AGR2 is a secretory-pathway, ER-retained anterior gradient/thioredoxin-fold protein expressed most prominently in mucus-producing epithelial cells. Its best-supported physiological role is as an ER foldase/protein disulfide-isomerase-family factor for gel-forming mucins, especially MUC2: AGR2 forms mixed disulfide-linked complexes with MUC2, is required for intestinal mucus production, and human AGR2 deficiency causes goblet-cell depletion, loss of gel-forming mucins, ER stress, mucus barrier failure, and infantile inflammatory bowel disease. AGR2 can also be detected extracellularly and has reported cancer-associated interactions with dystroglycan, LYPD3/C4.4a, EGFR, and cell-adhesion/inflammatory pathways, but these are best treated as context-dependent or non-core relative to its conserved ER mucin-processing function.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER localization is well supported and is central to AGR2 function: AGR2 enters the secretory pathway and is retained in the ER by its conserved KTEL motif, where it acts on mucin/secretory clients. Reason: The annotation matches the best-supported functional compartment for AGR2. ER residence is necessary for AGR2 activity, and AGR2 is directly detected in the ER of secretory epithelial cells. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:22184114 The present study determines whether AGR2 requires a specific ER localization signal to be functionally active. PMID:22184114 Deletion of the KTEL motif results in AGR2 secretion and loss of AGR2 function. file:human/AGR2/AGR2-deep-research-falcon.md AGR2 is widely characterized as a protein disulfide isomerase (PDI)-family / thioredoxin-like protein functioning in the endoplasmic reticulum (ER) |
| GO:0002162 dystroglycan binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: AGR2/dystroglycan binding was reported from yeast two-hybrid screens in a cancer context, but it is not the main conserved function of AGR2. Reason: The binding evidence is specific enough to retain the annotation, but the paper itself notes that clinical confirmation was still needed and the core function of AGR2 is ER mucin processing. 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:0048546 digestive tract morphogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Digestive tract morphogenesis is an over-broad phenotype/developmental inference for human AGR2. The mechanistic evidence supports mucin processing, mucus barrier function, and intestinal epithelial homeostasis rather than direct morphogenesis of the digestive tract. Reason: AGR2 deficiency affects goblet cells and mucus barrier integrity, but this is better captured by mucus secretion/protein folding terms and not by a broad morphogenesis term. Supporting Evidence: PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. file:human/AGR2/AGR2-deep-research-falcon.md Across reviews, these findings are summarized as AGR2 contributing to folding/maturation/secretion of MUC2 and MUC5AC/B |
| GO:0048639 positive regulation of developmental growth | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Positive regulation of developmental growth is too broad and phenotypic for AGR2. The evidence points to a secretory-epithelial ER foldase role rather than direct regulation of organismal developmental growth. Reason: Developmental/growth effects are downstream consequences or cross-species phenotype transfers; they should not be treated as the core human gene function. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. |
| GO:0070254 mucus secretion | IEA GO_REF:0000107 | ACCEPT | Summary: Mucus secretion is supported as a core biological process because AGR2 is required for production/processing of gel-forming mucins and human AGR2 deficiency causes mucus barrier dysfunction. Reason: Although AGR2 acts in the ER before secretion, the biological outcome of its core function is mucus production/secretion by mucin-producing epithelial cells. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: This is a generic high-throughput protein-binding annotation from a proteome-scale interaction map and does not identify a physiologically interpretable AGR2 function. Reason: Protein binding is uninformative for AGR2 curation, and this high-throughput interaction should not be treated as a core function. |
| GO:0005515 protein binding | IPI PMID:19359471 The protein disulfide isomerase AGR2 is essential for produc... | MODIFY | Summary: The underlying evidence is AGR2 interaction with MUC2 via mixed disulfide bonds during mucin processing, not merely generic protein binding. Reason: Replace the vague protein binding annotation with the more informative AGR2 molecular role as a PDI-family foldase for mucin processing. Proposed replacements: protein disulfide isomerase activity protein folding in endoplasmic reticulum Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: This proteome-scale interactome annotation collapses several high-throughput binary interactions into generic protein binding and does not add meaningful AGR2 functional information. Reason: The term protein binding is too general, especially for high-throughput interactome hits that are not tied to AGR2 core mucin-folding biology. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: This genetic-disorder interactome annotation is a generic protein-binding statement and does not establish a curated AGR2 function. Reason: The annotation should not be used to infer core AGR2 biology because it is a broad high-throughput interaction label without functional specificity. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: The reference map reports many binary interactome partners, but the resulting GO term protein binding is too broad to be useful for AGR2. Reason: A generic protein binding annotation for dozens of interactome partners obscures rather than clarifies AGR2 function. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: The neurodegenerative-disease interactome protein-binding annotation is context-specific and generic, with no evidence that it represents AGR2 core function. Reason: Retaining generic protein binding as a core AGR2 annotation would overemphasize a high-throughput interaction unrelated to the main ER mucin-processing function. |
| GO:0005515 protein binding | IPI PMID:34237462 Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and I... | MODIFY | Summary: The underlying evidence is impaired AGR2-MUC2 binding in human AGR2 deficiency, which is more informative as mucin processing/PDI-family foldase activity than as generic protein binding. Reason: The paper supports a specific AGR2-MUC2 functional interaction in gel-forming mucin processing; the generic protein binding term should be replaced by more informative ER protein-folding/PDI terms. Proposed replacements: protein disulfide isomerase activity protein folding in endoplasmic reticulum Supporting Evidence: PMID:34237462 AGR2-MUC2 binding was evaluated using co-immunoprecipitation. PMID:34237462 The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. |
| GO:0002162 dystroglycan binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA transfer of dystroglycan binding is consistent with experimental AGR2/DAG1 yeast two-hybrid evidence, but this cancer/extracellular interaction is not the core AGR2 function. Reason: Keep the specific binding term as non-core because direct experimental evidence exists, while core AGR2 biology is ER mucin processing. 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:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: AGR2 can be detected extracellularly/secreted, especially in cancer biomarker studies and when ER retention is perturbed, but extracellular localization is not its primary functional site. Reason: Retain as a non-core localization: extracellular AGR2 is real in some contexts, while its conserved core function requires ER residence. Supporting Evidence: PMID:24251762 Anterior gradient 2 (AGR2) is a secreted, cancer-associated protein in many types of epithelial cancer cells. PMID:24251762 we aimed to develop a reliable and highly sensitive PRISM-SRM assay for quantification of AGR2 at low pg/mL levels in both urine and serum samples in this study. PMID:31040128 modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: Automated ER localization is consistent with experimental and orthology evidence and with the conserved KTEL retention motif. Reason: ER is the principal compartment for AGR2 mucin-processing activity. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:22184114 The present study determines whether AGR2 requires a specific ER localization signal to be functionally active. PMID:22184114 Deletion of the KTEL motif results in AGR2 secretion and loss of AGR2 function. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based ER annotation is consistent with direct literature showing AGR2 in the ER of intestinal secretory epithelial cells. Reason: This is a core localization for AGR2 function. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence/orthology transfer of ER localization is consistent with human and mouse evidence and with the conserved ER-retention motif. Reason: The ER location is conserved and functionally required for AGR2. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:22184114 The present study determines whether AGR2 requires a specific ER localization signal to be functionally active. PMID:22184114 Deletion of the KTEL motif results in AGR2 secretion and loss of AGR2 function. |
| GO:0005515 protein binding | IPI PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | MARK AS OVER ANNOTATED | Summary: PMID:31040128 identifies regulators of AGR2 dimerization and extracellular release, but generic protein binding is less informative than the specific homodimerization/proteostasis biology. Reason: Protein binding is too broad for this evidence; the useful curation is AGR2 homodimerization and ER proteostasis/inflammatory context. Supporting Evidence: PMID:31040128 Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). PMID:31040128 AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. |
| GO:0005576 extracellular region | IDA PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | KEEP AS NON CORE | Summary: AGR2 extracellular release is demonstrated in the dimerization/proteostasis study and is linked to pro-inflammatory monocyte chemoattraction. Reason: Extracellular AGR2 is a context-dependent inflammatory/cancer-related state rather than the main ER foldase location, so retain it as non-core. Supporting Evidence: PMID:31040128 modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes PMID:31040128 the extracellular release of AGR2 leads to the chemoattraction of monocytes, thereby suggesting extracellular AGR2's pro-inflammatory functions |
| GO:0005783 endoplasmic reticulum | IDA PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | ACCEPT | Summary: AGR2 is active in the ER in this study, where dimerization status reports ER homeostasis and affects proteostasis. Reason: This reinforces ER as the core active site of AGR2. Supporting Evidence: PMID:31040128 Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). PMID:31040128 AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. |
| GO:0006954 inflammatory response | IMP PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | KEEP AS NON CORE | Summary: AGR2 dimerization/secreted monomer state can drive pro-inflammatory phenotypes and is linked to intestinal inflammation, but this is a downstream/pathological outcome of perturbed ER proteostasis. Reason: Inflammatory response is supported but should be non-core relative to AGR2's primary ER mucin-folding role. Supporting Evidence: PMID:31040128 modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes PMID:31040128 the extracellular release of AGR2 leads to the chemoattraction of monocytes, thereby suggesting extracellular AGR2's pro-inflammatory functions PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IDA PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | KEEP AS NON CORE | Summary: AGR2 dimerization is connected to ER homeostasis/UPR-associated stress biology, and newer IRE1beta studies support a narrow negative IRE1-mediated annotation in mucin-producing cells, but the broad ER UPR term remains non-core. Reason: Retain the UPR-related annotation as non-core because it describes regulatory/stress biology around AGR2 rather than AGR2's main molecular activity. The supported PN projection is the narrower PDI-family foldase activity, not broad propagation to generic ER UPR participation. Supporting Evidence: PMID:31040128 Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). PMID:31040128 AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. PMID:34237462 The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. |
| GO:0034975 protein folding in endoplasmic reticulum | IDA PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | ACCEPT | Summary: AGR2 participates in protein folding in the ER, especially processing/folding of gel-forming mucins such as MUC2. This is curated despite the competing PMID:25666625 interpretation that EGFR, rather than MUC2, was the major AGR2 mixed-disulfide substrate in the tested cancer-cell models. Reason: This is a core biological process for AGR2. PMID:25666625 reported no MUC2 in its AGR2 mixed-disulfide mass-spectrometry analysis and cited a re-evaluation against MUC2 folding, but earlier AGR2-MUC2 mixed-disulfide trapping and later human AGR2 H117Y data showing reduced MUC2 binding and ER-stress relief support retaining the ER protein-folding annotation. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. PMID:34237462 The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. PMID:25666625 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. |
| GO:0034975 protein folding in endoplasmic reticulum | IMP PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | ACCEPT | Summary: Mutant/perturbation evidence supports AGR2 as required for ER protein-folding/proteostasis, especially mucin processing. This conclusion accounts for PMID:25666625, which favored EGFR as the major AGR2 substrate and disputed MUC2 as an AGR2 folding client in its model system. Reason: Loss-of-function and perturbation data support protein folding in the ER as part of AGR2 core function. The MUC2 substrate question is not unanimous in the literature, but PMID:19359471 and the later human AGR2 H117Y evidence in PMID:34237462 provide direct support for AGR2-MUC2 binding and mucin-processing relevance. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. PMID:34237462 The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. PMID:25666625 None of the proteins previously reported to bind AGR2 such as LYPD3 (C4.4a), DAG1, or MUC2 ( 33 , 46 ) were detected in the mass spectrometry analysis of AGR2 mixed disulfides. |
| GO:0042803 protein homodimerization activity | IPI PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | ACCEPT | Summary: AGR2 homodimerization is a well-supported molecular property that controls ER homeostasis and extracellular release. Reason: Homodimerization is a key mechanistic feature of AGR2 function and is directly supported by dimerization assays and structural/biochemical studies. Supporting Evidence: PMID:31040128 Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). PMID:31040128 AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. |
| GO:0060326 cell chemotaxis | IDA PMID:31040128 Control of anterior GRadient 2 (AGR2) dimerization links end... | KEEP AS NON CORE | Summary: Extracellular AGR2 can chemoattract monocytes in the inflammation study, but this is a context-dependent extracellular alarm/inflammatory activity. Reason: Retain as non-core because chemotaxis is a downstream response to secreted AGR2 under perturbed ER/pro-inflammatory conditions, not AGR2's primary conserved function. Supporting Evidence: PMID:31040128 modulation of AGR2 dimer formation, whether enhancing or inhibiting the process, yields pro-inflammatory phenotypes PMID:31040128 the extracellular release of AGR2 leads to the chemoattraction of monocytes, thereby suggesting extracellular AGR2's pro-inflammatory functions |
| GO:0005576 extracellular region | IDA PMID:15834940 AGR2, an androgen-inducible secretory protein overexpressed ... | KEEP AS NON CORE | Summary: AGR2 is described and measured as a secretory/secreted protein in prostate cancer contexts, but this is not the main functional site for mucin processing. Reason: Extracellular/secreted AGR2 is supported but should be non-core relative to ER-localized foldase activity. Supporting Evidence: PMID:15834940 the androgen-induced secretory protein AGR2 may serve as a potential therapeutic target and/or molecular marker for prostate cancer. |
| GO:0042802 identical protein binding | IPI PMID:23220234 Dimerization of pro-oncogenic protein Anterior Gradient 2 is... | MODIFY | Summary: The BiP/GRP78 paper reports AGR2 homo-dimerization, so identical protein binding should be curated more specifically as protein homodimerization activity. Reason: GO:0042803 captures the observed AGR2 self-association more precisely than identical protein binding. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:23220234 Herein we show that AGR2 homo-dimerizes through an intermolecular disulfide bond. Moreover, dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78. |
| GO:0042802 identical protein binding | IPI PMID:23274113 Metastasis-promoting anterior gradient 2 protein has a dimer... | MODIFY | Summary: The NMR/structure paper reports AGR2 monomer-dimer equilibrium and a dimeric thioredoxin fold, so protein homodimerization activity is the better term. Reason: Identical protein binding is less specific than the demonstrated homodimerization activity. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:23274113 The protein exists in monomer-dimer equilibrium with a K(d) of 8.83ΞΌM |
| GO:0005515 protein binding | IPI PMID:23220234 Dimerization of pro-oncogenic protein Anterior Gradient 2 is... | MODIFY | Summary: The interaction with BiP/GRP78 is a specific chaperone interaction; generic protein binding is too broad. Reason: Replace with protein-folding chaperone binding to capture the BiP/GRP78 association more specifically. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:23220234 Herein we show that AGR2 homo-dimerizes through an intermolecular disulfide bond. Moreover, dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78. |
| GO:0005576 extracellular region | IDA PMID:22184114 AGR2 gene function requires a unique endoplasmic reticulum l... | KEEP AS NON CORE | Summary: This paper mainly shows that perturbing the KTEL ER-retention motif can cause AGR2 secretion, so by itself it is weak evidence for wild-type extracellular localization; however extracellular AGR2 is supported by other studies and should be retained only as non-core. Reason: Use a consistent non-core extracellular-region action for AGR2: extracellular AGR2 is real in biomarker/inflammatory contexts, but this specific KTEL paper should not be read as evidence that extracellular localization is the normal core site of AGR2 action. Supporting Evidence: PMID:22184114 The present study determines whether AGR2 requires a specific ER localization signal to be functionally active. PMID:22184114 Deletion of the KTEL motif results in AGR2 secretion and loss of AGR2 function. |
| GO:0005783 endoplasmic reticulum | IMP PMID:22184114 AGR2 gene function requires a unique endoplasmic reticulum l... | ACCEPT | Summary: The KTEL paper strongly supports ER localization/residence as required for AGR2 function. Reason: ER residence is a core functional requirement for AGR2. Supporting Evidence: PMID:22184114 The present study determines whether AGR2 requires a specific ER localization signal to be functionally active. PMID:22184114 Deletion of the KTEL motif results in AGR2 secretion and loss of AGR2 function. |
| GO:0010628 positive regulation of gene expression | IMP PMID:22184114 AGR2 gene function requires a unique endoplasmic reticulum l... | MARK AS OVER ANNOTATED | Summary: AGR2-dependent induction of AREG/CDX2 in cell models is an indirect downstream transcriptional readout and should not be treated as a core gene-expression regulatory function. Reason: AGR2 is not a transcriptional regulator; this broad BP term overstates an indirect effect of ER-localized AGR2 activity in adenocarcinoma/IEC cell models. Supporting Evidence: PMID:22184114 Using two different cell lines in which AGR2 induces expression of either the EGFR ligand amphiregulin or the transcription factor CDX2, only the highly conserved wild-type carboxyl-terminal KTEL motif results in the appropriate outcome. PMID:22184114 The present study demonstrates that AGR2 residence within the ER is required for its function as reflected by AREG expression in OE33 adenocarcinoma cells or CDX2 expression by IEC-6 intestinal cells. |
| GO:1903896 positive regulation of IRE1-mediated unfolded protein response | IDA PMID:23220234 Dimerization of pro-oncogenic protein Anterior Gradient 2 is... | MARK AS OVER ANNOTATED | Summary: The PMID:23220234 abstract describes AGR2 dimers as attenuating ER stress-induced cell death via BiP/GRP78 association, with no arm-specific IRE1 evidence. Citing literature with full-text access (Sicari et al. 2019, PMID:31040128; Alsereihi et al. 2019, PMID:31247903) places canonical AGR2 downstream of UPR sensors (IRE1Ξ±/ATF6Ξ± regulate AGR2 expression, AGR2 dimers dissociate upon ER stress) rather than as a positive regulator of the IRE1 arm. The IRE1 mention in PMID:31040128 is the ERMIT mammalian two-hybrid bait scaffold, not a biological regulatory target. Reason: No literature supports canonical AGR2 (UniProt O95994) as a positive regulator of the IRE1-mediated UPR arm. The directionality established by citing literature is the inverse: IRE1Ξ±/ATF6Ξ± regulate AGR2 expression. Retain in record as historical IDA but flag as over-annotation. Supporting Evidence: PMID:23220234 Herein we show that AGR2 homo-dimerizes through an intermolecular disulfide bond. Moreover, dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78. PMID:31247903 This was demonstrated when IREΞ± and ATF6Ξ± were knocked down using small interfering RNA (siRNA) in HeLa cells, resulting in the decreased expression levels of the AGR2 protein PMID:31040128 the luminal domain of IRE1 was replaced by different bait proteins PMID:31040128 dissociation of AGR2 homodimers as assessed by the decrease in luminescence observed for all the constructs tested |
| GO:1903899 positive regulation of PERK-mediated unfolded protein response | IDA PMID:23220234 Dimerization of pro-oncogenic protein Anterior Gradient 2 is... | MARK AS OVER ANNOTATED | Summary: The PMID:23220234 abstract describes AGR2 dimers as attenuating ER stress-induced cell death via BiP/GRP78 association, with no PERK-specific evidence. Citing-literature reviews (Alsereihi et al. 2019, PMID:31247903) summarize the mechanistic AGR2/UPR landscape without mentioning AGR2 as a regulator of the PERK arm β the only reported AGR2/UPR-sensor relationships involve IRE1Ξ± and ATF6Ξ± regulating AGR2 expression, not vice versa, and PMID:31040128 places canonical AGR2 dimers downstream of ER stress (dissociation upon stress). Reason: PERK-mediated UPR is conspicuously absent from the AGR2 mechanistic literature for canonical AGR2 (UniProt O95994). The PMID:23220234 abstract's BiP/GRP78 attenuation finding is downstream of UPR sensing rather than driving the PERK arm. Retain in record as historical IDA but flag as over-annotation. Supporting Evidence: PMID:23220234 Herein we show that AGR2 homo-dimerizes through an intermolecular disulfide bond. Moreover, dimerization of AGR2 attenuates ER stress-induced cell death through the association with BiP/GRP78. PMID:31247903 The top molecules implicated in regulating the expression of AGR2 included IRE1Ξ±, ATF6Ξ±, AKT, FOXA1/2, HIF-1, TMED2, and the frequently mutated tumor suppressor p53. PMID:31040128 dissociation of AGR2 homodimers as assessed by the decrease in luminescence observed for all the constructs tested |
| GO:0005576 extracellular region | IDA PMID:24251762 A highly sensitive targeted mass spectrometric assay for qua... | KEEP AS NON CORE | Summary: Targeted mass spectrometry detected AGR2 in human urine and serum, supporting extracellular/body-fluid localization. Reason: Extracellular AGR2 is a supported non-core localization, especially in biomarker/cancer contexts. Supporting Evidence: PMID:24251762 Anterior gradient 2 (AGR2) is a secreted, cancer-associated protein in many types of epithelial cancer cells. PMID:24251762 we aimed to develop a reliable and highly sensitive PRISM-SRM assay for quantification of AGR2 at low pg/mL levels in both urine and serum samples in this study. |
| GO:0005154 epidermal growth factor receptor binding | IPI PMID:25666625 Epidermal growth factor receptor (EGFR) signaling requires a... | KEEP AS NON CORE | Summary: AGR2 binds EGFR in the ER and is required for receptor delivery to the plasma membrane in cancer-cell models. Reason: The term is supported, but EGFR appears to be a context-specific client/pathway rather than the main conserved AGR2 function. Supporting Evidence: PMID:25666625 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. PMID:25666625 Reduced AGR2 protein levels or mutation of an essential cysteine in the active site result in decreased cell surface EGFR and a concomitant decrease in signaling as reflected by AREG , EGR1 , and FOS expression. |
| GO:0010811 positive regulation of cell-substrate adhesion | IMP PMID:23274113 Metastasis-promoting anterior gradient 2 protein has a dimer... | KEEP AS NON CORE | Summary: AGR2 can promote cell-substrate adhesion in cancer/metastasis assays, but this extracellular N-terminal activity is context-dependent. Reason: Cell adhesion is supported but is not the core ER mucin-processing function. Supporting Evidence: PMID:23274113 The unstructured region is primarily responsible for the ability of AGR2 to promote cell adhesion, while dimerization is less important for this activity. |
| GO:0034976 response to endoplasmic reticulum stress | IMP NOT PMID:25666625 Epidermal growth factor receptor (EGFR) signaling requires a... | REMOVE | Summary: The NOT annotation conflicts with later evidence that AGR2 contributes to ER stress/proteostasis regulation and that AGR2 H117Y is impaired in alleviating tunicamycin-induced ER stress. Reason: A gene-level NOT annotation to response to ER stress is no longer defensible; if PMID:25666625 only showed lack of induction in one context, that should not negate AGR2's ER stress/homeostasis role. Supporting Evidence: PMID:31040128 Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). PMID:31040128 AGR2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR2 monomers. PMID:34237462 The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. PMID:34237462 AGR2 H117Y has a reduced capacity to regulate ER stress even in the absence of gel-forming mucins in vitro. |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IMP PMID:25666625 Epidermal growth factor receptor (EGFR) signaling requires a... | KEEP AS NON CORE | Summary: AGR2 supports EGFR signaling by enabling EGFR delivery to the cell surface in tested cancer-cell models. Reason: This is supported as a client-specific, context-dependent process, but it is not the conserved core AGR2 function. Supporting Evidence: PMID:25666625 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. PMID:25666625 Reduced AGR2 protein levels or mutation of an essential cysteine in the active site result in decreased cell surface EGFR and a concomitant decrease in signaling as reflected by AREG , EGR1 , and FOS expression. |
| GO:0048546 digestive tract morphogenesis | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Digestive tract morphogenesis remains an over-broad orthology transfer relative to the known AGR2 mechanism. Reason: Human and mouse evidence supports mucin processing/mucus barrier maintenance, not direct digestive tract morphogenesis. Supporting Evidence: PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. |
| GO:0048639 positive regulation of developmental growth | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Positive regulation of developmental growth is too broad and likely reflects indirect developmental/phenotypic transfer from orthologs. Reason: The direct AGR2 mechanism is ER mucin/client processing; growth/developmental phenotypes should not be elevated to core gene function. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. |
| GO:1903078 positive regulation of protein localization to plasma membrane | IMP PMID:25666625 Epidermal growth factor receptor (EGFR) signaling requires a... | KEEP AS NON CORE | Summary: AGR2 promotes EGFR localization to the plasma membrane by binding EGFR in the ER, but the GO term is broad and substrate-specific. Reason: The annotation is supported for EGFR in tested cell models but should be non-core because it is a client-specific cancer/developmental signaling effect. Supporting Evidence: PMID:25666625 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. PMID:25666625 Reduced AGR2 protein levels or mutation of an essential cysteine in the active site result in decreased cell surface EGFR and a concomitant decrease in signaling as reflected by AREG , EGR1 , and FOS expression. |
| 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; use the available specific dystroglycan binding term for the DAG1 interaction, while noting the LYPD3/C4.4a interaction lacks a specific GO binding term. 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 AGR2 binding to alpha-dystroglycan, but this is a cancer/extracellular interaction and not AGR2's core ER foldase function. Reason: Retain the specific molecular interaction as non-core. 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:0070254 mucus secretion | ISS GO_REF:0000024 | ACCEPT | Summary: Mucus secretion transferred from mouse orthology is supported by human AGR2 deficiency and mouse Agr2 loss-of-function evidence. Reason: Mucus production/secretion is a principal biological outcome of AGR2's core role in mucin processing. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:34237462 Patient biopsy specimens showed reduced goblet cells; depletion of MUC2, MUC5AC, and MUC6; up-regulation of AGR2; and increased ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. |
| GO:0003756 protein disulfide isomerase activity | IC PMID:19359471 The protein disulfide isomerase AGR2 is essential for produc... | NEW | Summary: AGR2 should have a new molecular-function annotation for PDI-family foldase activity, matching the AGR2-specific PN projection from the ER protein disulfide isomerase bucket. The IC rationale is based on direct AGR2-MUC2 mixed-disulfide evidence, ER protein-folding/proteostasis annotations, and human AGR2 H117Y data rather than sequence similarity alone; PMID:25666625 is a competing EGFR-focused interpretation that did not detect MUC2 in its AGR2 mixed-disulfide analysis. Reason: GOA currently lacks an informative AGR2 catalytic/foldase molecular-function term. GO:0003756 is the best available GO molecular-function term for the literature-described AGR2 PDI-family activity and is the only PN-projected AGR2 term accepted here. Although PMID:25666625 argues for EGFR as the principal substrate and disputes MUC2 folding in its system, PMID:19359471 directly trapped AGR2-MUC2 mixed disulfides and PMID:34237462 later showed reduced MUC2 binding and ER-stress relief by AGR2 H117Y, supporting a specialized mucin-biased PDI-family annotation. Supporting Evidence: PMID:19359471 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 PMID:19359471 A cysteine residue within the AGR2 thioredoxin-like domain forms mixed disulfide bonds with MUC2, indicating a direct role for AGR2 in mucin processing. PMID:34237462 The mutant AGR2 showed reduced capacity to bind MUC2 and alleviate tunicamycin-induced ER stress. PMID:34237462 The Mendelian deficiency of AGR2, termed "Enteropathy caused by AGR2 deficiency, Goblet cell Loss, and ER Stress" (EAGLES), results in a mucus barrier defect, the inability to mitigate ER stress, and causes infantile-onset inflammatory bowel disease. PMID:31040128 Anterior gradient 2 (AGR2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum (ER). PMID:25666625 The absence of another dominant AGR2 mixed disulfide ( Figs. 1 , A , C , and D , and 5 D ) suggests that EGFR is a major substrate for AGR2. file:human/AGR2/AGR2-deep-research-falcon.md AGR2βs best-supported substrates/clients are cysteine-rich secreted mucins |
| GO:0005788 endoplasmic reticulum lumen | IC PMID:19359471 The protein disulfide isomerase AGR2 is essential for produc... | NEW | Summary: AGR2 is a soluble secretory-pathway protein with an N-terminal signal peptide and C-terminal KTEL ER-retention motif; the literature places its mucin-processing function within the ER lumen rather than merely the broad ER compartment. Reason: The existing GOA annotations use the broader endoplasmic reticulum term. ER lumen is the more precise cellular-component annotation for an ER-retained soluble foldase acting on luminal mucin clients. Supporting Evidence: PMID:19359471 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 PMID:19359471 PDI thioredoxin-like domains contain cysteine residues that can form mixed disulfide bonds with client proteins during processing in the ER. PMID:22184114 Soluble proteins are targeted to the endoplasmic reticulum (ER) 2 by two major mechanisms. The first is signal peptide-directed translocation of newly translated proteins into the ER. |
| GO:1903895 negative regulation of IRE1-mediated unfolded protein response | IC PMID:38177501 Activation of goblet-cell stress sensor IRE1Ξ² is controlled ... | NEW | Summary: Recent EMBO Journal studies show that AGR2 directly binds the goblet-cell stress sensor IRE1Ξ²/ERN2 and represses IRE1Ξ² dimerization and endonuclease outputs. This annotation should be interpreted for IRE1Ξ²-expressing mucin-producing/goblet-cell contexts, not as evidence for AGR2 repression of ubiquitous IRE1Ξ±. It is more precise than the existing historical positive IRE1-mediated UPR annotation, which remains marked as over-annotated. Reason: AGR2 has direct evidence for negative, not positive, regulation of IRE1Ξ²-mediated unfolded protein response signaling in mucin-producing cells. GO:1903895 captures this directionality while keeping the main core-function model centered on ER mucin folding/proteostasis; it should not be generalized to positive IRE1/PERK or broad UPR propagation. Supporting Evidence: PMID:38177501 AGR2 binding to IRE1Ξ² disrupts IRE1Ξ² oligomerization, thereby blocking its downstream endonuclease activity. PMID:38177501 Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1Ξ² activation, suggesting that alterations in AGR2 availability in the endoplasmic reticulum set the threshold for IRE1Ξ² activation. PMID:38177498 The mucin-specific chaperone AGR2 repressed IRE1 activity in cells expressing the domain-swapped IRE1Ξ²/Ξ± chimera, but had no effect on IRE1Ξ±. file:human/AGR2/AGR2-deep-research-falcon.md AGR2 binds IRE1Ξ² (selectively vs IRE1Ξ±) and inhibits IRE1Ξ² oligomerization/dimerization |
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Download this section (compressed HTML)Q: Is AGR2 best annotated as a bona fide protein disulfide isomerase enzyme for MUC2, or should GO eventually represent a more specific mucin-client foldase/thiol-retention activity?
Suggested experts: Park SW, Erle DJ, Lo B, Uhlig HH
Q: Which extracellular AGR2 activities, if any, are normal physiological functions rather than cancer- or inflammation-associated consequences of altered ER retention/dimerization?
Suggested experts: Chevet E, Ogier-Denis E, Lowe AW
Experiment: Reconstitute purified AGR2 with recombinant MUC2 cysteine-rich domains or MUC2 folding intermediates and compare wild-type AGR2 with Cys81/His117/dimerization mutants in disulfide-shuffling, mixed-disulfide trapping, and client-folding assays.
Hypothesis: AGR2 directly catalyzes or stabilizes disulfide-dependent folding intermediates in gel-forming mucins.
Type: in vitro biochemical foldase assay
Experiment: Compare secretion state, oligomeric state, and monocyte/goblet-cell responses to endogenous AGR2 under normal mucin secretion, tunicamycin/ER stress, TMED2 perturbation, and AGR2 KTEL/dimerization mutant conditions in intestinal epithelial organoids.
Hypothesis: Extracellular AGR2 monomer functions mainly as a damage/inflammation signal when ER proteostasis is perturbed.
Type: intestinal organoid perturbation and chemotaxis assay
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