Affinage

AREG

Amphiregulin · UniProt P15514

Round 2 corrected
Length
252 aa
Mass
27.9 kDa
Annotated
2026-04-28
130 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Amphiregulin (AREG) is an EGF-family ligand synthesized as a 252-amino-acid transmembrane precursor that undergoes ADAM17/TACE-mediated ectodomain shedding to release a soluble heparin-binding growth factor that signals exclusively through EGFR (ErbB1), activating MAPK/ERK, PI3K/Akt, and NF-κB cascades to drive cell proliferation, survival, migration, and epithelial-mesenchymal transition (PMID:2466334, PMID:12743035, PMID:32323797). AREG transcription is controlled by diverse upstream inputs including WT1, YAP/TEAD (downstream of Hippo/LATS1/2), HIF-2α, CRTC1-MAML2/CREB, IL-17A→ACT1→MST1→YAP, mitochondrial stress via c-JUN/YAP1, and GPR174→Gαs/cAMP/PKA→EGR1 in regulatory T cells, while AREG mRNA stability is post-transcriptionally regulated by METTL3-mediated m6A modification and miR-34c-5p targeting of the 3′UTR (PMID:10490105, PMID:19935651, PMID:35304250, PMID:36095121, PMID:36473866, PMID:37604948, PMID:28459431). Beyond classical autocrine/paracrine shedding, AREG is packaged into exosomes for intercellular delivery, driving osteoclastogenesis in myeloma bone disease and promoting invasiveness in recipient cancer cells (PMID:21514161, PMID:30621731). Physiologically, AREG is essential for liver regeneration after partial hepatectomy and for dermal fibrosis downstream of EGFR→MEK signaling, and its overexpression in keratinocytes is sufficient to produce psoriasis-like skin pathology (PMID:15685553, PMID:33622407, PMID:9410906).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1988 High

    Identification of AREG as a novel bifunctional growth factor resolved the question of whether breast carcinoma cells secrete factors with both growth-inhibitory and growth-stimulatory activities depending on target cell type.

    Evidence Purification from PMA-treated MCF-7 conditioned medium with bioassays on carcinoma and fibroblast cells

    PMID:3413110

    Open questions at the time
    • Receptor identity unknown
    • Gene structure unknown
    • Mechanism of bifunctional activity not defined
  2. 1989 High

    Sequencing revealed AREG as an EGF-family member that binds EGFR, establishing its receptor specificity and positioning it within the broader EGF ligand family.

    Evidence Complete amino acid sequencing, EGF receptor competition binding assay, keratinocyte growth assay

    PMID:2466334

    Open questions at the time
    • Binding affinity quantification incomplete
    • Signaling pathway downstream of EGFR not yet mapped
    • No structure-function dissection of heparin-binding domain
  3. 1990 High

    Cloning of the AREG gene revealed a 252-amino-acid transmembrane precursor architecture analogous to TGF-α, establishing that AREG is synthesized as a membrane-anchored protein requiring proteolytic processing.

    Evidence Gene cloning, sequencing, chromosomal mapping to 4q13–q21, Northern blot

    PMID:2325643

    Open questions at the time
    • Identity of the processing protease unknown
    • Whether juxtacrine signaling occurs from unprocessed precursor untested
  4. 1996 High

    Systematic receptor pairing experiments demonstrated that AREG signals exclusively through EGFR (ErbB1) and does not directly activate ErbB-2, ErbB-3, or ErbB-4, distinguishing it from neuregulins and defining its receptor exclusivity.

    Evidence Ba/F3 cells expressing individual and pairwise ErbB receptors; tyrosine phosphorylation and survival assays

    PMID:8702723

    Open questions at the time
    • Whether AREG induces EGFR heterodimerization with other ErbB members in endogenous contexts not addressed
  5. 1997 High

    Transgenic keratinocyte-specific AREG overexpression producing a psoriasis-like phenotype established that AREG gain-of-function is sufficient to drive inflammatory hyperproliferative skin disease in vivo.

    Evidence K14 promoter-driven AREG transgenic mice; histological analysis

    PMID:9410906

    Open questions at the time
    • Whether endogenous AREG upregulation is necessary for human psoriasis not tested
    • Downstream immune cell recruitment mechanism undefined
  6. 1999 High

    Identification of WT1 as a direct transcriptional activator of the AREG promoter, coupled with AREG's ability to stimulate kidney epithelial branching, linked AREG to developmental morphogenesis downstream of a tumor suppressor.

    Evidence Inducible WT1 expression, EMSA/promoter binding, reporter assays, kidney organ culture with recombinant AREG

    PMID:10490105

    Open questions at the time
    • In vivo requirement for AREG in kidney development not tested via knockout
    • Other WT1 targets may contribute to branching
  7. 2003 High

    ADAM17/TACE was identified as the specific sheddase for AREG, and GPCR-induced EGFR transactivation was shown to require TACE-mediated AREG release, solving the long-standing question of how GPCRs activate EGFR.

    Evidence siRNA of AREG and TACE, dominant-negative TACE, TIMP-3 inhibitor, neutralizing antibodies; LPA/carbachol stimulation

    PMID:12711607 PMID:12743035

    Open questions at the time
    • Whether other ADAMs contribute under specific conditions not excluded
    • Structural basis for TACE recognition of AREG cleavage site unknown
  8. 2005 High

    AREG-null mice revealed an essential, non-redundant role for AREG in hepatocyte proliferation during liver regeneration, induced by IL-1β/PGE2 rather than HGF or IL-6.

    Evidence Areg knockout mice, partial hepatectomy, primary hepatocyte proliferation assays, cytokine stimulation

    PMID:15685553

    Open questions at the time
    • Compensatory upregulation of other EGFR ligands at later time points not fully characterized
    • Mechanism of IL-1β/PGE2 induction of AREG transcription not defined
  9. 2006 High

    Demonstration that membrane-anchored AREG activates EGFR in adjacent cells via juxtacrine signaling, in addition to autocrine shedding-dependent signaling, established a dual-mode signaling capability.

    Evidence Juxtacrine overlay assay, metalloprotease inhibitor GM6001, EGFR inhibitors, invasion/motility assays in SUM149 breast cancer cells

    PMID:17035230

    Open questions at the time
    • Relative physiological importance of juxtacrine vs. autocrine signaling in tissues unknown
    • Structural basis for juxtacrine EGFR activation not resolved
  10. 2009 High

    YAP was established as a transcriptional inducer of AREG downstream of Hippo pathway suppression, and AREG secretion was shown to mediate YAP's non-cell-autonomous proliferative effects, linking the Hippo pathway to EGFR ligand production.

    Evidence YAP overexpression, AREG knockdown, EGFR inhibitor, co-culture paracrine assay, LATS1/2 siRNA, Drosophila yorkie/EGFR epistasis

    PMID:19935651

    Open questions at the time
    • Whether YAP binds the AREG promoter directly or through TEAD cofactors not resolved at this point
    • Relative contribution of AREG vs. other YAP targets to organ size control unclear
  11. 2011 High

    Discovery that cancer-cell-derived exosomes carry signaling-competent AREG that is more potent than soluble AREG in promoting invasiveness revealed an unconventional paracrine delivery mechanism for EGFR ligands.

    Evidence Exosome isolation, quantitative mass spectrometry (~24 AREG/exosome), invasion assays, KRAS isogenic cell lines

    PMID:21514161

    Open questions at the time
    • Mechanism of AREG sorting into exosomes unknown
    • Whether exosomal AREG is cleaved or full-length transmembrane form not fully resolved
    • In vivo exosomal AREG bioavailability not quantified
  12. 2017 High

    miR-34c-5p was shown to directly target the AREG 3′UTR, and AREG→EGFR→ERK signaling was demonstrated to promote cancer stemness and chemoresistance, establishing post-transcriptional control and a functional link to tumor-initiating cell properties.

    Evidence Luciferase reporter with wild-type/mutant AREG 3′UTR, sphere formation, drug resistance assays, ERK pathway analysis in ovarian cancer

    PMID:28459431

    Open questions at the time
    • Broader miRNA regulatory landscape of AREG not mapped
    • In vivo relevance of miR-34c-5p→AREG axis in chemoresistance untested
  13. 2019 High

    Senescent stromal cells were found to secrete AREG as a SASP component that confers chemoresistance and induces PD-L1 on cancer cells, establishing AREG as a mediator of the immunosuppressive tumor microenvironment.

    Evidence DNA damage-induced senescence, AREG neutralization, PD-L1 measurement, humanized animal xenograft models

    PMID:31493351

    Open questions at the time
    • Whether AREG-induced PD-L1 operates via NF-κB or another pathway not defined
    • Clinical relevance of anti-AREG immunosensitization not tested in patients
  14. 2019 High

    Exosomal AREG from myeloma cells was shown to activate EGFR in osteoclast precursors and suppress osteoblast differentiation, defining a mechanism for myeloma bone disease mediated by AREG-containing exosomes.

    Evidence Exosome isolation from MM cell lines and patient bone marrow, anti-AREG neutralizing antibody, osteoclast differentiation assays, MSC co-culture

    PMID:30621731

    Open questions at the time
    • In vivo bone lesion formation studies with AREG blockade not performed
    • Whether other exosomal cargo synergizes with AREG not investigated
  15. 2021 High

    AREG-null mice were completely protected from bleomycin-induced skin fibrosis, and MEK inhibition phenocopied this protection, defining the AREG→EGFR→MEK axis as essential for dermal fibrotic responses.

    Evidence Areg knockout mice, bleomycin fibrosis model, selumetinib (MEK inhibitor), histology and proliferation markers

    PMID:33622407

    Open questions at the time
    • Whether AREG drives fibrosis in other organs (lung, kidney) via the same mechanism untested
    • Cell source of AREG in fibrotic dermis not identified
  16. 2022 High

    Multiple studies converged on the transcriptional regulation of AREG: IL-17A→ACT1→MST1→YAP in psoriatic keratinocytes, mitochondrial stress→c-JUN/YAP1/TEAD enhancer activation, and GPR174→Gαs/cAMP/PKA repression of EGR1→AREG in Tregs, revealing context-specific regulatory inputs that funnel through distinct pathways onto the AREG locus.

    Evidence Co-IP of ACT1-MST1, YAP phosphorylation assays, imiquimod mouse model, TFAM knockout with ChIP-seq/ATAC-seq, Treg-specific GPR174 knockout with hindlimb ischemia model

    PMID:35304250 PMID:36095121 PMID:36473866

    Open questions at the time
    • Relative contribution of each transcriptional input in different tissues not quantified
    • Enhancer architecture at the AREG locus not fully characterized across cell types
    • Whether c-JUN/YAP1 and IL-17A/YAP converge on the same enhancer elements not tested
  17. 2023 High

    METTL3-mediated m6A modification of AREG mRNA was shown to stabilize the transcript and increase AREG protein output, adding an epitranscriptomic layer to AREG regulation.

    Evidence RNA bisulfite sequencing mapping m6A sites on AREG mRNA, METTL3 knockdown/overexpression, mRNA stability assays, rescue experiments in pancreatic cancer cells

    PMID:37604948

    Open questions at the time
    • Identity of the m6A reader protein mediating AREG mRNA stabilization unknown
    • Whether m6A regulation of AREG is tissue-specific not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for AREG's exclusive EGFR specificity and lower binding affinity compared to EGF, the mechanism by which AREG is selectively sorted into exosomes, whether AREG's juxtacrine versus autocrine/exosomal signaling modes have distinct physiological roles in vivo, and the identity of the m6A reader that stabilizes AREG mRNA.
  • No crystal structure of AREG-EGFR complex available
  • Exosomal sorting mechanism of AREG uncharacterized
  • Relative in vivo contributions of juxtacrine, autocrine, and exosomal AREG signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 5 R-HSA-1500931 Cell-Cell communication 2 R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1
Partners
ADAM17EGFREGR1METTL3TEADWT1YAP1

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 Amphiregulin (AREG) was purified to homogeneity from conditioned medium of PMA-treated MCF-7 human breast carcinoma cells as a bifunctional glycoprotein that inhibits growth of certain human carcinoma cells while stimulating proliferation of human fibroblasts and other tumor cells; biological activity requires intact disulfide bonds. Protein purification (heparin affinity, HPLC, gel permeation), SDS-PAGE, bioassays, chemical modification Proceedings of the National Academy of Sciences of the United States of America High 3413110
1989 Amphiregulin is a 78–84 amino acid protein whose C-terminal half (residues 46–84) is homologous to the EGF family, while the N-terminal half is unusually hydrophilic and heparin-binding; it binds the EGF receptor but with lower affinity than EGF and fully substitutes for EGF in murine keratinocyte growth. Protein sequencing, receptor binding competition assay, keratinocyte growth assay Science High 2466334
1990 The AREG gene encodes a 252-amino-acid transmembrane precursor (similar to TGF-α precursor organization) from which the mature 84-aa protein is derived; AREG gene was localized to chromosomal region 4q13–4q21; AREG exhibits tumor-inhibitory activity on aggressive carcinoma lines while promoting normal epithelial cell growth. Gene cloning and sequencing, Northern blot, chromosomal mapping, cell growth assays Molecular and cellular biology High 2325643
1990 Schwannoma-derived growth factor (SDGF) is identical to amphiregulin and functions as an autocrine mitogen for Schwann cells and a mitogen for astrocytes and fibroblasts, demonstrating AREG's role in the nervous system. Protein purification, sequence determination, mitogenesis assays on glial cells and fibroblasts Nature High 2234093
1991 Keratinocyte autocrine factor (KAF) is identical to amphiregulin; heparin sulfate inhibits AREG mitogenic activity by blocking its ability to compete with EGF for cell surface binding, establishing a negative regulatory mechanism for AREG signaling. Protein purification, N-terminal microsequencing, ELISA, competitive binding assay, cell proliferation assay with heparin sulfate Molecular and cellular biology High 2017164
1992 CRDGF (colorectum cell-derived growth factor) produced by HT29 colon cancer cells is identical to amphiregulin; AREG stimulates phosphorylation of the EGF receptor on tyrosine residues, indicating the AR intracellular signaling pathway involves activation of EGF-R kinase. Protein purification, N-terminal sequencing, Western blot with AR-specific antiserum, EGF receptor phosphorylation assay Growth factors High 1333777
1995 Areg and Btc (betacellulin) are tightly linked on mouse chromosome 5; a previously described growth factor SDGF is confirmed as a species variant of Areg, clarifying the evolutionary relationships within the EGF ligand family. Interspecific backcross mapping, genomic analysis Genomics Medium 7590736
1996 AREG, like EGF, TGF-α, and HB-EGF, couples primarily through EGFR (ErbB1) to drive tyrosine phosphorylation and physiological proliferative responses; these ligands do not directly activate ErbB-2 (Neu) alone but require EGFR as an intermediary, distinguishing them functionally from neuregulins which directly bind ErbB-3/4. Ba/F3 cell lines expressing single and pairwise ErbB receptors, receptor tyrosine phosphorylation assays, IL-3-independent survival/proliferation assays The Journal of biological chemistry High 8702723
1997 Transgenic overexpression of human AREG driven by the keratin-14 promoter in basal keratinocytes induces a psoriasis-like skin phenotype with hyperkeratosis, acanthosis, and inflammatory infiltration, establishing that aberrant AREG expression is sufficient to drive psoriatic-like pathology in vivo. Transgenic mouse model (K14-ARGE), histological analysis, phenotypic characterization The Journal of clinical investigation High 9410906
1999 The Wilms tumor suppressor WT1 (−KTS isoform) directly binds the amphiregulin promoter and acts as a potent transcriptional activator of AREG; recombinant AREG stimulates epithelial branching in embryonic mouse kidney organ cultures, implicating the WT1→AREG axis in kidney differentiation. Oligonucleotide microarray (gene expression after inducible WT1), reporter assays, EMSA/promoter binding, kidney organ culture with recombinant AREG Cell High 10490105
2000 Ectodomain shedding of membrane-anchored EGFR ligands including amphiregulin is required for keratinocyte migration in cutaneous wound healing; wound stimuli induce shedding of HB-EGF as the predominant soluble EGFR ligand; inhibition of shedding with OSU8-1 blocked EGFR activation and keratinocyte migration in vitro and reepithelialization in vivo. In vitro wound assay, EGFR activation assays, metalloprotease inhibitor (OSU8-1), soluble EGFR-Fc neutralization, mouse wound healing model with rescue by recombinant HB-EGF The Journal of cell biology High 11038170
2003 TACE/ADAM17 metalloprotease is the specific enzyme responsible for cleavage and release of amphiregulin from the membrane in response to GPCR agonists (LPA, carbachol); AREG release is required for GPCR-induced EGFR transactivation, downstream mitogenic signaling, cell proliferation, migration, and Akt/PKB survival activation. siRNA silencing of AREG or TACE blocks all these responses. siRNA gene silencing of AREG and TACE, dominant-negative TACE mutant, neutralizing antibodies, TACE inhibitor (TIMP-3), EGFR phosphorylation assays, cell proliferation and migration assays The EMBO journal High 12743035
2003 Tobacco smoke activates ADAM17/TACE via oxygen radical generation, which cleaves transmembrane amphiregulin to produce soluble AREG that binds EGFR and stimulates lung epithelial cell proliferation, defining a smoke→ROS→ADAM17→AREG→EGFR signaling axis. Cell proliferation assays, ADAM17 inhibitors, ROS scavengers, metalloprotease inhibitors, EGFR inhibitors, smoke condensate stimulation The Journal of biological chemistry High 12711607
2005 AREG is rapidly induced after partial hepatectomy in rodents via IL-1β and prostaglandin E2 (but not HGF, IL-6, or TNF-α); AREG acts as a primary mitogen for hepatocytes through EGFR; AREG-null mice show impaired hepatocyte proliferative responses after partial hepatectomy, demonstrating an essential role for AREG in early liver regeneration. AREG-null mice, partial hepatectomy model, primary hepatocyte proliferation assays, cytokine stimulation experiments, EGFR inhibition Gastroenterology High 15685553
2006 AREG maintains a self-sustaining autocrine loop in SUM149 breast cancer cells requiring metalloprotease-dependent cleavage of the membrane precursor; juxtacrine AREG (membrane-anchored, uncleaved) can also activate EGFR in adjacent cells; AREG autocrine signaling promotes cell invasiveness and motility by upregulating invasion/motility genes. EGFR phosphorylation assays, AR-neutralizing antibodies, pan-ErbB inhibitor CI1033, anti-EGFR antibody C225, metalloprotease inhibitor GM6001, juxtacrine overlay assay, invasion/motility assays, gene expression analysis The Journal of biological chemistry High 17035230
2006 The human AREG promoter contains three conserved TCF/LEF binding sites (conserved in chimpanzee but not rodent), identifying AREG as a direct transcriptional target of the canonical WNT/β-catenin signaling pathway; WNT signaling activation may drive AREG upregulation and consequent EGFR ligand-mediated gefitinib resistance. Bioinformatic promoter analysis, comparative genomics of primate vs. rodent AREG promoters International journal of molecular medicine Low 16685431
2009 YAP (yes-associated protein), the transcriptional co-activator and Hippo pathway effector, directly induces AREG gene transcription; YAP-expressing cells secrete AREG to stimulate proliferation of neighboring untransfected cells in a non-cell-autonomous manner; AREG-EGFR signaling mediates YAP's proliferative and migratory (but not EMT) effects; suppression of LATS1/2 is sufficient to induce AREG expression. YAP overexpression in MCF10A cells, AREG knockdown, EGFR kinase inhibitor, co-culture/paracrine proliferation assay, LATS1/2 siRNA knockdown, Drosophila yorkie/EGFR genetic interaction Nature cell biology High 19935651
2011 Cancer cells release exosomes containing full-length, signaling-competent AREG; exosomal AREG increases invasiveness of recipient breast cancer cells 4-fold over soluble recombinant AREG, with AREG exosomes displaying significantly greater membrane stability than other EGFR ligands; an average of 24 AREG molecules are packaged per exosome; mutant KRAS elevates exosomal AREG levels. Exosome isolation, Western blot, quantitative mass spectrometry of exosomal AREG content, invasion assays in recipient cells, MDCK cells expressing individual EGFR ligands, KRAS isogenic cell lines Current biology High 21514161
2011 HIF-2α drives AREG expression through the endogenous AREG promoter via a non-canonical mechanism lacking a classical HIF-DNA interaction motif (HRE), establishing a novel mode of HIF-mediated gene regulation; HIF-2α-dependent AREG secretion activates EGF receptor family members in an autocrine loop promoting breast cancer cell self-sufficiency. HIF-2α knockdown/overexpression, ChIP assay on endogenous AREG promoter, EGFR family phosphorylation assays, patient tumor data correlation Oncogene High 21927022
2011 AREG upregulates MMP-9 in metastatic breast cancer cells and promotes invasion through the MAPK/ERK pathway; MEK inhibition (PD98059) and MAPK antisense oligonucleotides significantly reduce AREG/EGF-induced MMP-9 secretion and invasion, placing AREG upstream of MAPK→MMP-9 in invasion signaling. MEK inhibitor PD98059, Ras inhibitor, PI3K inhibitor, MAPK antisense oligonucleotides, MMP-9 ELISA, invasion through Matrigel International journal of cancer Medium 10389762
2013 The CRTC1-MAML2 fusion oncogene upregulates AREG by co-activating the transcription factor CREB at the AREG promoter; secreted AREG then activates EGFR in an autocrine manner to promote mucoepidermoid carcinoma (MEC) cell growth and survival; CRTC1-MAML2-positive MEC cells are highly sensitive to EGFR inhibition. RNA interference of CRTC1-MAML2 and AREG, CREB co-activation reporter assay, EGFR inhibitor treatment, xenograft mouse models, gene expression analysis Oncogene High 23975434
2013 RASSF1A tumor suppressor activates the Hippo pathway (via MST kinases) to suppress YAP oncogenic activity, resulting in reduced AREG secretion from hepatocellular carcinoma cells; RASSF1A overexpression inhibits HCC cell proliferation and apoptosis induction via this RASSF1A→Hippo→YAP→AREG axis. RASSF1A overexpression in HCC cells, AREG secretion measurement (ELISA), apoptosis assays, proliferation assays, immunohistochemistry of human specimens Molecular cancer research High 23594797
2017 miR-34c-5p directly targets the AREG 3'UTR (confirmed by luciferase reporter and mutant analysis) and suppresses AREG expression; AREG promotes ovarian cancer stemness (sphere formation, self-renewal) and drug resistance via the AREG→EGFR→ERK pathway, which is inhibited by miR-34c-5p. Luciferase reporter assay with wild-type and mutant AREG 3'UTR, miR-34c-5p overexpression, AREG overexpression, sphere formation assays, drug resistance assays, ERK pathway analysis Oncogenesis High 28459431
2019 Senescent stromal cells secrete AREG as a SASP (senescence-associated secretory phenotype) component in response to DNA damage; paracrine AREG activates EGFR on cancer cells to mediate acquired chemoresistance; senescent stromal AREG also induces PD-L1 expression in recipient cancer cells, creating immunosuppression; targeting AREG restores chemosensitivity and immunocompetency in humanized animal models. DNA damage-induced senescence models, AREG neutralization, EGFR inhibition, PD-L1 measurement, drug resistance assays, humanized animal xenograft models Aging cell High 31493351
2019 Multiple myeloma-derived exosomes are enriched in AREG; exosomal AREG activates EGFR in osteoclast precursors, inducing SNAIL mRNA expression; AREG-enriched exosomes promote osteoclast differentiation and block osteoblast differentiation in mesenchymal stromal cells, and stimulate IL-8 release from MSCs to drive osteoclastogenesis indirectly; anti-AREG neutralizing antibody reverses these effects. Exosome isolation from MM cell lines and patient BM plasma, EGFR activation assays, SNAIL qPCR, anti-AREG neutralizing antibody, OC differentiation assays (RAW264.7 and CD14+ primary cells), MSC co-culture, IL-8 ELISA Journal of hematology & oncology High 30621731
2019 AREG expression in granulosa cells is elevated in OHSS patients; exogenous AREG treatment of granulosa cells stimulates VEGF expression and secretion via EGFR/HER2 signaling; siRNA-mediated knockdown of EGFR or AREG attenuates hCG-induced VEGF upregulation, establishing an AREG→EGFR/HER2→VEGF pathway in OHSS pathology. RT-qPCR of patient granulosa cells, AREG treatment of cultured granulosa cells, siRNA knockdown of EGFR and AREG, VEGF secretion assays Biology of reproduction High 31167229
2020 AREG mediates epithelial-mesenchymal transition (EMT) in pancreatic cancer via the EGFR→ERK→NF-κB signaling pathway; AREG stimulation increases NF-κB nuclear accumulation; NF-κB inhibitor blocks AREG-induced EMT, migration, and invasion; AREG silencing reduces tumor growth and metastasis in an orthotopic pancreatic cancer model. siRNA knockdown, exogenous AREG stimulation, wound-healing and Transwell invasion assays, Western blot for EMT markers and pathway components, NF-κB inhibitor, immunofluorescence, orthotopic xenograft model Oncology reports High 32323797
2021 AREG deficiency in mice essentially prevents bleomycin-induced skin fibrosis; bleomycin-induced dermal cell proliferation is absent in Areg-null mice; inhibiting MEK (a downstream effector of AREG-EGFR signaling) with selumetinib effectively blocks skin fibrosis, defining the Areg→EGFR→MEK signaling axis as critical for fibrosis development. Areg knockout mice, bleomycin-induced skin fibrosis model, histology, cell proliferation markers in dermis, MEK inhibitor (selumetinib) treatment, gene expression comparison between oral mucosa wound healing and skin fibrosis datasets Cell & bioscience High 33622407
2022 IL-17A promotes keratinocyte proliferation in psoriasis by stimulating recruitment of MST1 to the adaptor ACT1, which reduces MST1-LATS1 interaction, leading to YAP dephosphorylation and nuclear accumulation, which then activates AREG transcription; blocking YAP or IL-17A (secukinumab) suppresses the YAP-AREG axis in psoriatic skin. IL-17A stimulation of HaCaT and NHEK cells, ACT1 co-immunoprecipitation with MST1, YAP phosphorylation assays, AREG expression measurement, imiquimod mouse model, secukinumab treatment in patients The Journal of investigative dermatology High 35304250
2022 Mitochondrial dysfunction (loss of mitochondrial transcription factor A, TFAM) dramatically induces AREG expression as a hallmark retrograde signaling response; mitochondrial stress activates enhancers at the AREG locus through c-JUN/YAP1/TEAD axis; BRG1 chromatin remodeler represses these enhancers under normal conditions; this stress-responsive AREG induction is observed in murine liver injury models. TFAM knockout cells, transcriptomic analysis, ChIP-seq and ATAC-seq (epigenomic), c-JUN/YAP1 co-immunoprecipitation, motif enrichment analysis, mitochondrial stressor treatments, murine liver injury model Nucleic acids research High 36095121
2022 GPR174 negatively regulates AREG expression in regulatory T cells (Tregs) by activating the Gαs/cAMP/PKA signaling pathway, which inhibits nuclear accumulation of EGR1 (early growth response protein 1), a transcriptional activator of AREG; GPR174 deletion in Tregs upregulates AREG, thereby enhancing endothelial cell function and reducing pro-inflammatory macrophage polarization to promote post-ischemic angiogenesis. Treg-specific GPR174 knockout mice, hindlimb ischemia model, EGR1 nuclear localization assay, cAMP/PKA pathway inhibitors, AREG expression measurement, endothelial cell functional assays, macrophage polarization assays Nature communications High 36473866
2023 METTL3 methyltransferase induces m6A modification on AREG mRNA, stabilizing it and increasing AREG protein levels in pancreatic cancer; miR-33a-3p targets and suppresses METTL3, thereby reducing m6A-stabilization of AREG mRNA and inhibiting pancreatic cancer proliferation, migration, and invasion. RNA bisulfite sequencing (m6A mapping on AREG mRNA), METTL3 knockdown/overexpression, miR-33a-3p mimic/inhibitor, mRNA stability assays, rescue experiments, migration/invasion assays Scientific reports High 37604948
2011 Small molecule inhibitors targeting the COX/AREG/EGFR/ERK autocrine loop (including COX inhibitors, EGFR inhibitors, and MEK/ERK inhibitors) attenuate CMV-induced salivary gland dysplasia, and ERK phosphorylation is required for initial mCMV-induced pathogenesis; this positions AREG as a critical node in CMV-triggered proliferative signaling. Mouse postnatal salivary gland organ culture model of mCMV infection, pathway-specific small molecule inhibitors (COX inhibitors, EGFR inhibitors, ERK inhibitors), ERK phosphorylation assays Experimental and molecular pathology Medium 21565184

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. The New England journal of medicine 2223 25184630
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2002 Androgen receptor (AR) coregulators: an overview. Endocrine reviews 706 11943742
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell 610 16713569
1989 Structure and function of human amphiregulin: a member of the epidermal growth factor family. Science (New York, N.Y.) 550 2466334
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 Plasma AR and abiraterone-resistant prostate cancer. Science translational medicine 385 26537258
2009 YAP-dependent induction of amphiregulin identifies a non-cell-autonomous component of the Hippo pathway. Nature cell biology 356 19935651
1990 The amphiregulin gene encodes a novel epidermal growth factor-related protein with tumor-inhibitory activity. Molecular and cellular biology 356 2325643
1988 Amphiregulin: a bifunctional growth-modulating glycoprotein produced by the phorbol 12-myristate 13-acetate-treated human breast adenocarcinoma cell line MCF-7. Proceedings of the National Academy of Sciences of the United States of America 330 3413110
2011 Amphiregulin exosomes increase cancer cell invasion. Current biology : CB 285 21514161
2003 TACE cleavage of proamphiregulin regulates GPCR-induced proliferation and motility of cancer cells. The EMBO journal 283 12743035
2008 AR, the cell cycle, and prostate cancer. Nuclear receptor signaling 270 18301781
2014 Amphiregulin. Seminars in cell & developmental biology 257 24463227
2000 Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing. The Journal of cell biology 246 11038170
1999 The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 238 10490105
1991 A heparin sulfate-regulated human keratinocyte autocrine factor is similar or identical to amphiregulin. Molecular and cellular biology 235 2017164
2011 The multiple roles of amphiregulin in human cancer. Biochimica et biophysica acta 225 21658434
1997 Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. The Journal of clinical investigation 183 9410906
2013 Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver. Oncogene 180 23873027
2008 Diverse roles of androgen receptor (AR) domains in AR-mediated signaling. Nuclear receptor signaling 176 18612376
2005 Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology 165 15685553
2019 Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands. Journal of medicinal chemistry 162 31804827
1996 The epidermal growth factor receptor couples transforming growth factor-alpha, heparin-binding epidermal growth factor-like factor, and amphiregulin to Neu, ErbB-3, and ErbB-4. The Journal of biological chemistry 153 8702723
2003 Tobacco smoke-induced lung cell proliferation mediated by tumor necrosis factor alpha-converting enzyme and amphiregulin. The Journal of biological chemistry 151 12711607
1990 Structure, expression and function of a schwannoma-derived growth factor. Nature 149 2234093
2017 AR Signaling and the PI3K Pathway in Prostate Cancer. Cancers 140 28420128
2012 Androgen receptor (AR) aberrations in castration-resistant prostate cancer. Molecular and cellular endocrinology 135 22245783
1999 Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells. International journal of cancer 133 10389762
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
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