Affinage

AGR2

Anterior gradient protein 2 homolog · UniProt O95994

Length
175 aa
Mass
20.0 kDa
Annotated
2026-06-09
100 papers in source corpus 36 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AGR2 is an endoplasmic reticulum-resident protein disulfide isomerase that enables the folding and secretion of gel-forming mucins and other secretory clients, and whose function is essential for goblet cell biology and intestinal mucus production (PMID:19359471, PMID:20025862). It engages mucins both covalently and non-covalently: it forms mixed disulfide bonds with MUC2 through a cysteine in its thioredoxin-like domain in intestinal epithelium (PMID:19359471), complexes with immature airway mucins MUC5AC/MUC5B (PMID:22403803), and acts as a chaperone for the cancer mucin MUC1 (PMID:22945649, PMID:32304027). Client recognition is sequence-specific—AGR2 binds a TTIYY-type peptide motif through a structural loop (residues 131-135), the basis for its stable interaction with EpCAM (PMID:29339412). AGR2 expression is induced by ER stress and its loss elevates the unfolded protein response and disrupts ER-associated degradation (PMID:20025862, PMID:22025610); mechanistically, AGR2 directly represses the goblet-cell UPR transducer IRE1β by destabilizing its luminal-domain dimer in a manner reversed by the client mucin MUC2, an activity requiring its catalytic cysteine (PMID:38177498, PMID:38177501). Retention in the ER depends on a specific KTEL motif, and loss of this motif or modification of its single cysteine (C81S) shifts AGR2 to a secreted, extracellular form (eAGR2) with distinct, often opposing functions (PMID:22184114, PMID:25111734, PMID:27240165, PMID:30575818). Intracellular AGR2 signals through KDEL receptors to activate Gs-PKA and drive transcription of EMT regulators SNAIL/SLUG (PMID:34216690) and promotes EGFR trafficking and YAP1-dependent proliferation and tissue regeneration (PMID:21454516, PMID:27764193); it also directs nuclear import of RNA Polymerase II via a C-terminal NLS to suppress p53/DNA-damage responses during pancreatic tumor initiation (PMID:34303658). Secreted AGR2 acts through cell-surface receptors C4.4A and CD98hc to activate non-canonical Wnt, RhoA/ROCK2 and other pro-invasive cascades and modulates the extracellular matrix to promote invasion and metastasis (PMID:25646014, PMID:35086885, PMID:29427622, PMID:27240165). AGR2 dimerization, enhanced by TMED2 and mediated by lysine adducts, governs ER homeostasis versus inflammatory secretion (PMID:31040128, PMID:23780840), and the protein is regulated post-translationally by S-glutathionylation that blocks MUC2 maturation (PMID:36565645) and by UBR5-mediated K48 ubiquitination at K89 with autophagic clearance via NBR1 (PMID:30647455). A homozygous AGR2 missense variant that impairs MUC2 binding and ER-stress relief causes an infantile inflammatory bowel disease (EAGLES) in humans, phenocopying the AGR2-null mouse (PMID:34237462).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2003 Low

    The first candidate AGR2 interactors were identified, raising the possibility that this protein engages cell-surface and metastasis-associated partners.

    Evidence Yeast two-hybrid screen identifying C4.4A and alpha-dystroglycan

    PMID:12592373

    Open questions at the time
    • Y2H only, no Co-IP or pulldown validation in mammalian cells
    • Functional significance of binding not established
    • Did not distinguish intracellular vs extracellular interaction
  2. 2008 Medium

    Established that AGR2 has oncogenic activity rather than being merely a marker, by showing it drives transformation and tumor growth.

    Evidence RNAi and stable overexpression in cell lines with xenograft and anchorage-independent growth assays

    PMID:18199544

    Open questions at the time
    • Molecular mechanism of transformation not defined
    • Did not address ER-resident vs secreted contributions
  3. 2009 High

    Defined AGR2's core physiological function as an ER-resident enzyme that covalently processes mucins and is essential for mucus production, answering what AGR2 does in normal epithelium.

    Evidence ER fractionation, mixed disulfide detection with MUC2, and AGR2-null mouse phenotype; siRNA and inducible/germline knockouts linking AGR2 to ER stress and Paneth cells

    PMID:19359471 PMID:20025862

    Open questions at the time
    • Precise cysteine residue and disulfide partner geometry on MUC2 not fully mapped
    • Range of mucin clients beyond MUC2 not yet defined
  4. 2011 Medium

    Connected AGR2's ER chaperone role to broader ER proteostasis and to oncogenic signaling outputs, and showed the KTEL retention motif itself is required for intracellular function.

    Evidence Proteomics of ER membrane-bound ribosomes and ERAD components; AREG/YAP1 and CTSB/CTSD downstream effects; KTEL deletion/substitution mutants with functional reporters

    PMID:21454516 PMID:21948970 PMID:22025610 PMID:22184114

    Open questions at the time
    • How the specific KTEL sequence (vs KDEL/KSEL) confers function was not mechanistically resolved at this stage
    • Direct vs indirect engagement of nascent chains unclear
  5. 2012 Medium

    Generalized the mucin-chaperone role across tissues and species and to cancer-associated mucins, showing conservation of AGR2's secretory function.

    Evidence Co-IP with immature MUC5AC and airway Agr2-/- model; MUC1 gain/loss in pancreatic cancer with SMAD4-dependent regulation; zebrafish morpholino goblet-cell differentiation

    PMID:22403803 PMID:22514630 PMID:22945649

    Open questions at the time
    • Zebrafish data showed UPR induction is not universally coupled to AGR2 loss, indicating species/context differences
    • Direct vs indirect MUC1 chaperoning not fully separated
  6. 2014 Medium

    Identified a biochemical switch—single-cysteine modification (C81S)—that permits AGR2 secretion past the KTEL signal, establishing how AGR2 escapes the ER.

    Evidence Mucus fractionation and CHO-K1 secretion assays with C81S mutant; negative covalent MUC2-terminus binding result

    PMID:25111734

    Open questions at the time
    • Physiological trigger for C81 modification in vivo not identified
    • Apparent conflict with covalent MUC2 binding data not reconciled
  7. 2015 Medium

    Defined a receptor-based mechanism for extracellular AGR2, showing it signals through C4.4A to promote malignant phenotypes, and described an intracellular pro-survival pathway suppressing p53.

    Evidence Reciprocal Co-IP with recombinant proteins, C4.4A knockdown and blocking antibodies, orthotopic xenografts; DUSP10/p38/p53 pathway dissection

    PMID:25646014 PMID:26733232

    Open questions at the time
    • Co-receptor requirements (laminin/integrin) not fully mechanistically dissected
    • Generality of C4.4A axis across cancer types untested
  8. 2016 Medium

    Demonstrated that secreted AGR2 is sufficient on its own, independent of its catalytic and retention domains, to confer invasive/metastatic features and to remodel the microenvironment.

    Evidence Domain-deletion mutants, ECM interaction and 3D morphogenesis assays, invasion/metastasis assays; FOXM1 ChIP and reporter with transgenic models defining transcriptional control

    PMID:27240165 PMID:29267283

    Open questions at the time
    • Extracellular receptor(s) for catalytic-independent eAGR2 activity in this system not specified
    • ECM-binding partners unresolved
  9. 2017 Medium

    Placed AGR2 within EMT control and tissue regeneration, showing context-dependent (intracellular) roles in EGFR trafficking and epithelial identity.

    Evidence Caerulein pancreatitis in Agr2-/- mice with EGFR localization and inhibitor studies; TGF-β/Smad/ERK regulation of AGR2 with CRISPR/siRNA EMT readouts

    PMID:27764193 PMID:28810836

    Open questions at the time
    • Direct mechanism of AGR2-driven EGFR trafficking not defined
    • Whether EMT effects are intracellular vs secreted AGR2 not cleanly separated
  10. 2018 Medium

    Mapped multiple receptor and signaling outputs for secreted and cytosolic AGR2, distinguishing localization-dependent, often opposing, functions.

    Evidence Wnt11/CaMKII/JNK dissection; recombinant VEGFA disulfide binding and p65/NF-κB Co-IP; mTORC2/RICTOR phosphorylation with localization mutants and metastasis models

    PMID:29410027 PMID:29427622 PMID:30575818

    Open questions at the time
    • Opposing iAGR2 vs eAGR2 effects on Hippo/mTORC2 mechanistically incompletely resolved
    • Single-lab pathway assignments not cross-validated
  11. 2018 High

    Defined the structural basis of AGR2 client recognition, establishing it as a sequence-specific peptide-binding chaperone.

    Evidence HDX-MS structural mapping, peptide affinity purification, mutant peptide library, PLA and in vitro binding with EpCAM Tyr251 mutant

    PMID:29339412

    Open questions at the time
    • Full client repertoire bearing the TTIYY motif not enumerated
    • Co-existence of covalent disulfide and non-covalent peptide recognition not unified structurally
  12. 2019 Medium

    Established that AGR2 dimerization state is a regulatory switch between ER homeostasis and inflammatory secretion, and defined its post-translational degradation route.

    Evidence TMED2 interaction screen and dimerization assays with IBD tissue; DSS-crosslinking, K95 adduct and Reptin binding mutants; UBR5/K89 ubiquitination, NBR1-autophagy and proteasome-inhibitor studies; RAD9A transcriptional control

    PMID:23780840 PMID:30295739 PMID:30647455 PMID:31040128

    Open questions at the time
    • How dimerization is sensed and reversed in vivo unclear
    • Relationship between K89 ubiquitination, K95 dimer adducts, and secretion not integrated
  13. 2021 High

    Revealed unexpected nuclear and KDELR-coupled signaling functions, showing AGR2 controls RNAPII import and PKA-driven EMT transcription, and confirmed human disease causation.

    Evidence AGR2-RNAPII Co-IP, nuclear import assays, pancreas-specific KO and competitive hexapeptide; AGR2-KDELR Co-IP with PKA/NF-κB/H3K9ac readouts; whole-genome sequencing of EAGLES patients with functional MUC2-binding and ER-stress validation

    PMID:34216690 PMID:34237462 PMID:34303658

    Open questions at the time
    • How the same KTEL motif serves both KDELR signaling and ER retention not fully reconciled
    • Structural basis of RNAPII NLS-mediated import undefined
  14. 2022 Medium

    Extended AGR2 biology to the tumor microenvironment and defined CD98hc as an extracellular receptor, plus a redox post-translational control of mucin maturation.

    Evidence Neutrophil-specific Agr2 KO, AGR2-CD98hc Co-IP, xCT/RhoA/ROCK2 assays; AGR2 S-glutathionylation and G6PD/NADPH axis in burn-sepsis model; AGR2/ERp44 as DDA targets controlling DR5 oligomerization; AGR2-MUC1-HIF1α axis

    PMID:32304027 PMID:35086885 PMID:35247515 PMID:36565645

    Open questions at the time
    • Cross-talk between AGR2's pro-survival disulfide functions and apoptosis (DR5) needs integration
    • In vivo relevance of S-glutathionylation beyond burn-sepsis model untested
  15. 2023 High

    Resolved a direct mechanism by which AGR2 governs the goblet-cell UPR, showing it actively represses IRE1β and links client load to UPR signaling.

    Evidence IRE1β/α chimeras in CHO cells, in vitro reconstitution of AGR2-IRE1β luminal-domain destabilization, catalytic-cysteine and H117Y mutants, MUC2 rescue; independent replication across two papers

    PMID:38177498 PMID:38177501

    Open questions at the time
    • Structural detail of AGR2 destabilizing the IRE1β dimer not fully resolved
    • How disease mutations alter this specific repression in vivo not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AGR2's multiple, sometimes opposing, intracellular (ER chaperone, IRE1β repressor, KDELR signaler, RNAPII importer) and extracellular (C4.4A/CD98hc receptor agonist) activities are coordinated by localization, dimerization, and redox state within a single cell remains unresolved.
  • No unified model linking modification state (C81/C95/K89, glutathionylation) to functional partitioning
  • Structural basis for nuclear import and KDELR signaling undefined
  • Receptor specificity determinants for eAGR2 not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0044183 protein folding chaperone 4 GO:0060089 molecular transducer activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0016853 isomerase activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4 GO:0005783 endoplasmic reticulum 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1643685 Disease 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
C4.4ACD98HCEPCAMIRE1BMUC1MUC2MUC5ACTMED2

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 AGR2 localizes to the ER lumen of intestinal secretory epithelial cells and forms mixed disulfide bonds with MUC2 via a cysteine residue within its thioredoxin-like domain, directly participating in mucin processing. AGR2-null mice fail to produce intestinal mucus and develop colitis. Immunolocalization (ER fractionation), mixed disulfide bond detection, AGR2 knockout mouse phenotype Proceedings of the National Academy of Sciences of the United States of America High 19359471
2009 AGR2 expression is induced by ER stress, and siRNA knockdown of AGR2 increases ER stress response in intestinal cells. AGR2-null mice show elevated ER stress, reduced MUC2, expansion of the Paneth cell compartment, and abnormal Paneth cell localization. siRNA knockdown, germline and inducible Agr2-/- mice, ER stress marker analysis Developmental biology High 20025862
2008 AGR2 expression promotes cellular transformation, anchorage-independent growth, and tumor xenograft formation. RNAi-mediated reduction of AGR2 in esophageal adenocarcinoma cells decreased anchorage-independent colony growth by 82% and xenograft size by 60%. RNA interference, NIH3T3 stable transfection, xenograft assay, anchorage-independent growth assay Cancer research Medium 18199544
2003 Yeast two-hybrid screening identified the metastasis-associated GPI-anchored protein C4.4A and extracellular alpha-dystroglycan (DAG-1) as binding partners for AGR2 (hAG-2). Yeast two-hybrid cloning British journal of cancer Low 12592373
2011 AGR2 localizes to both the ER lumen and the external surface of pancreatic tumor cells. Induction of AGR2 regulates ER chaperones (PDI, CALU, RCN1), ubiquitin-proteasome pathway components, and lysosomal proteases cathepsin B and D (CTSB, CTSD), including secretion of pro-CTSD. CTSB and CTSD are functional downstream targets of AGR2's proinvasive activity in vivo. Confocal microscopy, flow cytometry, proteomics/mass spectrometry, siRNA knockdown, in vivo dissemination assay Cancer research Medium 21948970
2011 AGR2 associates with nascent cargo proteins at ER membrane-bound ribosomes (indirectly, through nascent chains) and is involved in the maintenance of ER homeostasis. siRNA-mediated knockdown of AGR2 alters expression of ER-associated degradation (ERAD) machinery components and reduces the ability of cells to cope with acute ER stress. Proteomics of ER membrane-bound ribosomes, imaging, biochemical fractionation, siRNA knockdown The Journal of biological chemistry Medium 22025610
2011 AGR2 induces expression of the EGFR ligand amphiregulin (AREG) through activation of the Hippo signaling pathway co-activator YAP1. AREG expression rescues the transformed phenotype lost when AGR2 is reduced. AGR2 overexpression/knockdown in adenocarcinoma cells, rescue experiments, Hippo pathway reporter assays The Journal of biological chemistry Medium 21454516
2011 AGR2 function requires specifically its KTEL endoplasmic reticulum retention motif. Deletion of KTEL causes AGR2 secretion and loss of intracellular function (including induction of AREG or CDX2). Replacement of KTEL with KDEL or KSEL also abolishes function, indicating that the specific ER retention sequence—not simply ER residence—is required for AGR2 activity. KTEL deletion and substitution mutants in cell lines, functional reporter assays (amphiregulin induction, CDX2 expression), secretion assays The Journal of biological chemistry Medium 22184114
2012 AGR2 localizes to the ER of MUC5AC- and MUC5B-producing airway cells and forms a complex with immature MUC5AC (detected by co-immunoprecipitation). Loss of AGR2 impairs allergen-induced MUC5AC and MUC5B overproduction and increases the proportion of mucins retained in the ER with evidence of ER stress. Immunofluorescence, co-immunoprecipitation, Agr2-/- mouse allergic airway disease model American journal of respiratory cell and molecular biology High 22403803
2012 AGR2 is both sufficient and required for MUC1 expression in pancreatic cancer cells, functioning as an ER chaperone for the cancer-associated mucin MUC1. AGR2 is also a TGF-β-responsive gene whose downregulation is SMAD4-dependent. AGR2 overexpression/knockdown in pancreatic cancer cells, SMAD4-dependent regulation assays, genetically engineered mouse models (Pdx1-Cre/LSL-KrasG12D/Smad4lox/lox heterozygous for Agr2) Oncogene Medium 22945649
2014 AGR2 is secreted into the gastrointestinal mucus. AGR2 cysteine-to-serine mutation (C81S) allows secretion, suggesting that modification of the single Cys residue provides a mechanism for circumventing the KTEL ER retention signal. No covalent binding of AGR2 to recombinant MUC2 N- or C-termini was detected in this study (negative result). Mucus fractionation from murine gastrointestinal tract, CHO-K1 cell culture secretion assays, C81S mutant expression PloS one Medium 25111734
2015 AGR2 upregulates DUSP10, which subsequently inhibits p38 MAPK and prevents p53 activation by phosphorylation, establishing a pro-oncogenic signaling pathway that attenuates wild-type p53 activity. AGR2 overexpression/knockdown, DUSP10 expression analysis, p38 MAPK and p53 phosphorylation assays, breast cancer cohort analysis Molecular oncology Medium 26733232
2015 Extracellular AGR2 signals through the GPI-anchored receptor C4.4A to promote proliferation, migration, invasion, and chemoresistance of pancreatic cancer cells. AGR2-C4.4A interaction was confirmed by co-immunoprecipitation from cell lysates and with recombinant proteins; signaling requires laminins 1 or 5 and integrin β1. Co-immunoprecipitation (cell lysate and recombinant proteins), siRNA knockdown of C4.4A, blocking monoclonal antibodies, orthotopic xenograft mouse model Molecular cancer therapeutics Medium 25646014
2016 Extracellular AGR2 (eAGR2) is secreted as a functionally active protein independently of its thioredoxin-like CXXS domain and its KTEL ER-retention signal, and is sufficient by itself to promote acquisition of invasive and metastatic features. eAGR2 interacts with the ECM and acts as a microenvironmental regulator of epithelial tissue architecture. Domain deletion mutants, ECM interaction assays, 3D morphogenesis assays, invasion/metastasis assays eLife Medium 27240165
2016 FOXM1 transcription factor directly binds to the AGR2 gene promoter (at the -257/-247 bp region) and transcriptionally activates AGR2. AGR2 is required for FOXM1-driven mucinous phenotype and tumor invasion in lung adenocarcinoma. ChIP, luciferase reporter assay with promoter deletions, transgenic mouse models (FOXM1 overexpression, KrasG12D), orthotopic xenografts with AGR2/FOXM1 inhibition PLoS genetics High 29267283
2017 AGR2 promotes EGFR translocation from the ER to the plasma membrane during pancreatitis, enabling EGFR signaling, cell proliferation, and tissue regeneration. AGR2-null mice failed to regenerate after caerulein-induced pancreatitis and died. YAP1 activation during pancreatitis was also dependent on AGR2 expression. Caerulein pancreatitis model in Agr2-/- mice, EGFR localization assays, EGFR tyrosine kinase inhibitor (AG1478), cell proliferation assays PloS one Medium 27764193
2017 TGF-β suppresses AGR2 expression via mutually complementary Smad and ERK1/2 signaling cascades. Loss of AGR2 promotes EMT (reduced E-cadherin, increased vimentin and N-cadherin, actin reorganization), and forced re-expression of AGR2 reverses mesenchymal phenotype back to epithelial. TGF-β treatment with pathway inhibitors (PD98059 for ERK, SB431542 for TGFβR), siRNA and CRISPR/Cas9 AGR2 knockdown, EMT marker analysis by western blot, qPCR, immunofluorescence, invasion and adhesion assays BMC cancer Medium 28810836
2018 Secreted AGR2 (eAGR2) promotes CRC cell migration and metastasis by elevating Wnt11 expression and triggering non-canonical Wnt signaling via CaMKII and JNK pathways. eAGR2 also antagonizes canonical Wnt/β-catenin signaling through CaMKII activation. Wnt11 knockdown, CaMKII/JNK pharmacological inhibitors, in vitro migration assays, in vivo metastasis assays Experimental cell research Medium 29427622
2018 Secreted AGR2 interacts physically with VEGFA via formation of a disulfide bond (dependent on its thioredoxin motif) to enhance VEGFR2 activity and angiogenesis. Cytosolic AGR2 stabilizes p65 protein, activates NF-κB signaling, and facilitates EMT. In vitro binding assay with purified recombinant AGR2 and VEGFA, thioredoxin motif deletion/mutation, p65 co-IP/western blot, angiogenesis assays, xenograft models Biochimica et biophysica acta. Molecular basis of disease Medium 29410027
2018 AGR2 binds sequence-specifically to a peptide motif (TTIYY; consensus Tx[IL][YF][YF]) via a structural loop (amino acids 131-135, VDPSL). AGR2 stably interacts with the oncogenic receptor EpCAM via its TLIYY motif (Tyr251 of EpCAM critical for binding), demonstrated by HDX-MS, proximity ligation assay, and in vitro protein-protein interaction. Synthetic peptide affinity purification, hydrogen-deuterium exchange mass spectrometry (HDX-MS), mutant peptide library, proximity ligation assay, in vitro dose-dependent protein-protein interaction with recombinant proteins, EpCAM Tyr251Ala mutant Molecular & cellular proteomics : MCP High 29339412
2018 Loss of the AGR2 ER retention motif (KTEL) shifts AGR2 to extracellular/secreted form (eAGR2). eAGR2 promotes tumor metastasis and interacts with the mTORC2 pathway, increasing RICTOR phosphorylation at T1135. Intracellular AGR2 (iAGR2) antagonizes RICTOR phosphorylation. The two localizations have opposing effects on the Hippo pathway and spheroid formation. Protein-protein interaction screen, phosphorylation assays, in vivo metastasis models, AGR2 localization mutants Oncogene Medium 30575818
2019 AGR2 dimerization state controls ER homeostasis and inflammation. TMED2 was identified as an enhancer of AGR2 dimerization. Disruption of AGR2 dimer formation (either enhancement or inhibition) leads to pro-inflammatory phenotypes: enhancing dimerization triggers autophagy-dependent processes, while inhibiting dimerization promotes secretion of AGR2 monomers as inflammatory alarm signals. In IBD/Crohn's disease, levels of AGR2 dimerization modulators are selectively deregulated. Protein-protein interaction screen, dimerization assays, autophagy assays, AGR2 secretion assays, IBD patient tissue analysis EMBO molecular medicine Medium 31040128
2019 AGR2 dimerization involves K95-K95 adducts. The N-terminal intrinsically disordered region of AGR2 stabilizes dimer formation in trans. The AGR2 dimer (Δ45-AGR2, more stable) shows greater binding activity to its interacting protein Reptin than wild-type or monomeric AGR2(E60A). Dimer stability thus controls binding to Reptin. DSS-crosslinking assay, two-site sandwich microtiter assay with DyLight800-labeled antibody, AGR2 mutants (Δ45-AGR2 stable dimer; E60A monomer), Reptin binding assays Protein science : a publication of the Protein Society Medium 23780840
2019 Proteasome inhibition (MG132/bortezomib) suppresses AGR2 at mRNA and protein levels; MG132-mediated transcriptional repression is partially due to downregulation of E2F1. MG132 also facilitates degradation of polyubiquitinated AGR2 through autophagy activation via NBR1 as an autophagy receptor. The E3 ligase UBR5 conjugates K48-linked polyubiquitin chains onto K89 of AGR2. Pharmacological inhibitors (MG132, bortezomib, rapamycin), Atg5/Atg7 genetic depletion, K89 mutation, autophagy receptor (NBR1) knockdown, western blot, in vivo mouse samples Oncogene Medium 30647455
2021 AGR2 directs nuclear import of RNA Polymerase II (RNAPII) via its C-terminal nuclear localization signal and binds to the largest subunit of RNAPII in a peptide motif-dependent manner. This nuclear import undermines ATR-dependent p53 activation in acinar-to-ductal metaplasia lesions. A competitive hexapeptide disrupting the AGR2-RNAPII complex blocks RNAPII nuclear import and activates DNA damage response, dramatically compromising PDAC initiation in vivo. AGR2-RNAPII Co-immunoprecipitation, nuclear import assays, pancreas-specific Agr2 knockout mouse model, competitive hexapeptide in liposomes, patient-derived organoids, RNAPII inhibitor combination studies Gastroenterology High 34303658
2021 A homozygous missense variant in AGR2 in human patients causes infantile IBD (termed EAGLES). The mutant AGR2 shows reduced capacity to bind MUC2 (by co-immunoprecipitation) and reduced ability to alleviate tunicamycin-induced ER stress in HEK293T cells. Patient biopsies show reduced goblet cells, depletion of gel-forming mucins, and increased ER stress. Whole-genome sequencing, co-immunoprecipitation (AGR2-MUC2 binding with mutant vs. wild-type), ER stress assay in HEK293T cells with tunicamycin, immunohistochemistry of patient biopsies Cellular and molecular gastroenterology and hepatology High 34237462
2021 Intracellular AGR2 binds to KDEL receptors (KDELRs) via its KTEL motif to activate downstream Gs-PKA signaling. Activated PKA upregulates NF-κB subunit c-Rel (REL) and acetylates histone H3 at K9 (H3K9ac), promoting transcription of SNAIL and SLUG to drive EMT and CRC metastasis. AGR2 is transcriptionally upregulated by prostaglandin E2 via the EP4-PI3K-AKT pathway. Co-immunoprecipitation (AGR2-KDELR), PKA activity assays, ChIP (H3K9ac), NF-κB reporter, SNAIL/SLUG expression, AGR2 promoter analysis with EP4 inhibitors Cancer letters Medium 34216690
2022 Tumour-associated neutrophil (TAN)-secreted AGR2 promotes CRC cell migration by binding the heavy chain of CD98 (CD98hc) as its functional receptor, increasing xCT activity in a CD98hc-dependent manner and activating the RhoA/ROCK2 cascade. Neutrophil-specific Agr2 knockout in mice reduced CRC liver metastases. CRC-derived TGF-β1 educates peripheral neutrophils to become AGR2+ TANs. Neutrophil-specific Agr2 knockout mice, Co-immunoprecipitation (AGR2-CD98hc), xCT activity assays, RhoA/ROCK2 signaling assays, orthotopic CRC models Gut High 35086885
2022 Oxidative stress-induced S-glutathionylation of AGR2 interferes with its processing and modification of MUC2 precursors, blocking synthesis of mature MUC2. NADPH (produced by G6PD) inhibits this S-glutathionylation and promotes AGR2 activity. Glutamine enhances G6PD O-GlcNAcylation, increasing G6PD homodimer formation and NADPH synthesis, which suppresses AGR2 S-glutathionylation. Burn-sepsis animal model, AGR2 S-glutathionylation assays, G6PD O-GlcNAc modification assays, G6PD homodimerization assay, NADPH measurement, MUC2 maturation assays Redox biology Medium 36565645
2023 AGR2 represses IRE1β UPR transducer activity in goblet cells. In vitro, AGR2 actively destabilizes the IRE1β luminal domain dimer and forms a reversible complex with the inactive monomer. Depletion of endogenous AGR2 from goblet cells induces spontaneous IRE1β activation. AGR2 mutants lacking catalytic cysteine or carrying disease-associated H117Y mutation failed to dampen IRE1β activity. Introduction of the goblet-cell client MUC2 reversed AGR2-mediated repression of IRE1β. AGR2 had no effect on IRE1α. IRE1β/α chimera in CHO cells, in vitro reconstitution (AGR2-IRE1β luminal domain interaction), AGR2 depletion in goblet cells, catalytic cysteine and H117Y mutants, MUC2 rescue experiment The EMBO journal High 38177498 38177501
2012 Zebrafish Agr2 is expressed specifically in intestinal goblet cells and is essential for their terminal differentiation. Morpholino knockdown results in accumulation of immature goblet cells containing few mucous granules. Notably, in contrast to mouse, agr2 knockdown in zebrafish did not extensively induce UPR pathway genes (hspa5, xbp1s, chop, atf4b1). Morpholino antisense knockdown, mRNA overexpression, fluorescent whole-mount in situ hybridization, transmission electron microscopy, ER stress marker qPCR PloS one Medium 22514630
2019 RAD9A transcriptionally controls AGR2 by binding a partial p53 consensus sequence at position +3136 in the AGR2 5'-UTR, as demonstrated by ChIP and luciferase reporter assay. Mutation of the RAD9A-binding sequence abolished luciferase activity. Ectopic AGR2 expression in RAD9A-depleted cells restored cell migration and anchorage-independent growth phenotypes. Chromatin immunoprecipitation (ChIP), luciferase reporter assay with binding-site mutation, stable/transient RAD9A knockdown, rescue by ectopic AGR2 expression Carcinogenesis Medium 30295739
2020 AGR2 binds to MUC1 and induces MUC1 and HIF-1α expression in endometrial cancer cells. The pro-proliferative, migratory, and glycolytic effects of AGR2 are abolished by MUC1 knockdown, placing MUC1 downstream of AGR2 in the AGR2/MUC1/HIF-1α axis. Co-immunoprecipitation (AGR2-MUC1), MUC1 overexpression rescue of AGR2 knockdown, glycolysis assays, xenograft model Human cell Medium 32304027
2014 AGR2 expression in breast cancer requires both FOXA1 and ERα for transcriptional regulation in tamoxifen-sensitive cells. In tamoxifen-resistant cells, constitutive AGR2 expression requires FOXA1 but loses ERα dependence, indicating a FOXA1-ERα-AGR2 regulatory loop disrupted during endocrine resistance. AGR2 knockdown in tamoxifen-sensitive and -resistant breast cancer cells, FOXA1/ERα siRNA knockdown, in vivo xenograft tumor growth, migration assays Molecular cancer research : MCR Medium 25100862
2022 shRNA-mediated knockdown of AGR2 or ERp44 enhances basal DR5 oligomerization. AGR2 and ERp44 are identified as targets of Disulfide bond Disrupting Agents (DDAs) by biotinylated-DDA affinity purification, and their inhibition triggers DR4/DR5 disulfide-mediated oligomerization and caspase-8 activation in breast cancer cells. Biotinylated-DDA affinity purification, shRNA knockdown of AGR2/ERp44, DR5 oligomerization assays, ERp44 mutant expression, caspase-8 activation assays Cancer letters Medium 35247515

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proceedings of the National Academy of Sciences of the United States of America 336 19359471
2009 Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2-/- mice. Developmental biology 181 20025862
2008 The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation. Cancer research 176 18199544
2019 LINC02273 drives breast cancer metastasis by epigenetically increasing AGR2 transcription. Molecular cancer 170 31856843
2003 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. British journal of cancer 158 12592373
1998 hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. Biochemical and biophysical research communications 143 9790916
1998 Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2. Mechanisms of development 142 9533957
2011 AGR2 is a novel surface antigen that promotes the dissemination of pancreatic cancer cells through regulation of cathepsins B and D. Cancer research 125 21948970
2005 AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. Genes, chromosomes & cancer 120 15834940
2006 Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease. Genes and immunity 110 16222343
2011 Role of pro-oncogenic protein disulfide isomerase (PDI) family member anterior gradient 2 (AGR2) in the control of endoplasmic reticulum homeostasis. The Journal of biological chemistry 104 22025610
2022 Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT. Gut 103 35086885
2012 AGR2 is induced in asthma and promotes allergen-induced mucin overproduction. American journal of respiratory cell and molecular biology 100 22403803
2013 The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker. Breast cancer research : BCR 99 23635006
2016 ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation. Oncogene 86 27941872
2017 miR-342-3p suppresses cell proliferation and migration by targeting AGR2 in non-small cell lung cancer. Cancer letters 84 29107102
2011 AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration. Experimental & molecular medicine 82 21200134
2011 The human adenocarcinoma-associated gene, AGR2, induces expression of amphiregulin through Hippo pathway co-activator YAP1 activation. The Journal of biological chemistry 80 21454516
2010 The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection. The Prostate 80 20945500
2006 Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients. British journal of cancer 77 16598187
2016 Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties. eLife 75 27240165
2007 Expression of AGR2 in non small cell lung cancer. Histology and histopathology 73 17455144
2019 Proteasome inhibition boosts autophagic degradation of ubiquitinated-AGR2 and enhances the antitumor efficiency of bevacizumab. Oncogene 67 30647455
2019 Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO molecular medicine 65 31040128
2014 AGR2, an endoplasmic reticulum protein, is secreted into the gastrointestinal mucus. PloS one 64 25111734
2007 Physiological stress induces the metastasis marker AGR2 in breast cancer cells. Molecular and cellular biochemistry 63 17694278
2015 New Blocking Antibodies against Novel AGR2-C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice. Molecular cancer therapeutics 59 25646014
2012 AGR2 is a SMAD4-suppressible gene that modulates MUC1 levels and promotes the initiation and progression of pancreatic intraepithelial neoplasia. Oncogene 59 22945649
2021 Human AGR2 Deficiency Causes Mucus Barrier Dysfunction and Infantile Inflammatory Bowel Disease. Cellular and molecular gastroenterology and hepatology 58 34237462
2012 Anterior gradient 2 (AGR2): blood-based biomarker elevated in metastatic prostate cancer associated with the neuroendocrine phenotype. The Prostate 55 22911164
2013 A highly sensitive targeted mass spectrometric assay for quantification of AGR2 protein in human urine and serum. Journal of proteome research 53 24251762
2017 FOXM1 activates AGR2 and causes progression of lung adenomas into invasive mucinous adenocarcinomas. PLoS genetics 52 29267283
2010 Differential expression of anterior gradient gene AGR2 in prostate cancer. BMC cancer 51 21144054
2018 Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling. Experimental cell research 49 29427622
2015 AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway. Molecular oncology 47 26733232
2011 Development of an ELISA to detect the secreted prostate cancer biomarker AGR2 in voided urine. The Prostate 47 22072305
2019 Long non-coding RNA LINC01207 silencing suppresses AGR2 expression to facilitate autophagy and apoptosis of pancreatic cancer cells by sponging miR-143-5p. Molecular and cellular endocrinology 45 30991076
2011 AGR2 gene function requires a unique endoplasmic reticulum localization motif. The Journal of biological chemistry 45 22184114
2020 Secretion of pro-oncogenic AGR2 protein in cancer. Heliyon 43 33005802
2017 AGR2 ameliorates tumor necrosis factor-α-induced epithelial barrier dysfunction via suppression of NF-κB p65-mediated MLCK/p-MLC pathway activation. International journal of molecular medicine 42 28339048
2015 The role of AGR2 and AGR3 in cancer: similar but not identical. European journal of cell biology 42 25666661
2013 AGR2 expression is regulated by HIF-1 and contributes to growth and angiogenesis of glioblastoma. Cell biochemistry and biophysics 42 23712868
2012 Evaluation of the adenocarcinoma-associated gene AGR2 and the intestinal stem cell marker LGR5 as biomarkers in colorectal cancer. International journal of molecular sciences 42 22605983
2012 Zebrafish Agr2 is required for terminal differentiation of intestinal goblet cells. PloS one 41 22514630
2022 Glutamine promotes O-GlcNAcylation of G6PD and inhibits AGR2 S-glutathionylation to maintain the intestinal mucus barrier in burned septic mice. Redox biology 39 36565645
2020 CircPVT1 Promoted the Progression of Breast Cancer by Regulating MiR-29a-3p-Mediated AGR2-HIF-1α Pathway. Cancer management and research 39 33223849
2018 Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway. Biochimica et biophysica acta. Molecular basis of disease 39 29410027
2014 Agr2 mediates paracrine effects on stromal fibroblasts that promote invasion by gastric signet-ring carcinoma cells. Cancer research 39 25488752
2019 AGR2 is a target of canonical Wnt/β-catenin signaling and is important for stemness maintenance in colorectal cancer stem cells. Biochemical and biophysical research communications 38 31178140
2017 Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition. BMC cancer 37 28810836
2016 MicroRNA-1291 targets the FOXA2-AGR2 pathway to suppress pancreatic cancer cell proliferation and tumorigenesis. Oncotarget 37 27322206
2006 Characterization of the agr2 gene, a homologue of X. laevis anterior gradient 2, from the zebrafish, Danio rerio. Gene expression patterns : GEP 37 17175205
2021 Effect of m6A methyltransferase METTL3 -mediated MALAT1/E2F1/AGR2 axis on adriamycin resistance in breast cancer. Journal of biochemical and molecular toxicology 35 34964205
2014 Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer. Molecular cancer research : MCR 34 25100862
2012 Knockdown of AGR2 induces cellular senescence in prostate cancer cells. Carcinogenesis 33 22467239
2012 CD147 and AGR2 expression promote cellular proliferation and metastasis of head and neck squamous cell carcinoma. Experimental cell research 33 22659167
2021 Intracellular AGR2 transduces PGE2 stimuli to promote epithelial-mesenchymal transition and metastasis of colorectal cancer. Cancer letters 32 34216690
2018 Loss of ER retention motif of AGR2 can impact mTORC signaling and promote cancer metastasis. Oncogene 32 30575818
2012 Loss of anterior gradient 2 (Agr2) expression results in hyperplasia and defective lineage maturation in the murine stomach. The Journal of biological chemistry 31 23209296
2023 The IRE1β-mediated unfolded protein response is repressed by the chaperone AGR2 in mucin producing cells. The EMBO journal 30 38177498
2020 AGR2-induced glucose metabolism facilitated the progression of endometrial carcinoma via enhancing the MUC1/HIF-1α pathway. Human cell 29 32304027
2013 Prostate cancer cell phenotypes based on AGR2 and CD10 expression. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 29 23348903
2013 AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients. Disease markers 29 24167368
2010 2,3,7,8-tetrachlorodibenzo-p-dioxin counteracts the p53 response to a genotoxicant by upregulating expression of the metastasis marker agr2 in the hepatocarcinoma cell line HepG2. Toxicological sciences : an official journal of the Society of Toxicology 29 20299546
2018 The role of protein disulphide isomerase AGR2 in the tumour niche. Biology of the cell 27 30238476
2012 The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development. Developmental biology 27 22819674
2021 From development to cancer - an ever-increasing role of AGR2. American journal of cancer research 25 34873459
2023 Activation of goblet-cell stress sensor IRE1β is controlled by the mucin chaperone AGR2. The EMBO journal 24 38177501
2021 Effects of ER-resident and secreted AGR2 on cell proliferation, migration, invasion, and survival in PANC-1 pancreatic cancer cells. BMC cancer 24 33413231
2018 Knockdown of AGR2 induces cell apoptosis and reduces chemotherapy resistance of pancreatic cancer cells with the involvement of ERK/AKT axis. Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 24 30055941
2013 AGR2, ERp57/GRP58, and some other human protein disulfide isomerases. Biochemistry. Biokhimiia 24 24490732
2014 Aberrant hypomethylation-mediated AGR2 overexpression induces an aggressive phenotype in ovarian cancer cells. Oncology reports 23 24920423
2012 AGR2 as a potential biomarker of human lung adenocarcinoma. Osaka city medical journal 23 23094510
2022 Induction of cancer cell stemness in glioma through glycolysis and the long noncoding RNA HULC-activated FOXM1/AGR2/HIF-1α axis. Laboratory investigation; a journal of technical methods and pathology 22 35013529
2021 125I seeds inhibit proliferation and promote apoptosis in cholangiocarcinoma cells by regulating the AGR2-mediated p38 MAPK pathway. Cancer letters 22 34656689
2020 Long noncoding RNA LINC00460 conduces to tumor growth and metastasis of hepatocellular carcinoma through miR-342-3p-dependent AGR2 up-regulation. Aging 22 32493835
2015 Induction of anterior gradient 2 (AGR2) plays a key role in insulin-like growth factor-1 (IGF-1)-induced breast cancer cell proliferation and migration. Medical oncology (Northwood, London, England) 22 25956506
2020 FOXA1 Promotes Cell Proliferation and Suppresses Apoptosis in HCC by Directly Regulating miR-212-3p/FOXA1/AGR2 Signaling Pathway. OncoTargets and therapy 21 32606743
2016 Bladder cancer cells secrete while normal bladder cells express but do not secrete AGR2. Oncotarget 21 26894971
2016 Anterior Gradient 2 (AGR2) Induced Epidermal Growth Factor Receptor (EGFR) Signaling Is Essential for Murine Pancreatitis-Associated Tissue Regeneration. PloS one 21 27764193
2021 AGR2-Dependent Nuclear Import of RNA Polymerase II Constitutes a Specific Target of Pancreatic Ductal Adenocarcinoma in the Context of Wild-Type p53. Gastroenterology 20 34303658
2020 Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers. Anticancer research 20 32234873
2018 The Sequence-specific Peptide-binding Activity of the Protein Sulfide Isomerase AGR2 Directs Its Stable Binding to the Oncogenic Receptor EpCAM. Molecular & cellular proteomics : MCP 20 29339412
2013 AGR2 expression in ovarian tumours: a potential biomarker for endometrioid and mucinous differentiation. Pathology 20 23222243
2013 Development of a fluorescent monoclonal antibody-based assay to measure the allosteric effects of synthetic peptides on self-oligomerization of AGR2 protein. Protein science : a publication of the Protein Society 20 23780840
2012 Proteomic study explores AGR2 as pro-metastatic protein in HCC. Molecular bioSystems 20 22828706
2022 Inhibitors of ERp44, PDIA1, and AGR2 induce disulfide-mediated oligomerization of Death Receptors 4 and 5 and cancer cell death. Cancer letters 19 35247515
2020 ZEB1/miR-200c/AGR2: A New Regulatory Loop Modulating the Epithelial-Mesenchymal Transition in Lung Adenocarcinomas. Cancers 18 32570918
2018 Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma. Cancer medicine 18 29845750
2017 AGR2 promotes the proliferation, migration and regulates epithelial-mesenchymal transition in salivary adenoid cystic carcinoma. American journal of translational research 18 28337279
2016 Cancer-secreted AGR2 induces programmed cell death in normal cells. Oncotarget 18 27283903
2017 Serum AGR2 as a useful biomarker for pituitary adenomas. Clinical neurology and neurosurgery 17 28092730
2017 Tamoxifen-Dependent Induction of AGR2 Is Associated with Increased Aggressiveness of Endometrial Cancer Cells. Cancer investigation 17 28402678
2020 Long Noncoding RNA LINC00460 Promotes Hepatocellular Carcinoma Progression via Regulation of miR-342-3p/AGR2 Axis. OncoTargets and therapy 16 32184630
2020 Extracellular AGR2 triggers lung tumour cell proliferation through repression of p21CIP1. Biochimica et biophysica acta. Molecular cell research 16 33278424
2019 RAD9A promotes metastatic phenotypes through transcriptional regulation of anterior gradient 2 (AGR2). Carcinogenesis 16 30295739
2019 TP53 mediated miR-3647-5p prevents progression of cervical carcinoma by targeting AGR2. Cancer medicine 16 31436390
2023 AGR2: a secreted protein worthy of attention in diagnosis and treatment of breast cancer. Frontiers in oncology 15 37197416
2022 Agr2-associated ER stress promotes adherent-invasive E. coli dysbiosis and triggers CD103+ dendritic cell IL-23-dependent ileocolitis. Cell reports 15 36384110
2017 AGR2 associates with HER2 expression predicting poor outcome in subset of estrogen receptor negative breast cancer patients. Experimental and molecular pathology 15 28238761

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