ; https://doi.org/10.1165/rcmb.2014-0318oc | Annotation-level facts; not itself a direct functional assay |
| Domains / family | AGR3 is a small, single-domain PDI-family protein with a thioredoxin-like fold; it carries an N-terminal signal peptide for secretory-pathway entry and a noncanonical ER-retention motif QSEL (nguyen2018crystalstructureof pages 1-2, boisteau2022anteriorgradientproteins pages 6-10) | Crystal structure; review | Nguyen, Acta Crystallogr F Struct Biol Commun; Boisteau, Oncogene | Jun 2018; Sep 2022 | https://doi.org/10.1107/S2053230X18009093 ; https://doi.org/10.1038/s41388-022-02452-1 | Signal peptide/retention motif support localization but do not identify client proteins |
| Active-site motif / catalytic implication | AGR3 lacks the canonical PDI/thioredoxin CXXC or WCXXC motif; structure paper reports a DCYQS motif with solvent-exposed Cys71 in reduced state. Because the second catalytic cysteine is absent and an adjacent acidic residue likely raises cysteine pKa, AGR3 is inferred to have reduced/atypical thiol-disulfide exchange activity relative to classical PDIs (nguyen2018crystalstructureof pages 1-2, nguyen2018crystalstructureof pages 3-5, nguyen2018crystalstructureof pages 5-6, obaczUnknownyearinvestigationofagr3 pages 61-62) | Crystal structure; comparative structural inference | Nguyen, Acta Crystallogr F Struct Biol Commun | Jun 2018 | https://doi.org/10.1107/S2053230X18009093 | Catalytic activity is inferred structurally; no direct AGR3 enzymatic rate/substrate assay in provided snippets |
| Structural features / oligomerization | AGR3 adopts a thioredoxin fold with four β-strands and four α-helices, a bent helix 2, and cis-Pro117 near the DCYQS motif. Two molecules appear in the asymmetric unit, but biochemical/PISA analysis found no evidence for a stable dimer in solution; AGR3 lacks an AGR2-like inter-subunit salt-bridge component (nguyen2018crystalstructureof pages 3-5, nguyen2018crystalstructureof pages 5-6) | X-ray crystal structure | Nguyen, Acta Crystallogr F Struct Biol Commun | Jun 2018 | https://doi.org/10.1107/S2053230X18009093 | Structural study does not establish physiological oligomer state in cells |
| Subcellular localization | AGR3 is ER luminal/ER resident in ciliated airway cells. In human airway epithelium, 99.5% of AGR3 signal colocalized with ER markers GRP78/GRP94, and 97.7% of AGR3 staining was spatially distinct from AGR2. Review evidence also notes membrane and extracellular detection in some cancer contexts (bonser2015theendoplasmicreticulum pages 5-10, boisteau2022anteriorgradientproteins pages 6-10) | Immunostaining / colocalization; review synthesis | Bonser, Am J Respir Cell Mol Biol; Boisteau, Oncogene | Oct 2015; Sep 2022 | https://doi.org/10.1165/rcmb.2014-0318oc ; https://doi.org/10.1038/s41388-022-02452-1 | Membrane/extracellular localization in cancer is less mechanistically resolved than ER localization |
| Expression pattern | AGR3 is enriched in ciliated airway epithelial cells and increases strongly with epithelial differentiation; AGR3 mRNA rose by ~1000-fold from day 7 to day 21 in differentiated airway epithelial cultures. It is not induced by ER stress; tunicamycin increased AGR2 mRNA 13-fold but not AGR3 (bonser2015theendoplasmicreticulum pages 10-13, bonser2015theendoplasmicreticulum pages 5-10, bonser2015theendoplasmicreticulum pages 1-5, boisteau2022anteriorgradientproteins pages 1-6) | Differentiation time course; ER-stress perturbation | Bonser, Am J Respir Cell Mol Biol; Boisteau, Oncogene | Oct 2015; Sep 2022 | https://doi.org/10.1165/rcmb.2014-0318oc ; https://doi.org/10.1038/s41388-022-02452-1 | Expression data do not by themselves reveal molecular clients |
| Airway / ciliary function | Agr3-/- mice were viable and had morphologically normal cilia, but tracheal ciliary beat frequency (CBF) was reduced by ~20% at baseline; with ATP stimulation CBF was ~35% lower than controls. Mucociliary particle transport speed was reduced by 35%, supporting a role in mucociliary clearance rather than ciliogenesis (bonser2015theendoplasmicreticulum pages 10-13, bonser2015theendoplasmicreticulum pages 1-5) | Mouse knockout; ex vivo tracheal physiology | Bonser, Am J Respir Cell Mol Biol | Oct 2015 | https://doi.org/10.1165/rcmb.2014-0318oc | Evidence is strong for airway physiology, but does not identify direct AGR3 molecular substrate(s) |
| Calcium-linked mechanism | The CBF defect in Agr3-/- airways disappeared in calcium-free solution, and intracellular Ca2+ in cultured tracheal epithelial cells was lower in Agr3-/- vs wild type (139.7 ± 98.2 nM vs 362.1 ± 55.0 nM; n=6; p<0.001), implicating AGR3 in calcium-dependent regulation of ciliary activity (bonser2015theendoplasmicreticulum pages 10-13, bonser2015theendoplasmicreticulum pages 1-5) | Mouse knockout; calcium imaging | Bonser, Am J Respir Cell Mol Biol | Oct 2015 | https://doi.org/10.1165/rcmb.2014-0318oc | Mechanistic link to specific calcium-handling proteins remains unresolved in provided evidence |
| Cancer association (intracellular/expression) | AGR3 was first identified in breast tumor membranes; review evidence states expression correlates with estrogen receptor status, correlates with AGR2, and is reported to promote migration/metastasis. AGR3 has also been detected at the cell membrane and extracellularly in cancer contexts (boisteau2022anteriorgradientproteins pages 6-10) | Review synthesis drawing on earlier primary literature | Boisteau, Oncogene | Sep 2022 | https://doi.org/10.1038/s41388-022-02452-1 | Broad cancer statements are summarized from prior literature; quantitative tumor-outcome estimates are not given in the snippet |
| Extracellular AGR3 secretion | ER-positive breast cancer cell lines MCF-7 and T-47D secrete AGR3; conditioned media contained extracellular AGR3 at nanomolar concentrations. Serum eAGR3 was reported significantly elevated in breast cancer patients versus healthy controls (obacz2019extracellularagr3regulates pages 2-4, obacz2019extracellularagr3regulates pages 6-8) | Cell culture secretion assays; patient serum measurement | Obacz, Oncology Letters | Sep 2019 | https://doi.org/10.3892/ol.2019.10849 | Provided snippets do not include absolute serum concentrations or fold change |
| Extracellular AGR3 function in cancer | Recombinant eAGR3 promoted breast-cancer-cell migration and increased resistance to detachment/adhesion-related phenotypes. Functional assays used 5 ng/ml eAGR3 commonly, with testing across 0.5–50 ng/ml; migration was measured in wound-healing assays and adhesion in detachment assays (obacz2019extracellularagr3regulates pages 4-6, obacz2019extracellularagr3regulates pages 2-4, obacz2019extracellularagr3regulates pages 1-2) | Recombinant-protein treatment in breast cancer cell culture | Obacz, Oncology Letters | Sep 2019 | https://doi.org/10.3892/ol.2019.10849 | Exact effect sizes are not present in the provided snippets |
| Src signaling downstream of eAGR3 | eAGR3 increased tyrosine phosphorylation and c-Src phosphorylation. Dasatinib blocked c-Src phosphorylation and significantly reduced migration of control and eAGR3-stimulated cells; genetic interference with kinase-dead Src (K298R) abolished the migratory response to eAGR3. Dasatinib did not fully abolish migration, implying additional pathways may contribute (obacz2019extracellularagr3regulates pages 4-6, obacz2019extracellularagr3regulates pages 6-8, obacz2019extracellularagr3regulates pages 1-2) | Pharmacologic inhibition and dominant-negative Src in cell culture | Obacz, Oncology Letters | Sep 2019 | https://doi.org/10.3892/ol.2019.10849 | Strong evidence for Src involvement in vitro, but receptor(s) for eAGR3 and in vivo relevance remain unresolved |
| Known gaps | Across the provided evidence, no definitive AGR3-specific enzymatic substrate, direct folding client, or biochemical turnover measurement is established. Review and structure sources suggest possible roles in secretory/transmembrane protein biogenesis and possible mucin interaction by family analogy, but direct AGR3 client validation is lacking in the cited snippets (nguyen2018crystalstructureof pages 1-2, boisteau2022anteriorgradientproteins pages 1-6, boisteau2022anteriorgradientproteins pages 6-10) | Cross-source synthesis | Nguyen, Acta Crystallogr F Struct Biol Commun; Boisteau, Oncogene | Jun 2018; Sep 2022 | https://doi.org/10.1107/S2053230X18009093 ; https://doi.org/10.1038/s41388-022-02452-1 | Important limitation for functional annotation: much of AGR3 biochemistry remains inferential rather than directly measured |
Table: This table summarizes the key experimentally supported properties and functions of human AGR3 (UniProt Q8TD06) from the provided evidence only. It highlights what is well supported—especially ER localization, ciliary function, and extracellular cancer signaling—and where important mechanistic gaps remain.
References
(bonser2015theendoplasmicreticulum pages 1-5): Luke R. Bonser, Bradley W. Schroeder, Lisa A. Ostrin, Nathalie Baumlin, Jean L. Olson, Matthias Salathe, and David J. Erle. The endoplasmic reticulum resident protein agr3. required for regulation of ciliary beat frequency in the airway. American journal of respiratory cell and molecular biology, 53 4:536-43, Oct 2015. URL: https://doi.org/10.1165/rcmb.2014-0318oc, doi:10.1165/rcmb.2014-0318oc. This article has 32 citations and is from a peer-reviewed journal.
(boisteau2022anteriorgradientproteins pages 6-10): Emeric Boisteau, Céline Posseme, Federico Di Modugno, Julien Edeline, Cédric Coulouarn, Roman Hrstka, Andrea Martisova, Frédéric Delom, Xavier Treton, Leif A. Eriksson, Eric Chevet, Astrid Lièvre, and Eric Ogier-Denis. Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology. Oncogene, 41:4673-4685, Sep 2022. URL: https://doi.org/10.1038/s41388-022-02452-1, doi:10.1038/s41388-022-02452-1. This article has 15 citations and is from a domain leading peer-reviewed journal.
(nguyen2018crystalstructureof pages 1-2): Van Dat Nguyen, Ekaterina Biterova, Mikko Salin, Rik K. Wierenga, and Lloyd W. Ruddock. Crystal structure of human anterior gradient protein 3. Acta Crystallographica Section F Structural Biology Communications, 74:425-430, Jun 2018. URL: https://doi.org/10.1107/s2053230x18009093, doi:10.1107/s2053230x18009093. This article has 7 citations.
(boisteau2022anteriorgradientproteins pages 1-6): Emeric Boisteau, Céline Posseme, Federico Di Modugno, Julien Edeline, Cédric Coulouarn, Roman Hrstka, Andrea Martisova, Frédéric Delom, Xavier Treton, Leif A. Eriksson, Eric Chevet, Astrid Lièvre, and Eric Ogier-Denis. Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology. Oncogene, 41:4673-4685, Sep 2022. URL: https://doi.org/10.1038/s41388-022-02452-1, doi:10.1038/s41388-022-02452-1. This article has 15 citations and is from a domain leading peer-reviewed journal.
(nguyen2018crystalstructureof pages 5-6): Van Dat Nguyen, Ekaterina Biterova, Mikko Salin, Rik K. Wierenga, and Lloyd W. Ruddock. Crystal structure of human anterior gradient protein 3. Acta Crystallographica Section F Structural Biology Communications, 74:425-430, Jun 2018. URL: https://doi.org/10.1107/s2053230x18009093, doi:10.1107/s2053230x18009093. This article has 7 citations.
(nguyen2018crystalstructureof pages 3-5): Van Dat Nguyen, Ekaterina Biterova, Mikko Salin, Rik K. Wierenga, and Lloyd W. Ruddock. Crystal structure of human anterior gradient protein 3. Acta Crystallographica Section F Structural Biology Communications, 74:425-430, Jun 2018. URL: https://doi.org/10.1107/s2053230x18009093, doi:10.1107/s2053230x18009093. This article has 7 citations.
(bonser2015theendoplasmicreticulum pages 5-10): Luke R. Bonser, Bradley W. Schroeder, Lisa A. Ostrin, Nathalie Baumlin, Jean L. Olson, Matthias Salathe, and David J. Erle. The endoplasmic reticulum resident protein agr3. required for regulation of ciliary beat frequency in the airway. American journal of respiratory cell and molecular biology, 53 4:536-43, Oct 2015. URL: https://doi.org/10.1165/rcmb.2014-0318oc, doi:10.1165/rcmb.2014-0318oc. This article has 32 citations and is from a peer-reviewed journal.
(bonser2015theendoplasmicreticulum pages 10-13): Luke R. Bonser, Bradley W. Schroeder, Lisa A. Ostrin, Nathalie Baumlin, Jean L. Olson, Matthias Salathe, and David J. Erle. The endoplasmic reticulum resident protein agr3. required for regulation of ciliary beat frequency in the airway. American journal of respiratory cell and molecular biology, 53 4:536-43, Oct 2015. URL: https://doi.org/10.1165/rcmb.2014-0318oc, doi:10.1165/rcmb.2014-0318oc. This article has 32 citations and is from a peer-reviewed journal.
(obacz2019extracellularagr3regulates pages 2-4): Joanna Obacz, Lucia Sommerova, Daria Sicari, Michal Durech, Tony Avril, Filippo Iuliano, Silvia Pastorekova, Roman Hrstka, Eric Chevet, Frederic Delom, and Delphine Fessart. Extracellular agr3 regulates breast cancer cells migration via src signaling. Oncology Letters, 18:4449-4456, Sep 2019. URL: https://doi.org/10.3892/ol.2019.10849, doi:10.3892/ol.2019.10849. This article has 22 citations and is from a peer-reviewed journal.
(obacz2019extracellularagr3regulates pages 6-8): Joanna Obacz, Lucia Sommerova, Daria Sicari, Michal Durech, Tony Avril, Filippo Iuliano, Silvia Pastorekova, Roman Hrstka, Eric Chevet, Frederic Delom, and Delphine Fessart. Extracellular agr3 regulates breast cancer cells migration via src signaling. Oncology Letters, 18:4449-4456, Sep 2019. URL: https://doi.org/10.3892/ol.2019.10849, doi:10.3892/ol.2019.10849. This article has 22 citations and is from a peer-reviewed journal.
(obacz2019extracellularagr3regulates pages 4-6): Joanna Obacz, Lucia Sommerova, Daria Sicari, Michal Durech, Tony Avril, Filippo Iuliano, Silvia Pastorekova, Roman Hrstka, Eric Chevet, Frederic Delom, and Delphine Fessart. Extracellular agr3 regulates breast cancer cells migration via src signaling. Oncology Letters, 18:4449-4456, Sep 2019. URL: https://doi.org/10.3892/ol.2019.10849, doi:10.3892/ol.2019.10849. This article has 22 citations and is from a peer-reviewed journal.
(obaczUnknownyearinvestigationofagr3 pages 61-62): J Obacz. Investigation of agr3 protein function and mechanisms triggering its expression in cancer cell. Unknown journal, Unknown year.
(obacz2019extracellularagr3regulates pages 1-2): Joanna Obacz, Lucia Sommerova, Daria Sicari, Michal Durech, Tony Avril, Filippo Iuliano, Silvia Pastorekova, Roman Hrstka, Eric Chevet, Frederic Delom, and Delphine Fessart. Extracellular agr3 regulates breast cancer cells migration via src signaling. Oncology Letters, 18:4449-4456, Sep 2019. URL: https://doi.org/10.3892/ol.2019.10849, doi:10.3892/ol.2019.10849. This article has 22 citations and is from a peer-reviewed journal.
just fetch-gene human AGR3; this created the UniProt record, GOA table, and a 10-entry review stub from 38 GOA rows. Falcon deep research completed at genes/human/AGR3/AGR3-deep-research-falcon.md.projects/PROTEOSTASIS/reports/pn_projection/pn_projected_annotations.tsv:219 proposes GO:0003756 protein disulfide isomerase activity for AGR3 from ER proteostasis|Folding enzyme|Protein disulfide isomerases.GO:0003756 for AGR3. AGR3 is ER-retained and thioredoxin-like, but Falcon synthesis highlights that AGR3 lacks the canonical PDI CXXC/WCXXC motif and "is not a canonical disulfide isomerase" [file:human/AGR3/AGR3-deep-research-falcon.md "Although structurally in the PDI/thioredoxin family, AGR3's DCYQS motif (lacking the second cysteine) supports the view that AGR3 is not a canonical disulfide isomerase"]. This makes the PN projection a family/context projection rather than a safe gene-level GO addition.protein binding rows from high-throughput interactome maps were marked over-annotated, except the PMID:12592373 row was modified to the more specific existing dystroglycan binding term.no_mapping.ER proteostasis|Folding enzyme|Protein disulfide isomerases ; PN-node mapping: group mapped ok_for_propagation GO:0003756 protein disulfide isomerase activity (goa_status=new_to_goa); class/branch no_mapping.no_mapping.This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.
id: Q8TD06
gene_symbol: AGR3
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
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.
existing_annotations:
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
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.
action: ACCEPT
reason: >-
ER residence is the best-supported compartment for AGR3 and is consistent with both phylogenetic transfer and direct
experimental localization evidence.
additional_reference_ids:
- PMID:18086916
- PMID:25751668
supported_by:
- reference_id: PMID:18086916
supporting_text: >-
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
reference_section_type: RESULTS
- reference_id: PMID:25751668
supporting_text: >-
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.
reference_section_type: ABSTRACT
- term:
id: GO:0002162
label: dystroglycan binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
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.
additional_reference_ids:
- PMID:12592373
supported_by:
- reference_id: PMID:12592373
supporting_text: >-
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
reference_section_type: ABSTRACT
- reference_id: PMID:12592373
supporting_text: >-
Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical
cancers
reference_section_type: RESULTS
- term:
id: GO:0002162
label: dystroglycan binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
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.
additional_reference_ids:
- PMID:12592373
supported_by:
- reference_id: PMID:12592373
supporting_text: >-
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
reference_section_type: ABSTRACT
- reference_id: PMID:12592373
supporting_text: >-
Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical
cancers
reference_section_type: RESULTS
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
Automated ER localization is consistent with experimental literature and the UniProt-recognized AGR3 ER retrieval motif.
action: ACCEPT
reason: >-
ER is the principal supported cellular compartment for AGR3.
additional_reference_ids:
- PMID:18086916
- PMID:25751668
supported_by:
- reference_id: PMID:18086916
supporting_text: >-
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
reference_section_type: RESULTS
- reference_id: PMID:25751668
supporting_text: >-
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.
reference_section_type: ABSTRACT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21516116
qualifier: enables
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: PMID:21516116
supporting_text: >-
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.
reference_section_type: ABSTRACT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
qualifier: enables
review:
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.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: PMID:25416956
supporting_text: >-
Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions.
reference_section_type: ABSTRACT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: >-
HuRI reports many AGR3 binary interaction partners, but generic protein binding obscures rather than explains the protein's
biological role.
action: MARK_AS_OVER_ANNOTATED
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.
supported_by:
- reference_id: PMID:32296183
supporting_text: >-
Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'.
reference_section_type: ABSTRACT
- term:
id: GO:0005783
label: endoplasmic reticulum
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: >-
Immunofluorescence-based ER localization is consistent with direct literature showing AGR3 as an ER-resident ciliated-airway
protein.
action: ACCEPT
reason: >-
The experimental cellular-component annotation matches the best-supported localization for AGR3.
additional_reference_ids:
- PMID:18086916
- PMID:25751668
supported_by:
- reference_id: PMID:18086916
supporting_text: >-
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
reference_section_type: RESULTS
- reference_id: PMID:25751668
supporting_text: >-
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.
reference_section_type: ABSTRACT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12592373
qualifier: enables
review:
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.
action: MODIFY
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_replacement_terms:
- id: GO:0002162
label: dystroglycan binding
supported_by:
- reference_id: PMID:12592373
supporting_text: >-
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
reference_section_type: ABSTRACT
- reference_id: PMID:12592373
supporting_text: >-
Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical
cancers
reference_section_type: RESULTS
- term:
id: GO:0002162
label: dystroglycan binding
evidence_type: IDA
original_reference_id: PMID:12592373
qualifier: enables
review:
summary: >-
Direct yeast-two-hybrid evidence supports AGR3 binding to alpha-dystroglycan, but this is not AGR3's main supported
physiological function.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: PMID:12592373
supporting_text: >-
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
reference_section_type: ABSTRACT
- reference_id: PMID:12592373
supporting_text: >-
Clearly, further analyses such as coimmunoprecipitation are required to confirm that these interactions occur in clinical
cancers
reference_section_type: RESULTS
- term:
id: GO:0003351
label: epithelial cilium movement involved in extracellular fluid movement
evidence_type: ISS
original_reference_id: PMID:25751668
qualifier: involved_in
review:
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.
action: NEW
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.
supported_by:
- reference_id: PMID:25751668
supporting_text: >-
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
reference_section_type: ABSTRACT
- reference_id: PMID:25751668
supporting_text: >-
Decreased CBF was associated with impaired mucociliary clearance in AGR3-deficient airways.
reference_section_type: ABSTRACT
- term:
id: GO:0019722
label: calcium-mediated signaling
evidence_type: ISS
original_reference_id: PMID:25751668
qualifier: involved_in
review:
summary: >-
NEW annotation. AGR3 deficiency affects ciliary beat frequency in a calcium-dependent manner, supporting involvement
in calcium-mediated control of airway ciliary function.
action: NEW
reason: >-
This term captures the calcium-dependent mechanism reported for AGR3 more conservatively than asserting a specific
calcium transporter, channel, or enzymatic activity.
supported_by:
- reference_id: PMID:25751668
supporting_text: >-
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.
reference_section_type: ABSTRACT
references:
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
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:12592373
title: 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.
findings:
- statement: AGR3 was reported to bind C4.4a/LYPD3 and alpha-dystroglycan in yeast two-hybrid screens.
supporting_text: >-
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
reference_section_type: ABSTRACT
- id: PMID:18086916
title: A molecular specificity code for the three mammalian KDEL receptors.
findings:
- statement: AGR3/hAG-3 is ER localized and loses ER localization when its C-terminal retrieval motif is removed.
supporting_text: >-
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
reference_section_type: RESULTS
- id: PMID:21516116
title: Next-generation sequencing to generate interactome datasets.
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25751668
title: The Endoplasmic Reticulum Resident Protein AGR3. Required for Regulation of Ciliary Beat Frequency in the Airway.
findings:
- statement: AGR3 is required for calcium-mediated ciliary beat regulation and mucociliary clearance in airway epithelium.
supporting_text: >-
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. Decreased CBF was associated
with impaired mucociliary clearance in AGR3-deficient airways.
reference_section_type: ABSTRACT
full_text_unavailable: true
- id: PMID:26170690
title: Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients.
findings:
- statement: AGR3 is expressed in ciliated cells of the oviduct and in several cancer contexts.
supporting_text: >-
AGR3 expression was demonstrated in various cancers, including breast,7 prostate,21 ovary,19,20 and liver.18
reference_section_type: DISCUSSION
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: file:human/AGR3/AGR3-deep-research-falcon.md
title: Falcon deep research report for human AGR3.
findings:
- statement: AGR3 is not currently supported as a canonical protein disulfide isomerase despite its PDI-family/thioredoxin-like fold.
supporting_text: >-
Although structurally in the PDI/thioredoxin family, AGR3's **DCYQS** motif (lacking the second cysteine) supports the
view that AGR3 is **not a canonical disulfide isomerase**; it likely mediates **selective protein interactions** or
specialized redox behavior rather than generalized thiol-disulfide exchange
core_functions:
- description: >-
AGR3 is an ER-retained AGR/thioredoxin-like protein in ciliated airway epithelial cells that is required for normal
calcium-dependent regulation of ciliary beat frequency and mucociliary clearance. The molecular client or catalytic activity
remains unresolved, and current evidence does not justify a canonical protein disulfide isomerase activity annotation.
directly_involved_in:
- id: GO:0003351
label: epithelial cilium movement involved in extracellular fluid movement
- id: GO:0019722
label: calcium-mediated signaling
locations:
- id: GO:0005783
label: endoplasmic reticulum
supported_by:
- reference_id: PMID:25751668
supporting_text: >-
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. Decreased CBF was associated
with impaired mucociliary clearance in AGR3-deficient airways.
reference_section_type: ABSTRACT
- reference_id: file:human/AGR3/AGR3-deep-research-falcon.md
supporting_text: >-
AGR3 lacks the canonical PDI/thioredoxin CXXC or WCXXC motif; structure paper reports a DCYQS motif with solvent-exposed
Cys71 in reduced state. Because the second catalytic cysteine is absent and an adjacent acidic residue likely raises
cysteine pKa, AGR3 is inferred to have reduced/atypical thiol-disulfide exchange activity relative to classical PDIs
proposed_new_terms: []
suggested_questions:
- question: >-
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?
- question: >-
Which ER client protein or calcium-handling pathway links AGR3 to airway epithelial ciliary beat regulation?
- question: >-
Is extracellular AGR3/Src signaling a physiological epithelial function, a cancer-specific state, or a consequence of altered
ER retention/secretion?
suggested_experiments:
- description: >-
Test purified AGR3, Cys71 mutants, and canonical PDI controls against standard disulfide isomerase/reductase substrates
and candidate airway epithelial client proteins.
experiment_type: biochemical activity assay
- description: >-
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.
experiment_type: structure-function rescue
- description: >-
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.
experiment_type: client discovery
tags:
- proteostasis-network-review
- pn-projection-reviewed
- ciliary-function
- er-localized