Affinage

HBEGF

Proheparin-binding EGF-like growth factor · UniProt Q99075

Length
208 aa
Mass
23.1 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HBEGF encodes a dual-form EGFR ligand that exists as a membrane-anchored precursor (proHB-EGF) and a proteolytically shed soluble form, and these two forms drive opposing cellular programs across morphogenesis, tissue repair, and cancer (PMID:15289334, PMID:14996914). Membrane-anchored proHB-EGF localizes to cell-cell contacts in a complex with the tetraspanin CD9 and integrin α3β1, where CD9 upregulates its juxtacrine activity, and its heparin-binding domain anchors it at contact sites through trans interaction with heparan sulfate proteoglycans; disrupting this interaction promotes proteolytic release and switches behavior from juxtacrine growth inhibition to autocrine proliferation (PMID:7790364, PMID:9514697, PMID:20530570). Ectodomain shedding is executed by metalloproteases—ADAM12 in cardiomyocytes, ADAM17/TACE downstream of GPCRs, and MMP-7/MMP2/MMP9 in epithelial and cancer contexts—and is triggered by GPCR agonists (estrogen via GPR30, angiotensin II, 5-HT2A), mechanical stretch, wounding, and hypoxia/Notch signaling, with ERK1/2 feeding back to phosphorylate and activate ADAM17 (PMID:11043579, PMID:11786904, PMID:16737974, PMID:18658095, PMID:19237431, PMID:23589494). Soluble HB-EGF transactivates EGFR to engage ERK and PI3K/Akt cascades, driving cardiac valve morphogenesis through suppression of BMP/Smad signaling, eyelid and corneal epithelial closure, intestinal restitution, glucose-stimulated β-cell proliferation via ChREBP-driven transcription, and angiogenesis through a PI3K/eNOS axis (PMID:12773386, PMID:14985295, PMID:16141218, PMID:16083716, PMID:18092233, PMID:18925469, PMID:31882563). In disease, soluble HB-EGF promotes tumorigenesis, EMT via Snail-2, and EGFR-dependent invadopodium formation, can initiate glioblastoma through coordinated EGFR and Axl activation, and mediates inflammatory tissue protection and regeneration including ILC3- and astrocyte-derived epithelial/CNS protection and zebrafish spinal cord regeneration (PMID:15289334, PMID:19244405, PMID:24013225, PMID:28368403, PMID:35102343, PMID:37567873, PMID:38409259). HBEGF expression is controlled transcriptionally (ChREBP, BHLHE40) and post-transcriptionally (miR-1207-5p, miR-96 acting on its 3'UTR) (PMID:22319602, PMID:25451232, PMID:31882563, PMID:30285805).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1995 High

    Established that the membrane-anchored precursor is not merely a latent ligand reservoir but a structured signaling unit at cell-cell contacts, defining its juxtacrine context.

    Evidence Co-IP, chemical cross-linking, and colocalization of proHB-EGF with CD9 and integrin α3β1 in Vero/A431/MG63 cells

    PMID:7790364

    Open questions at the time
    • Functional consequence of the CD9/integrin complex for signaling not resolved here
    • Stoichiometry and structure of the complex undefined
  2. 1998 Medium

    Mapped which tetraspanin partner and which protein domains confer juxtacrine mitogenic enhancement, distinguishing CD9 from related tetraspanins.

    Evidence Chimeric CD9/CD81 cotransfection in LM cells with diphtheria toxin receptor functional readout

    PMID:9514697

    Open questions at the time
    • Single lab
    • Mechanism by which the CD9 C-terminal region enhances activity unknown
  3. 2002 High

    Defined HB-EGF shedding as the mechanistic link in GPCR-to-EGFR transactivation across multiple receptors, converting diverse extracellular cues into EGFR signaling.

    Evidence Estrogen/GPR30, angiotensin II, and TGF-β systems using HB-EGF-AP shedding reporters, CRM-197, neutralizing antibodies, and EGFR/MMP/PKC inhibitors

    PMID:11043579 PMID:11737589 PMID:12164862

    Open questions at the time
    • Specific protease assignments varied by stimulus
    • In vivo relevance of individual GPCR-driven shedding events not fully established
  4. 2002 High

    Identified ADAM12 as the physiological sheddase coupling GPCR agonists to EGFR transactivation in cardiomyocyte hypertrophy, providing the first defined protease-ligand-receptor cardiac axis.

    Evidence Dominant-negative ADAM12, direct KB-R7785 binding, in vivo cardiac hypertrophy model

    PMID:11786904

    Open questions at the time
    • Whether ADAM12 is the sole sheddase in heart not excluded
    • Direct demonstration of HB-EGF as the only relevant ADAM12 substrate lacking
  5. 2003 High

    Demonstrated a developmental requirement: soluble HB-EGF activates EGFR to suppress BMP/Smad signaling during cardiac valvulogenesis, showing the genetic non-redundancy of the ligand.

    Evidence HB-EGF−/−, EGFR−/−, and TACE−/− knockout mice with convergent valve phenotype and pSmad1/5/8 staining

    PMID:12773386

    Open questions at the time
    • Direct biochemical link between EGFR activation and Smad suppression not delineated
    • Cell-type source of HB-EGF in valve not pinpointed
  6. 2004 High

    Distinguished the opposing functions of the two HB-EGF forms—soluble form is tumorigenic and pro-migratory while membrane form promotes adhesion and inhibits migration—establishing form-specific biology.

    Evidence Inducible and stable expression of soluble vs noncleavable proHB-EGF in bladder cancer and MDCK cells; xenograft, colony, migration, and adhesion assays

    PMID:14996914 PMID:15289334

    Open questions at the time
    • Molecular basis of membrane-form growth inhibition not fully resolved
    • Single-cell-line dependence of some readouts
  7. 2005 High

    Showed HB-EGF drives epithelial wound closure and restitution through EGFR-ERK and PI3K/Akt, defining the effector cascades for tissue repair.

    Evidence Corneal/eyelid wound models with HB-EGF null and secretion-deficient mice, EGFR hypomorphs, and intestinal I/R with pathway inhibitors

    PMID:14985295 PMID:16083716 PMID:16141218

    Open questions at the time
    • Relative contribution of ERK vs PI3K branches tissue-dependent
    • Identity of sheddase in each wound context not uniformly defined
  8. 2006 Medium

    Extended the sheddase repertoire to TACE/ADAM17 and MMP-7 for specific GPCR and bile-acid stimuli, showing protease usage is stimulus- and tissue-specific.

    Evidence TACE siRNA and Co-IP with HB-EGF in mesangial cells; MMP-7 siRNA/neutralizing antibody and colocalization in colon cancer cells

    PMID:16737974 PMID:17222808

    Open questions at the time
    • Single lab per system
    • Direct cleavage by these proteases not reconstituted biochemically
  9. 2008 High

    Revealed a feedback loop in which ERK1/2 phosphorylates and activates ADAM17, amplifying HB-EGF shedding and EGFR transactivation.

    Evidence MEK inhibitors, HB-EGF-AP shedding assay, ERK-ADAM17 Co-IP and serine phosphorylation in corneal epithelial cells

    PMID:18658095

    Open questions at the time
    • Phosphosite mapping incomplete
    • Generality beyond corneal epithelium untested
  10. 2009 Medium

    Defined how proHB-EGF is retained at contacts and how its release is gated, linking heparan sulfate binding to the juxtacrine-to-autocrine switch.

    Evidence Dual-domain tracking, heparin/HSPG disruption, and proliferation/wound assays; integrin/FAK masking of HB-EGF growth activity in 2D vs 3D

    PMID:19887590 PMID:20530570

    Open questions at the time
    • Single lab
    • In vivo relevance of HSPG-mediated retention not demonstrated
  11. 2009 Medium

    Connected HB-EGF to EMT and mechanotransduction-driven differentiation, broadening its program beyond proliferation.

    Evidence sHB-EGF overexpression with Snail-2 knockdown in renal cells; AP-tagged HB-EGF shedding under cyclic stretch in fetal type II cells

    PMID:19237431 PMID:19244405

    Open questions at the time
    • Single lab
    • Receptor-level coupling to Snail-2 induction not mapped
  12. 2013 Medium

    Placed HB-EGF at the center of cancer invasion machinery, linking hypoxia/Notch-induced ADAM12 shedding and autocrine EGFR signaling to invadopodium formation.

    Evidence Hypoxia/Notch manipulation, ADAM12 activity, and invadopodium assays in cancer cells; autocrine HB-EGF overexpression and EGFR inhibition with in vivo intravasation

    PMID:23589494 PMID:24013225

    Open questions at the time
    • Single lab per study
    • Quantitative contribution to metastasis in vivo limited
  13. 2015 Medium

    Profiled selective ADAM12 inhibition and Abl-mediated negative regulation of the HB-EGF autocrine loop, identifying therapeutic targeting and regulatory nodes.

    Evidence Recombinant ADAM12 prodomain selectivity profiling and migration assay; imatinib-induced HB-EGF shedding and EGFR-Src-cortactin cascade in HNSCC

    PMID:23146907 PMID:26477568

    Open questions at the time
    • High-affinity HB-EGF predicted hard to target by decoys
    • Single lab per study
  14. 2017 Medium

    Showed HB-EGF can act as a tumor initiator through coordinated activation of EGFR and the RTK Axl, with EGFR upstream of Axl.

    Evidence In vivo GBM model with Ink4a/Arf and Pten loss, conditional EGFR/Axl deletion, in vivo HBEGF silencing

    PMID:28368403

    Open questions at the time
    • Mechanism of EGFR-dependent Axl activation undefined
    • Single model system
  15. 2018 High

    Established the regulatory inputs controlling HBEGF gene expression, both transcriptional (ChREBP, BHLHE40 via HDAC blockade) and post-transcriptional (miR-1207-5p, miR-96), linking nutrient and oncogenic signals to ligand abundance.

    Evidence ChREBP and BHLHE40 ChIP/Co-IP with islet and breast cancer functional assays; luciferase 3'UTR reporters and miRNA mimics in podocytes and osteoblasts

    PMID:22319602 PMID:25451232 PMID:30285805 PMID:31882563

    Open questions at the time
    • Interplay among these regulators untested
    • Tissue-specificity of each control mechanism partially defined
  16. 2019 High

    Identified immune- and stroma-derived HB-EGF as a driver of tissue repair and pathology, including myeloid HB-EGF promoting DNA repair via EGFR nuclear translocation and macrophage HB-EGF driving fibroblast invasiveness.

    Evidence Conditional myeloid Hbegf KO with H4 methylation/DNA repair assays in pancreatitis; scRNA-seq and ex vivo EGFR-inhibition assays in rheumatoid arthritis synovium

    PMID:31068444 PMID:31125624

    Open questions at the time
    • Mechanism of EGFR nuclear translocation incompletely defined
    • Direct sheddase in immune contexts not specified
  17. 2020 Medium

    Expanded the receptor and partner network, showing APP physically binds proHB-EGF and synergizes with EGF in neuritogenesis, and that TMPRSS4 amplifies both HB-EGF precursor levels and its cleavage in HCC.

    Evidence Yeast two-hybrid and Co-IP for APP-proHB-EGF with EGFR-dependent neurite assays; TMPRSS4 gain/loss with MMP9 and EGFR/PI3K/Akt readouts in HCC

    PMID:31867749 PMID:33009641

    Open questions at the time
    • Functional significance of APP interaction in vivo unknown
    • Single lab per study
  18. 2022 High

    Defined protective and pathogenic context-dependent roles of HB-EGF in mucosal and neural tissue, from ILC3-derived epithelial protection to PIEZO1-coupled photoreceptor extrusion.

    Evidence ILC3-specific Hbegf conditional KO with TNF-injury models; human retinal organoid HBEGF+TNF treatment with PIEZO1/MAPK/actomyosin inhibitors

    PMID:35102343 PMID:36261438

    Open questions at the time
    • Receptor coupling for ILC3-derived protection not fully mapped
    • Organoid extrusion mechanism single study
  19. 2024 High

    Demonstrated regenerative and immunoprotective HB-EGF functions in the CNS, with ependymal HB-EGF required for spinal cord regeneration and astrocyte-derived HB-EGF limiting autoimmune pathology.

    Evidence hb-egfa zebrafish mutants with recombinant rescue and TREE characterization in mouse; CSF proteomics and intranasal HB-EGF in EAE

    PMID:37567873 PMID:38409259

    Open questions at the time
    • Downstream effector pathways in regeneration not detailed
    • Epigenetic control of astrocyte HB-EGF only partially characterized

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the choice between juxtacrine proHB-EGF signaling and autocrine/paracrine soluble HB-EGF signaling is integrated at the level of a single cell—and which sheddase dominates in each physiological context in vivo—remains unresolved.
  • No unified model of context-specific sheddase selection in vivo
  • Structural basis of the proHB-EGF/CD9/integrin complex undefined
  • Quantitative balance between membrane-form inhibition and soluble-form activation not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0060089 molecular transducer activity 4 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3
Partners
ADAM12ADAM17APPAXLCD9EGFRITGA3MMP7
Complex memberships
proHB-EGF/CD9/integrin α3β1 complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Membrane-anchored proHB-EGF forms a complex with the tetraspanin DRAP27/CD9 and integrin α3β1 at cell-cell contact sites, as demonstrated by co-immunoprecipitation, chemical cross-linking, and double-immunofluorescence colocalization in Vero, A431, and MG63 cells. Co-immunoprecipitation, chemical cross-linking, double-immunofluorescence microscopy The Journal of cell biology High 7790364
1997 CD9, but not CD81 or CD82, upregulates the juxtacrine mitogenic activity of transmembrane proHB-EGF as a diphtheria toxin receptor; chimeric CD9/CD81 molecules mapped this activity to the second half of CD9 (large extracellular loop, fourth TM domain, and C-terminal cytoplasmic domain). Cotransfection of chimeric CD9/CD81 constructs in murine LM cells, diphtheria toxin receptor functional assay Cellular immunology Medium 9514697
2000 Estrogen-induced ERK1/2 activation requires GPR30-dependent transactivation of the EGF receptor via release of HB-EGF; this was blocked by neutralizing HB-EGF antibodies or by down-modulating HB-EGF from the cell surface with the diphtheria toxin mutant CRM-197, and required Src-related tyrosine kinase activity and Shc-pY317 phosphorylation. Neutralizing antibody treatment, CRM-197 cell-surface depletion, EGFR kinase inhibition, GPR30 cDNA transfection, immunoblot for pERK Molecular endocrinology (Baltimore, Md.) High 11043579
2002 ADAM12 is the metalloprotease responsible for shedding HB-EGF in cardiomyocytes in response to GPCR agonists; dominant-negative ADAM12 expression abrogated shedding-dependent EGFR transactivation and cardiac hypertrophy, and the metalloprotease inhibitor KB-R7785 bound directly to ADAM12. ADAM12 cloning, dominant-negative expression, metalloprotease inhibitor (KB-R7785) direct binding, in vivo cardiac hypertrophy model Nature medicine High 11786904
2002 HB-EGF shedding via metalloprotease (MMP) and subsequent EGFR transactivation is required for Angiotensin II-induced fibronectin expression in mesangial cells; ALP-tagged HB-EGF chimera directly measured rapid HB-EGF release (~4-fold within 2 min of Ang II), blocked by PKC inhibitors or MMP inhibitor batimastat. HB-EGF-alkaline phosphatase chimera shedding assay, neutralizing anti-HB-EGF antibody, EGFR inhibitor AG1478, heparin blocking, batimastat MMP inhibition Kidney international High 11737589
2002 Helicobacter pylori triggers EGFR tyrosine phosphorylation via HB-EGF gene induction and metalloprotease-dependent ectodomain shedding (the 'triple membrane passing signal'); this signaling also enhances IL-8 secretion. EGFR phosphorylation assay, HB-EGF gene expression analysis, metalloprotease inhibition, EGFR and MEK1 inhibitors Biochemical and biophysical research communications Medium 12099696
2002 TGF-β mediates fibronectin expression in mesangial cells via PC-PLC/PKC-dependent metalloprotease-mediated HB-EGF release and subsequent EGFR transactivation; Smad2 phosphorylation by TGF-β was unaffected by EGFR inhibition, and HB-EGF did not activate Smad2, indicating a parallel pathway. HB-EGF-alkaline phosphatase chimera shedding assay, neutralizing anti-HB-EGF antibody, AG1478, PKC inhibitors, batimastat, FN mRNA quantification Kidney international High 12164862
2003 HB-EGF null mice exhibit enlarged, malformed cardiac valves due to abnormal mesenchymal cell proliferation during remodeling, associated with increased activated Smad1/5/8; similar defects occur in EGFR- and TACE-null mice, establishing that TACE-derived soluble HB-EGF activates EGFR to suppress BMP signaling during cardiac valvulogenesis. Homologous recombination knockout mice, genetic epistasis (HB-EGF−/−, EGFR−/−, TACE−/−), immunohistochemistry for pSmad1/5/8, histological analysis The EMBO journal High 12773386
2004 Wound-induced MMP-dependent ectodomain shedding of HB-EGF acts as an autocrine/paracrine EGFR ligand in corneal epithelial wound closure; wound-induced EGFR and ERK phosphorylation were blocked by CRM-197 (HB-EGF antagonist), HB-EGF function-blocking antibodies, and MMP inhibitor GM6001, with direct HB-EGF shedding demonstrated by HB-EGF-AP reporter. HB-EGF-alkaline phosphatase shedding assay, CRM-197, neutralizing HB-EGF antibodies, GM6001 MMP inhibitor, AG1478 EGFR inhibitor, immunoprecipitation + Western blot Investigative ophthalmology & visual science High 14985295
2004 Soluble HB-EGF, but not pro-HB-EGF (membrane-only form), confers tumorigenic properties including enhanced growth, colony formation, cell migration, cyclin D1 activation, VEGF induction, and MMP-9/MMP-3 upregulation in bladder cancer cells in vitro and in vivo. Tetracycline-regulatable expression system, soft agar colony assay, xenograft nude mouse tumorigenesis, zymography for MMP activity Cancer research High 15289334
2004 Membrane-anchored (noncleavable) HB-EGF promotes cell-matrix and cell-cell interactions and decreases migration and HGF-induced scattering in MDCK cells, while soluble HB-EGF has the opposite effects, demonstrating that the two forms of HB-EGF have distinctly different functional consequences. Stable transfection of proHB-EGF, noncleavable deletion mutant, or soluble HB-EGF in MDCK cells; migration, scattering, tubulogenesis, and adhesion assays Journal of cell science Medium 14996914
2004 HB-EGF directs stromal cell polyploidy and decidualization via upregulation of cyclin D3; adenoviral antisense delivery of cyclin D3 abrogated HB-EGF-induced polyploidy both in vitro and in vivo. Adenoviral antisense cyclin D3 delivery, BrdU labeling, flow cytometry, in vivo uterine decidualization model Developmental biology Medium 14697362
2005 HB-EGF promotes eyelid closure by activating EGFR-ERK signaling at the leading edge of migrating epithelium; HB-EGF null and secretion-deficient mutant mice show delayed eyelid closure with reduced actin bundle formation; genetic interaction with hypomorphic EGFR (waved-2) confirmed; TGFα acts synergistically and equally. HB-EGF null mouse KO, secretion-deficient knock-in (HB-uc/uc), EGFR kinase inhibitor in vivo, double null crosses (HB-EGF × TGFα), pEGFR and pERK immunostaining Development (Cambridge, England) High 16141218
2005 HB-EGF enhances intestinal restitution via PI3K/Akt and MEK/ERK1/2 signaling downstream of ErbB-1; blocking ErbB-1, PI3K/Akt, or MEK/ERK significantly reduced intrinsic and HB-EGF-induced restitution in vitro, and endogenous HB-EGF was shown to be essential for wound-induced ErbB-1 and ERK1/2 activation. Intestinal I/R model in rats, scrape wound assay in vitro, pharmacological inhibitors of ErbB-1/PI3K/MEK, CRM-197 HB-EGF blockade, immunoblot for pAkt and pERK Gastroenterology Medium 16083716
2006 5-HT2A receptor induces ERK phosphorylation and cellular proliferation via TACE (ADAM17) activation, HB-EGF shedding, and EGFR transactivation in mesangial cells; TACE was co-immunoprecipitated with HB-EGF, and TACE siRNA blocked HB-EGF shedding, ERK phosphorylation, and DNA content increase. TACE siRNA knockdown, neutralizing HB-EGF antibody, EGFR inhibitor AG1478, MMP inhibitors, co-immunoprecipitation of TACE with HB-EGF, DNA content measurement The Journal of biological chemistry High 16737974
2006 MMP-7 catalyzes release of HB-EGF to mediate bile acid (deoxycholyltaurine)-induced EGFR transactivation and colon cancer cell proliferation; MMP-7 and proHB-EGF co-localize at the cell surface, and specific MMP-7 knockdown (neutralizing antibody or siRNA) attenuated DCT-induced signaling and proliferation. MMP-7 siRNA, neutralizing antibody to MMP-7, CRM-197 HB-EGF inhibitor, EGFR ligand-domain antibody, immunofluorescence colocalization, qRT-PCR for MMP-7 Biochemical pharmacology Medium 17222808
2007 HB-EGF promotes angiogenesis (migration and tube formation) in HUVEC via activation of PI3K, MAPK, and eNOS pathways, in a VEGF-independent manner. Scratch wound migration assay, 2D tube formation assay, pharmacological inhibitors of PI3K, MAPK, eNOS Growth factors (Chur, Switzerland) Medium 18092233
2008 ERK1/2 mediates ADAM-dependent HB-EGF shedding and EGFR transactivation in corneal epithelial cells in response to wounding and GPCR ligands; ADAM17 was co-immunoprecipitated with active ERK and phosphorylated at serine residues in an ERK-dependent manner. MEK inhibitors PD98059/U0126, HB-EGF-AP shedding assay, co-immunoprecipitation of ERK with ADAM17, immunoprecipitation + Western blot for serine phosphorylation of ADAM17 Investigative ophthalmology & visual science High 18658095
2008 HB-EGF stimulates eNOS expression and NO production in endothelial cells via a PI3K-dependent pathway; eNOS siRNA and eNOS-specific inhibitors abolished HB-EGF-induced HUVEC migration and angiogenesis in vitro and in vivo (Matrigel plug assay). eNOS siRNA knockdown, L-NAME/L-NIO pharmacological eNOS inhibitors, PI3K inhibitor, Matrigel plug in vivo angiogenesis, Western blot for eNOS protein/phosphorylation Growth factors (Chur, Switzerland) Medium 18925469
2009 The heparin-binding domain of transmembrane proHB-EGF mediates localization to cell-cell contact sites via trans interaction with extracellular heparan sulfate proteoglycans (HSPGs); disruption of this interaction increases proteolytic release of soluble ligand and switches cell behavior from juxtacrine growth inhibition to autocrine proliferation. Independent tracking of extracellular EGF domain and cytoplasmic C-terminus with new labeling method, heparin treatment, HSPG disruption experiments, wound-closure assay, proliferation assays Journal of cell science Medium 20530570
2009 Soluble HB-EGF induces epithelial-to-mesenchymal transition (EMT) in renal collecting duct cells by upregulating the E-cadherin transcriptional repressor Snail-2; stable Snail-2 knockdown restored epithelial markers but not anchorage-independent growth. Stable overexpression of sHB-EGF, qRT-PCR and luciferase reporter for E-cadherin transcription, stable shRNA knockdown of Snail-2, Western blot for epithelial/mesenchymal markers American journal of physiology. Renal physiology Medium 19244405
2009 Mechanical stretch promotes fetal type II epithelial cell differentiation via ectodomain shedding of HB-EGF and TGF-α; 5% cyclic stretch of E19 fetal cells transfected with AP-tagged HB-EGF directly measured HB-EGF release, which was not enhanced by fibroblast co-culture. AP-tagged HB-EGF shedding assay under cyclic stretch, SP-B/C mRNA and protein measurement, recombinant HB-EGF/TGFα/amphiregulin/BTC/EPR comparison The Journal of physiology Medium 19237431
2009 Integrin/FAK signaling masks HB-EGF's growth-promoting activity in standard 2D monolayer culture; reducing integrin β1 or FAK by antibody or genetic knockout revealed HB-EGF-dependent cell growth; HB-EGF-driven growth was clearly demonstrated in 3D culture or when integrin signaling was attenuated. Integrin β1 antibody blocking, FAK knockout, 3D culture system, xenograft tumor growth comparison Journal of cell science Medium 19887590
2011 HB-EGF induces cardiomyocyte hypertrophy via an EGFR-MEK5-ERK5-MEF2A-COX-2 signaling pathway; MEK5 siRNA reduced HB-EGF-induced cell size and ANF mRNA expression, MEF2A siRNA attenuated COX-2 induction, and COX-2 inhibitor rofecoxib reduced ANF expression. MEK5 siRNA, MEF2A siRNA, COX-2 inhibitor rofecoxib, AG1478 EGFR inhibitor, [3H]-leucine incorporation, ANF mRNA measurement Cellular signalling Medium 21244855
2011 LIV-1 overexpression promotes EMT in prostate cancer cells via MMP2/MMP9-mediated shedding of HB-EGF, causing constitutive EGFR phosphorylation and downstream ERK signaling. LIV-1 overexpression, zymography for MMP2/MMP9 activity, EGFR phosphorylation by Western blot, ERK activation assay PloS one Low 22110740
2012 miR-1207-5p directly regulates HBEGF expression in podocytes via its 3'UTR; a miRSNP C1936T at position 2 of the seed region abolishes this regulation, as shown by luciferase reporter assay and western blot with miRNA mimics. Luciferase reporter assay with 3'UTR construct, miRNA mimic transfection, Western blot for HBEGF protein in podocytes PloS one Medium 22319602
2013 Hypoxia increases ADAM12 levels and activity in a Notch signaling-dependent manner, leading to increased HB-EGF ectodomain shedding; released HB-EGF induces invadopodium formation in cancer cells, linking Notch and EGFR pathways in promoting invasion. Hypoxia treatment, Notch pathway manipulation, ADAM12 activity assay, HB-EGF shedding measurement, invadopodium formation assay The Journal of cell biology Medium 23589494
2013 Autocrine HB-EGF expression in breast cancer cells enhances invadopodium formation and function via EGFR signaling, and upregulates MMP2 and MMP9; HB-EGF inhibition rapidly decreased invadopodia, demonstrating direct EGFR-dependent mechanism. HB-EGF overexpression, EGFR inhibition, in vivo intravasation assay, MMP2/9 expression analysis, invadopodium formation assay Oncogene Medium 24013225
2014 miR-96 promotes osteogenic differentiation by suppressing HB-EGF post-transcriptionally via binding to the 3'UTR of HB-EGF mRNA, thereby reducing EGFR and ERK1/AKT phosphorylation downstream. miR-96 overexpression in MC3T3-E1 cells, 3'UTR binding assay, Western blot for HB-EGF/pEGFR/pERK1/pAKT, osteogenic differentiation markers FEBS letters Medium 25451232
2014 HB-EGF promotes intestinal epithelial cell migration and adhesion via FAK phosphorylation; HB-EGF increased p-FAK expression and induced FAK redistribution and actin reorganization, and FAK inhibitor reversed HB-EGF-induced migration and adhesion. Scrape wound healing assay, FAK inhibitor 14, immunofluorescence for p-FAK redistribution, Western blot, fibronectin adhesion assay The Journal of surgical research Medium 24703506
2015 In head and neck squamous cell carcinoma, Abl kinases negatively regulate invadopodia through suppression of an HB-EGF autocrine loop; imatinib stimulated HB-EGF shedding from HNSCC cells, and soluble HB-EGF enhanced invadopodia ECM degradation via an EGFR-Src-cortactin cascade. Imatinib treatment, HB-EGF shedding measurement, Abl/Arg siRNA, invadopodium formation and ECM degradation assays, EGFR/Src inhibitors Oncogene Medium 23146907
2015 Recombinant ADAM12 prodomain (PA12) selectively inhibits ADAM12 but not ADAM10 or ADAM17, reducing HB-EGF shedding and cellular migration in endometriotic cells; computational modeling predicted that high-affinity ligands like HB-EGF are more difficult to target with decoy antibodies than low-affinity ligands. Recombinant ADAM12 prodomain protein, HB-EGF shedding assay, selectivity profiling against ADAM10/17, cell migration assay, computational modeling Scientific reports Medium 26477568
2017 HBEGF can initiate glioblastoma in mice with Ink4a/Arf and Pten loss; HBEGF stimulation activates both EGFR and the RTK Axl, and EGFR is required for Axl activation; silencing HBEGF in vivo caused tumor regression. In vivo mouse GBM model, EGFR/Axl conditional deletion, in vivo HBEGF silencing with survival analysis Oncogene Medium 28368403
2018 HB-EGF gene expression in β-cells is increased by glucose in a ChREBP-dependent manner; ChREBP binding sites near the HB-EGF gene were identified by ChIP; HB-EGF knockdown in rat islets blocked glucose-induced β-cell proliferation ex vivo and in vivo; Src family kinase inhibition abrogated glucose-induced proliferation, implicating Src in HB-EGF processing. HB-EGF siRNA knockdown in isolated islets, transplanted glucose-infused rats, ChREBP ChIP, EGFR and HB-EGF inhibitors, Src kinase inhibitors, β-cell proliferation assay Diabetes High 31882563
2018 BHLHE40 induces HBEGF transcription by blocking DNA binding of HDAC1 and HDAC2, as shown by ChIP and Co-IP assays; HBEGF is then secreted through exosomes to promote cell survival and migration. ChIP assay, Co-IP of BHLHE40 with HDAC1/2, exosome analysis, HBEGF knockdown, migration/survival assays, xenograft and experimental metastasis models Breast cancer research : BCR Medium 30285805
2019 Myeloid cell-derived HB-EGF induces epithelial EGFR nuclear translocation and methylation of histone H4 to facilitate DNA damage repair in pancreatic acinar cells; conditional knockout of HB-EGF in myeloid cells (LysM-Cre) delayed recovery from pancreatitis with impaired DNA repair and increased apoptosis. Conditional myeloid-specific Hbegf KO (LysM-Cre), myeloid cell depletion (CD11b-DTR), EGFR conditional KO in pancreatic epithelium, H4 methylation immunostaining, DNA damage assays, cell proliferation/apoptosis measurements Cellular and molecular gastroenterology and hepatology High 31125624
2019 s-HBEGF released from sorafenib-treated vascular endothelial cells activates EGFR on keratinocytes and promotes JNK2-mediated SIRT1 stabilization, driving hyper-keratinization; HBEGF neutralization, SIRT1 knockdown, or nicotinamide (SIRT1 inhibitor) all reduced sorafenib-induced hand-foot skin reaction in mouse models. In vivo mouse HFSR model, s-HBEGF administration, HBEGF neutralization antibody, SIRT1 siRNA knockdown, nicotinamide treatment, pJNK2 and SIRT1 Western blot, preliminary clinical study Cell research Medium 32296111
2019 HBEGF+ inflammatory macrophages in rheumatoid arthritis promote fibroblast invasiveness in an EGF receptor-dependent manner; this cross-talk is shaped by resident fibroblasts and TNF. Single-cell RNA sequencing, ex vivo synovial tissue assay with EGFR pathway inhibition, functional invasiveness assays Science translational medicine Medium 31068444
2020 TMPRSS4 increases both transcriptional/translational levels of HB-EGF precursor and promotes its proteolytic cleavage by enhancing MMP9 expression via EGFR/Akt/mTOR/HIF-1α signaling; HB-EGF in turn promotes HCC proliferation and invasion via EGFR/PI3K/Akt pathway. TMPRSS4 overexpression/knockdown, MMP9 activity assay, EGFR/Akt/mTOR pathway inhibitors, CRM-197 HB-EGF inhibitor, in vivo xenograft model Hepatology (Baltimore, Md.) Medium 31867749
2020 APP interacts with pro-HB-EGF (identified in yeast two-hybrid screen and confirmed by co-immunoprecipitation); APP and EGF synergistically activate ERK signaling and promote neuritogenesis via EGFR, as shown by EGFR inhibitor PD 168393 abrogation. Yeast two-hybrid screen, co-immunoprecipitation, EGFR inhibitor, immunofluorescence neurite analysis, Western blot for pERK Molecular neurobiology Medium 33009641
2022 Group 3 innate lymphoid cells (ILC3s) produce HB-EGF in response to prostaglandin E2/EP2 receptor engagement; ILC3-derived HB-EGF protects intestinal epithelium from TNF-induced cell death independently of IL-22; mice lacking ILC3-derived HB-EGF showed increased susceptibility to TNF-mediated epithelial death and experimental intestinal inflammation. Conditional HB-EGF KO in ILC3s (Hbegf f/f × ILC3-Cre), PGE2 stimulation assays, TNF-induced intestinal injury model, in vitro epithelial protection assays Nature immunology High 35102343
2022 Combined TNF and HBEGF treatment in human retinal organoids induces photoreceptor neurodegeneration via a previously unknown cell extrusion mechanism; pharmacological inhibitors of PIEZO1 (mechanosensor), MAPK, and actomyosin each prevented pathogenesis, and a PIEZO1 activator alone induced photoreceptor extrusion. Human retinal organoid system, combined HBEGF+TNF treatment, PIEZO1 pharmacological activation and inhibition, MAPK/actomyosin inhibitors, live imaging, transcriptome analysis Nature communications Medium 36261438
2023 Hb-egfa produced by ependymal cells is required for spinal cord regeneration in zebrafish; hb-egfa mutants show defective axon crossing, tissue bridging, and swim recovery after transection; local recombinant HB-EGF delivery alters ependymal cell cycling and enhances functional regeneration; a tissue regeneration enhancer element (TREE) linked to hb-egfa drives gene expression specifically at spinal cord injuries. hb-egfa mutant zebrafish, recombinant HB-EGF delivery, epigenetic profiling for TREE identification, AAV-based enhancer-driven delivery in neonatal mouse spinal cord crush, BrdU/EdU cell cycling assays Nature communications High 37567873
2024 Astrocyte-derived HB-EGF limits autoimmune CNS pathology; hypoxic conditions rapidly upregulate HB-EGF in astrocytes, while pro-inflammatory conditions suppress HB-EGF signaling through epigenetic modifications; intranasal HB-EGF administration attenuated disease in a mouse EAE model. Proteomic analysis of CSF, in vitro cell type studies, epigenetic modification analysis of HB-EGF locus, intranasal HB-EGF delivery in EAE model Nature immunology Medium 38409259

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Molecular endocrinology (Baltimore, Md.) 1166 11043579
2002 Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapy. Nature medicine 606 11786904
2003 Defective valvulogenesis in HB-EGF and TACE-null mice is associated with aberrant BMP signaling. The EMBO journal 321 12773386
2003 Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice. Aging cell 314 12882410
1995 Membrane-anchored heparin-binding EGF-like growth factor (HB-EGF) and diphtheria toxin receptor-associated protein (DRAP27)/CD9 form a complex with integrin alpha 3 beta 1 at cell-cell contact sites. The Journal of cell biology 234 7790364
2019 HBEGF+ macrophages in rheumatoid arthritis induce fibroblast invasiveness. Science translational medicine 205 31068444
2004 HB-EGF is a potent inducer of tumor growth and angiogenesis. Cancer research 177 15289334
2004 ADAM-mediated ectodomain shedding of HB-EGF in receptor cross-talk. Biochimica et biophysica acta 136 16054021
1997 Functional analysis of four tetraspans, CD9, CD53, CD81, and CD82, suggests a common role in costimulation, cell adhesion, and migration: only CD9 upregulates HB-EGF activity. Cellular immunology 128 9514697
2007 Validation of HB-EGF and amphiregulin as targets for human cancer therapy. Biochemical and biophysical research communications 126 18023415
2007 HB-EGF promotes angiogenesis in endothelial cells via PI3-kinase and MAPK signaling pathways. Growth factors (Chur, Switzerland) 124 18092233
2004 Wound-induced HB-EGF ectodomain shedding and EGFR activation in corneal epithelial cells. Investigative ophthalmology & visual science 124 14985295
2013 Notch increases the shedding of HB-EGF by ADAM12 to potentiate invadopodia formation in hypoxia. The Journal of cell biology 120 23589494
2006 ErbB and HB-EGF signaling in heart development and function. Cell structure and function 113 16508205
2002 Helicobacter pylori-stimulated EGF receptor transactivation requires metalloprotease cleavage of HB-EGF. Biochemical and biophysical research communications 106 12099696
2004 HB-EGF directs stromal cell polyploidy and decidualization via cyclin D3 during implantation. Developmental biology 99 14697362
2006 5-HT2A receptor induces ERK phosphorylation and proliferation through ADAM-17 tumor necrosis factor-alpha-converting enzyme (TACE) activation and heparin-bound epidermal growth factor-like growth factor (HB-EGF) shedding in mesangial cells. The Journal of biological chemistry 95 16737974
2005 HB-EGF enhances restitution after intestinal ischemia/reperfusion via PI3K/Akt and MEK/ERK1/2 activation. Gastroenterology 95 16083716
1999 Multiple trophic actions of heparin-binding epidermal growth factor (HB-EGF) in the central nervous system. The European journal of neuroscience 93 10510187
2011 LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling. PloS one 92 22110740
2002 Regulated expression of heparin-binding EGF-like growth factor (HB-EGF) in the human endometrium: a potential paracrine role during implantation. Molecular reproduction and development 90 12112577
2005 HB-EGF promotes epithelial cell migration in eyelid development. Development (Cambridge, England) 85 16141218
2013 Autocrine HBEGF expression promotes breast cancer intravasation, metastasis and macrophage-independent invasion in vivo. Oncogene 81 24013225
2002 Involvement of HB-EGF and EGF receptor transactivation in TGF-beta-mediated fibronectin expression in mesangial cells. Kidney international 80 12164862
2008 HBEGF, SRA1, and IK: Three cosegregating genes as determinants of cardiomyopathy. Genome research 79 19064678
2022 Group 3 innate lymphoid cells produce the growth factor HB-EGF to protect the intestine from TNF-mediated inflammation. Nature immunology 71 35102343
2006 Matrix metalloproteinase-7-catalyzed release of HB-EGF mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line. Biochemical pharmacology 66 17222808
2001 Angiotensin II signaling and HB-EGF shedding via metalloproteinase in glomerular mesangial cells. Kidney international 61 11737589
2022 HB-EGF induces mitochondrial dysfunction via estrogen hypersecretion in granulosa cells dependent on cAMP-PKA-JNK/ERK-Ca2+-FOXO1 pathway. International journal of biological sciences 60 35342363
2008 HB-EGF stimulates eNOS expression and nitric oxide production and promotes eNOS dependent angiogenesis. Growth factors (Chur, Switzerland) 60 18925469
2003 An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis. Blood 60 14576062
2000 Increased expression of heparin binding EGF (HB-EGF), amphiregulin, TGF alpha and epiregulin in androgen-independent prostate cancer cell lines. Anticancer research 60 10769639
2005 Heparin-binding EGF-like growth factor (HB-EGF) and necrotizing enterocolitis. Seminars in pediatric surgery 59 16084404
2008 ERK1/2 mediate wounding- and G-protein-coupled receptor ligands-induced EGFR activation via regulating ADAM17 and HB-EGF shedding. Investigative ophthalmology & visual science 58 18658095
2009 Diverse functions of HBEGF during pregnancy. Molecular reproduction and development 55 19565643
2007 Epidermal growth factor (EGF) receptor ligands in the chicken ovary: I. Evidence for heparin-binding EGF-like growth factor (HB-EGF) as a potential oocyte-derived signal to control granulosa cell proliferation and HB-EGF and kit ligand expression. Endocrinology 54 17395697
1998 Structure and function of heparin-binding EGF-like growth factor (HB-EGF). Frontiers in bioscience : a journal and virtual library 54 9473209
2018 BHLHE40 confers a pro-survival and pro-metastatic phenotype to breast cancer cells by modulating HBEGF secretion. Breast cancer research : BCR 53 30285805
2020 TMPRSS4 Drives Angiogenesis in Hepatocellular Carcinoma by Promoting HB-EGF Expression and Proteolytic Cleavage. Hepatology (Baltimore, Md.) 52 31867749
2013 Control of human endometrial stromal cell motility by PDGF-BB, HB-EGF and trophoblast-secreted factors. PloS one 47 23349855
2007 Injury and nucleotides induce phosphorylation of epidermal growth factor receptor: MMP and HB-EGF dependent pathway. Experimental eye research 47 17490650
2004 Membrane-associated HB-EGF modulates HGF-induced cellular responses in MDCK cells. Journal of cell science 45 14996914
2012 A miR-1207-5p binding site polymorphism abolishes regulation of HBEGF and is associated with disease severity in CFHR5 nephropathy. PloS one 44 22319602
2022 HBEGF-TNF induce a complex outer retinal pathology with photoreceptor cell extrusion in human organoids. Nature communications 43 36261438
2002 In vivo and in vitro evidence suggest that HB-EGF regulates endometrial expression of human decay-accelerating factor. The Journal of clinical endocrinology and metabolism 43 11889210
2013 HB-EGF affects astrocyte morphology, proliferation, differentiation, and the expression of intermediate filament proteins. Journal of neurochemistry 42 24188029
2005 Local overexpression of HB-EGF exacerbates remodeling following myocardial infarction by activating noncardiomyocytes. Laboratory investigation; a journal of technical methods and pathology 42 15856048
2003 Vanadium-induced HB-EGF expression in human lung fibroblasts is oxidant dependent and requires MAP kinases. American journal of physiology. Lung cellular and molecular physiology 42 12676768
2022 Identification of HBEGF+ fibroblasts in the remission of rheumatoid arthritis by integrating single-cell RNA sequencing datasets and bulk RNA sequencing datasets. Arthritis research & therapy 41 36068607
2014 miR-96 promotes osteogenic differentiation by suppressing HBEGF-EGFR signaling in osteoblastic cells. FEBS letters 41 25451232
2015 Cypermethrin Stimulates GSK3β-Dependent Aβ and p-tau Proteins and Cognitive Loss in Young Rats: Reduced HB-EGF Signaling and Downstream Neuroinflammation as Critical Regulators. Molecular neurobiology 38 25575682
2010 Metalloproteinase-mediated, context-dependent function of amphiregulin and HB-EGF in human keratinocytes and skin. The Journal of investigative dermatology 38 19609315
2001 HB-EGF is produced in the peritoneal cavity and enhances mesothelial cell adhesion and migration. Kidney international 38 11168942
2023 Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer. Nature communications 37 37567873
2020 SOX2 Promotes Brain Metastasis of Breast Cancer by Upregulating the Expression of FSCN1 and HBEGF. Molecular therapy oncolytics 37 32322668
2012 Ableson kinases negatively regulate invadopodia function and invasion in head and neck squamous cell carcinoma by inhibiting an HB-EGF autocrine loop. Oncogene 37 23146907
2019 HB-EGF Ameliorates Oxidative Stress-Mediated Uterine Decidualization Damage. Oxidative medicine and cellular longevity 35 31885807
2015 Pretreatment levels of the serum biomarkers CEA, CYFRA 21-1, SCC and the soluble EGFR and its ligands EGF, TGF-alpha, HB-EGF in the prediction of outcome in erlotinib treated non-small-cell lung cancer patients. SpringerPlus 35 25918681
2014 Synergistic effect of lung tumor-associated dendritic cell-derived HB-EGF and CXCL5 on cancer progression. International journal of cancer 35 24346967
2020 M2 macrophages reduce the radiosensitivity of head and neck cancer by releasing HB‑EGF. Oncology reports 34 32627036
2009 Integrin signal masks growth-promotion activity of HB-EGF in monolayer cell cultures. Journal of cell science 34 19887590
2008 High expression of heparanase is significantly associated with dedifferentiation and lymph node metastasis in patients with pancreatic ductal adenocarcinomas and correlated to PDGFA and via HIF1a to HB-EGF and bFGF. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract 33 18704599
2014 MiR-212 exerts suppressive effect on SKOV3 ovarian cancer cells through targeting HBEGF. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 32 25201063
2020 s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide. Cell research 31 32296111
2009 Mechanical stretch promotes fetal type II epithelial cell differentiation via shedding of HB-EGF and TGF-alpha. The Journal of physiology 31 19237431
1996 Measurement of regional cerebral plasma pool and hematocrit with copper-62-labeled HSA-DTS. Journal of nuclear medicine : official publication, Society of Nuclear Medicine 31 8965173
2024 The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology. Nature immunology 30 38409259
2010 The heparin-binding domain of HB-EGF mediates localization to sites of cell-cell contact and prevents HB-EGF proteolytic release. Journal of cell science 30 20530570
2019 Myeloid Cell-Derived HB-EGF Drives Tissue Recovery After Pancreatitis. Cellular and molecular gastroenterology and hepatology 29 31125624
2018 Heparin-binding epidermal growth factor (HB-EGF) drives EMT in patients with COPD: implications for disease pathogenesis and novel therapies. Laboratory investigation; a journal of technical methods and pathology 29 30451982
2018 Roles for HB-EGF in Mesenchymal Stromal Cell Proliferation and Differentiation During Skeletal Growth. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 29 30550637
2019 HB-EGF Signaling Is Required for Glucose-Induced Pancreatic β-Cell Proliferation in Rats. Diabetes 28 31882563
2022 Particulate matter promotes cancer metastasis through increased HBEGF expression in macrophages. Experimental & molecular medicine 27 36352257
2020 Estrogen deficiency induces memory loss via altered hippocampal HB-EGF and autophagy. The Journal of endocrinology 27 31648182
2018 Helicobacter pylori-Induced HB-EGF Upregulates Gastrin Expression via the EGF Receptor, C-Raf, Mek1, and Erk2 in the MAPK Pathway. Frontiers in cellular and infection microbiology 27 29379775
2006 Heparin-binding epidermal growth factor (HB-EGF) may improve embryonic development and implantation by increasing vitronectin receptor (integrin alphanubeta3) expression in peri-implantation mouse embryos. Journal of assisted reproduction and genetics 27 16622802
2006 Expression of HB-EGF by retinal pigment epithelial cells in vitreoretinal proliferative disease. Current eye research 27 17050278
2003 Upregulation of endogenous heparin-binding EGF-like growth factor (HB-EGF) expression after intestinal ischemia/reperfusion injury. Journal of investigative surgery : the official journal of the Academy of Surgical Research 27 12746188
2014 Heparin-binding EGF-like growth factor (HB-EGF) promotes cell migration and adhesion via focal adhesion kinase. The Journal of surgical research 26 24703506
2011 HB-EGF induces cardiomyocyte hypertrophy via an ERK5-MEF2A-COX2 signaling pathway. Cellular signalling 26 21244855
2012 Regulatory mechanisms of the HB-EGF autocrine loop in inflammation, homeostasis, development and cancer. Anticancer research 25 22641673
2009 Soluble HB-EGF induces epithelial-to-mesenchymal transition in inner medullary collecting duct cells by upregulating Snail-2. American journal of physiology. Renal physiology 25 19244405
2008 Preclinical toxicity, toxicokinetics, and antitumoral efficacy studies of DTS-201, a tumor-selective peptidic prodrug of doxorubicin. Clinical cancer research : an official journal of the American Association for Cancer Research 25 18281561
2002 Role of membrane-bound heparin-binding epidermal growth factor-like growth factor (HB-EGF) in renal epithelial cell branching. Kidney international 25 12028437
2021 CircRNA_30032 promotes renal fibrosis in UUO model mice via miRNA-96-5p/HBEGF/KRAS axis. Aging 24 33973871
2018 Correlation of IL-1 and HB-EGF with endometrial receptivity. Experimental and therapeutic medicine 24 30542468
2015 NMDA receptor agonists reverse impaired psychomotor and cognitive functions associated with hippocampal Hbegf-deficiency in mice. Molecular brain 24 26637193
2013 Roles for HB-EGF and CD9 in multiple sclerosis. Glia 24 24038577
2012 Effects of CRM197, a specific inhibitor of HB-EGF, in oral cancer. Medical molecular morphology 24 22718294
1998 Targeting tumor cells via EGF receptors: selective toxicity of an HBEGF-toxin fusion protein. International journal of cancer 24 9724101
2015 Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain. Scientific reports 23 26477568
2017 Both Autocrine Signaling and Paracrine Signaling of HB-EGF Enhance Ocular Neovascularization. Arteriosclerosis, thrombosis, and vascular biology 22 29191924
2015 Role of G protein-coupled receptors (GPCR), matrix metalloproteinases 2 and 9 (MMP2 and MMP9), heparin-binding epidermal growth factor-like growth factor (hbEGF), epidermal growth factor receptor (EGFR), erbB2, and insulin-like growth factor 1 receptor (IGF-1R) in trenbolone acetate-stimulated bovine satellite cell proliferation. Journal of animal science 22 26440329
2011 HB-EGF synthesis and release induced by cholesterol depletion of human epidermal keratinocytes is controlled by extracellular ATP and involves both p38 and ERK1/2 signaling pathways. Journal of cellular physiology 22 21413023
2020 HB-EGF Activates the EGFR/HIF-1α Pathway to Induce Proliferation of Arsenic-Transformed Cells and Tumor Growth. Frontiers in oncology 21 32695675
2020 APP Binds to the EGFR Ligands HB-EGF and EGF, Acting Synergistically with EGF to Promote ERK Signaling and Neuritogenesis. Molecular neurobiology 21 33009641
2008 HB-EGF is a paracrine growth stimulator for early tumor prestages in inflammation-associated hepatocarcinogenesis. Journal of hepatology 21 18929421
2007 HB-EGF induces delayed STAT3 activation via NF-kappaB mediated IL-6 secretion in vascular smooth muscle cell. Biochimica et biophysica acta 21 17822789
2023 Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis. Cancer cell international 20 37525152
2017 HBEGF promotes gliomagenesis in the context of Ink4a/Arf and Pten loss. Oncogene 20 28368403

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