Affinage

ADAM17

Disintegrin and metalloproteinase domain-containing protein 17 · UniProt P78536

Length
824 aa
Mass
93.0 kDa
Annotated
2026-04-28
100 papers in source corpus 43 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAM17 (TACE) is a membrane-anchored zinc-dependent metalloprotease that functions as the principal sheddase for a broad repertoire of transmembrane substrates—including TNF-α, EGFR ligands (TGF-α, amphiregulin, HB-EGF), IL-6R, NRG1 type III, ACE2, TNFR1, PD-L1, GPIbα, GPV, CD44, KIT, and p75NTR—thereby controlling inflammation, EGFR/ErbB signaling, Notch activation, myelination, cardiac development, and immune cell function (PMID:9042103, PMID:11823465, PMID:21666671, PMID:25186737, PMID:34919140). Its catalytic activity is regulated at multiple levels: iRhom2 controls ER-to-surface maturation, MAP kinase-dependent phosphorylation of iRhom2 recruits 14-3-3 proteins to release active ADAM17 at the cell surface, Trk-dependent phosphorylation of ADAM17 Thr735 stimulates shedding, clathrin-mediated endocytosis constitutively internalizes the protease, and redistribution out of lipid rafts (e.g., by cholesterol efflux or PMA/PKC stimulation) enhances sheddase activity (PMID:29045841, PMID:21411748, PMID:27731361, PMID:17786981). Tetraspanin CD9 directly associates with ADAM17 and acts as a negative regulator of shedding, while the LIM-domain protein FHL2 links ADAM17 to the actin cytoskeleton and modulates its surface localization and stimulated activity (PMID:21365281, PMID:16619241). Transcriptional upregulation of ADAM17 is driven by Sp1, p53, and HIF-1α binding to its promoter, the latter creating a positive-feedback loop with EGFR signaling under hypoxic or metabolic stress conditions (PMID:19772640, PMID:22772468, PMID:26175156, PMID:31640947).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1997 High

    Identification of ADAM17/TACE as the protease responsible for TNF-α shedding resolved the long-sought question of which enzyme generates soluble TNF-α from its membrane-anchored precursor.

    Evidence Biochemical purification from monocyte membranes and in vitro cleavage assay demonstrating cleavage at Ala76-Val77

    PMID:9042103

    Open questions at the time
    • Crystal structure of TACE with pro-TNF-α substrate not yet solved
    • Regulation of TACE activity unknown
    • Full-length cloning incomplete at this stage
  2. 2002 High

    Establishing ADAM17 as the sheddase for multiple EGFR ligands (TGF-α, amphiregulin, HB-EGF) and demonstrating genetic epistasis with EGFR in vivo expanded its role from a single-substrate protease to a master regulator of EGFR signaling.

    Evidence In vitro cleavage assay with purified TACE, TACE-deficient cell reconstitution, and genetic epistasis in Tace+/− × wa-2 mice

    PMID:11823465

    Open questions at the time
    • Mechanism by which ADAM17 selects among EGFR ligands versus other substrates
    • Structural basis of substrate recognition undetermined
  3. 2003 High

    TACE knockout mouse cardiac phenotype (enlarged trabeculated hearts, reduced ErbB4 cleavage) demonstrated that ADAM17-mediated shedding is required for normal cardiac development through ErbB signaling.

    Evidence ADAM17 null mouse phenotyping with ErbB4 cleavage and MAPK activation readouts

    PMID:14499647

    Open questions at the time
    • Identity of the specific ADAM17 substrate(s) driving cardiac phenotype not fully resolved
    • Redundancy with ADAM10 in heart not addressed
  4. 2005 High

    Demonstration that aspirin-induced platelet GPIbα/GPV shedding is entirely ADAM17-dependent (using catalytically inactive knock-in mice) established ADAM17 as a key platelet sheddase independent of COX-1.

    Evidence ADAM17 knock-in mice expressing inactive protease, COX-1 KO comparison, FACS and Western blot

    PMID:16179345

    Open questions at the time
    • How aspirin activates ADAM17 independently of COX-1 remains unclear
    • Physiological significance for hemostasis not fully defined
  5. 2006 High

    Discovery that FHL2 binds the ADAM17 cytoplasmic tail (aa 721-739) and links it to the actin cytoskeleton revealed that cytoskeletal association modulates ADAM17 surface localization and stimulated shedding.

    Evidence Yeast two-hybrid, co-IP, co-localization, FHL2 KO macrophages with altered surface ADAM17 and reduced PMA-stimulated shedding

    PMID:16619241

    Open questions at the time
    • Whether FHL2 regulation is tissue-specific
    • Mechanism by which actin dynamics translate into ADAM17 activation
  6. 2007 High

    Systematic transmembrane domain (TM) swap experiments showed that the TM sequence of ADAM17 is required for efficient substrate cleavage and confers substrate selectivity (e.g., TGF-α vs. TNF-α), establishing that ADAM17 substrate recognition extends beyond the catalytic domain.

    Evidence TM swap and GPI-anchor constructs in TACE-deficient cells with functional shedding assays

    PMID:18040288

    Open questions at the time
    • Structural basis of TM-substrate interaction unknown
    • Whether lipid environment modulates TM-dependent selectivity
  7. 2008 High

    Two advances defined contextual regulation of ADAM17: cholesterol efflux-mediated redistribution from lipid rafts activates shedding even on cell-free membranes, and tissue recombination showed ADAM17 on mammary epithelial cells releases amphiregulin to signal in trans to stromal EGFR.

    Evidence Cell-free membrane shedding assay with ABCA1-dependent cholesterol efflux; mammary tissue recombination with ADAM17-deficient epithelium and soluble AREG rescue

    PMID:17786981 PMID:18470483

    Open questions at the time
    • Precise lipid species controlling ADAM17 raft partitioning not identified
    • Whether paracrine ADAM17-EGFR axis operates in all epithelia
  8. 2011 High

    Multiple discoveries in 2011 established phosphorylation-dependent regulation and new biological roles: Trk/MEK-dependent phosphorylation of ADAM17 Thr735 activates p75NTR cleavage for neuronal survival; TACE cleaves NRG1 type III to negatively regulate PNS myelination (conditional KO causes hypermyelination); and CD9 tetraspanin directly associates with ADAM17 as a negative regulator of shedding.

    Evidence Phospho-site mapping with MEK inhibitor and p75NTR-ICD rescue in neurons; conditional motor neuron KO mice and NRG1 haploinsufficiency rescue; proximity ligation and co-IP with CD9 gain/loss-of-function shedding assays

    PMID:21365281 PMID:21411748 PMID:21666671

    Open questions at the time
    • Kinase(s) directly phosphorylating Thr735 not biochemically confirmed
    • Structural basis of CD9-ADAM17 interaction not resolved
    • Whether CD9 regulation is conserved across all ADAM17 substrates
  9. 2012 High

    Identification of p53 as a direct transcriptional activator of ADAM17, which in turn cleaves Notch1 to promote epidermal differentiation, revealed a tumor-suppressive p53→TACE→Notch1 axis in skin.

    Evidence Epidermal Fos-deletion mouse models, p53-dependent transcriptional assays, Notch1 activation readout

    PMID:22772468

    Open questions at the time
    • Whether p53-dependent ADAM17 transcription operates outside epidermis
    • Relative contribution of ADAM17 vs. ADAM10 to Notch cleavage in vivo in skin
  10. 2014 High

    Conditional deletion of ADAM17 in oligodendrocyte progenitors showed it is required for CNS myelination via shedding of TGF-α/HB-EGF to activate EGFR, and iRhom2 gain-of-function mutations (tylosis) increase ADAM17 maturation and EGFR ligand release in keratinocytes, validating the iRhom2-ADAM17 regulatory axis in human disease.

    Evidence OPC-specific conditional KO with EGFR rescue; patient-derived tylosis keratinocytes with ADAM17 maturation and EGFR phosphorylation readouts; IL-6R mutagenesis defining cleavage-site geometry for ADAM17 selectivity

    PMID:24643277 PMID:25186737 PMID:27151651

    Open questions at the time
    • Structural model of iRhom2-ADAM17 complex lacking
    • How cleavage-site distance from the membrane is sensed by the protease
  11. 2016 High

    Clathrin-dependent constitutive internalization of ADAM17 was defined, with PKC/PMA causing rapid surface upregulation followed by exosomal release of catalytically active ADAM17 that can shed substrates on distant cells, revealing regulated trafficking as a key control point.

    Evidence Live-cell imaging with clathrin inhibition; exosome isolation showing metalloproteinase-domain-outside orientation; iRhom2 requirement for exosomal release

    PMID:27599715 PMID:27731361

    Open questions at the time
    • Cargo sorting signals for ADAM17 exosomal incorporation unknown
    • Physiological relevance of exosomal ADAM17 shedding in vivo not established
  12. 2017 High

    The mechanism by which stimulated shedding activates ADAM17 was resolved: MAP kinase phosphorylates the iRhom2 N-terminal tail, recruiting 14-3-3 proteins that dissociate the iRhom2-ADAM17 complex, freeing ADAM17 for substrate cleavage.

    Evidence Phosphorylation mapping, 14-3-3 co-IP, iRhom2 mutant analysis, MAP kinase inhibitors

    PMID:29045841

    Open questions at the time
    • Which MAP kinase isoform(s) directly phosphorylate iRhom2
    • Whether 14-3-3 displacement is sufficient or additional cofactors are needed
    • Structural model of 14-3-3-iRhom2 interface absent
  13. 2019 High

    HIF-1α was shown to bind the ADAM17 promoter in macrophages, directly upregulating ADAM17 transcription during metabolic stress and fumarate accumulation, expanding the known transcriptional regulators and connecting ADAM17 to metabolic inflammation and vascular disease.

    Evidence ChIP for HIF-1α at ADAM17 promoter, metabolomics, HIF-1α inhibitor acriflavine, mouse aortic dissection model

    PMID:26175156 PMID:31640947

    Open questions at the time
    • Whether HIF-1α and Sp1/p53 cooperate or act independently at the ADAM17 promoter
    • Epigenetic regulation of ADAM17 expression unexplored
  14. 2020 Medium

    ADAM17 was identified as a sheddase for PD-L1 on tumor cells and extracellular vesicles; soluble PD-L1 generated by ADAM17 induces CD8+ T cell apoptosis, linking ADAM17 to immune checkpoint evasion.

    Evidence ADAM17 knockdown and pharmacological inhibition with CD8+ T cell apoptosis and killing assays

    PMID:32363112

    Open questions at the time
    • Relative contribution of ADAM17 vs. ADAM10 to PD-L1 shedding in different tumor types
    • Whether sPD-L1 from ADAM17 has distinct immunosuppressive potency vs. alternatively spliced sPD-L1
  15. 2021 High

    Endothelial ADAM17-mediated TNFR1 shedding followed by γ-secretase processing was shown to be required for TNF-induced necroptosis and tumor cell extravasation, defining a sequential proteolytic cascade in metastasis.

    Evidence Endothelial-specific ADAM17 KO mice, γ-secretase inhibitor, lung metastasis model

    PMID:34919140

    Open questions at the time
    • Whether ADAM17-TNFR1-necroptosis axis operates in non-pulmonary metastatic niches
    • Identity of downstream necroptosis mediators in endothelium
  16. 2022 High

    Therapeutic inhibition of ADAM17 (prodomain inhibitor or genetic hypomorph) ameliorated experimental pancreatitis by suppressing IL-6 trans-signaling/STAT3, providing in vivo validation of ADAM17 as a druggable target in inflammatory disease.

    Evidence Adam17ex/ex hypomorphic mice and prodomain inhibitor in pancreatitis models with STAT3 pathway and histological readouts

    PMID:36215509

    Open questions at the time
    • Long-term safety of ADAM17 therapeutic inhibition given its broad substrate repertoire
    • Whether prodomain inhibitor achieves substrate-selective inhibition in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive characterization, outstanding questions include the structural basis of iRhom2-ADAM17 complex assembly and 14-3-3-mediated dissociation, the rules governing substrate selectivity among >80 substrates, and whether tissue- or stimulus-specific ADAM17 inhibition can be achieved therapeutically without disrupting essential homeostatic shedding.
  • No high-resolution structure of full-length ADAM17-iRhom2 complex
  • Substrate selectivity code not defined
  • Tissue-selective therapeutic targeting strategy not validated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 11 GO:0016787 hydrolase activity 3
Localization
GO:0005886 plasma membrane 7 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 11 R-HSA-168256 Immune System 5 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-112316 Neuronal System 3 R-HSA-1643685 Disease 3
Partners
ADAM8CD9FHL2NOX1PXNRHBDF2YWHAZ
Complex memberships
ADAM17-14-3-3 regulatory complexiRhom2-ADAM17 complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TACE/ADAM17 was purified and partially cloned as a novel metalloprotease responsible for cleaving the Ala76-Val77 bond of the 26 kDa pro-TNF-α precursor to generate the mature 17 kDa soluble form. Protein purification, partial cloning, enzymatic cleavage assay Journal of neuroimmunology High 9042103
2002 ADAM17/TACE cleaves pro-TGF-α at its N-terminal and C-terminal ectodomain sites in vitro, and mediates shedding of amphiregulin and HB-EGF in cells; TACE-deficient cells shed dramatically less TGF-α, restored by TACE adenovirus infection. In vitro cleavage assay with purified TACE, TACE-deficient cell reconstitution, cotransfection, adenoviral rescue The Journal of biological chemistry High 11823465
2002 Genetic evidence that TACE regulates EGFR ligand availability in vivo: mice heterozygous for Tace and homozygous for impaired EGFR allele (wa-2) were born with open eyes more frequently, indicating epistatic interaction between TACE and EGFR signaling. Genetic epistasis (double mutant mouse crosses) The Journal of biological chemistry High 11823465
2003 TACE/ADAM17 null mutant mice exhibit enlarged fetal hearts with increased trabeculation, reduced cell compaction, larger cardiomyocytes and increased proliferation, accompanied by attenuated ErbB4 cleavage and changes in MAPK activation, demonstrating a role for ADAM17-mediated shedding in cardiac development. Knockout mouse phenotyping, Western blot for ErbB4 cleavage and MAPK activation Developmental biology High 14499647
2004 TACE/ADAM17 acts as a constitutive and PMA-stimulated sheddase for MUC1 on human uterine epithelial cells; TACE-deficient cells lose PMA-stimulated MUC1 shedding, which is distinct from pervanadate-stimulated shedding mediated by MT1-MMP. TACE-deficient cell lines, pharmacological inhibitors, co-transfection The Biochemical journal Medium 15130087
2005 Aspirin induces shedding of platelet GPIbα and GPV via an ADAM17-dependent mechanism; shedding was completely blocked in platelets expressing inactive ADAM17, but occurred normally in COX-1-deficient platelets. ADAM17 knock-in mutant mice (inactive form), COX-1 KO mice, FACS, immunoprecipitation, Western blot The Journal of biological chemistry High 16179345
2006 ADAM17 interacts with the LIM domain protein FHL2 via amino acids 721–739 of ADAM17; FHL2 colocalizes with ADAM17 and the actin cytoskeleton in cardiomyoblasts, and FHL2-deficient macrophages show increased surface ADAM17 but reduced PMA-stimulated substrate shedding, indicating FHL2 regulates ADAM17 localization and activity. Yeast two-hybrid, co-immunoprecipitation, co-localization, FHL2 KO macrophages, substrate shedding assay Journal of cellular physiology High 16619241
2007 The transmembrane domain (TM) of TACE is required for efficient cleavage of TGF-α, TNF-α and L-selectin; GPI-anchored TACE lacking TM fails to restore shedding, and substitution of TM with prolactin receptor or PDGFR TM abolishes TGF-α shedding but not TNF-α/L-selectin shedding, revealing TM sequence-dependent substrate specificity. Molecular engineering (TM swap/GPI anchor constructs), functional shedding assay in TACE-deficient cells Cell research High 18040288
2008 HDL-induced cholesterol efflux from lipid rafts redistributes ADAM17 out of lipid rafts and activates ADAM17-dependent shedding of TNFR1, TNFR2, and TNF; this was demonstrated even on cell-free isolated plasma membranes, indicating a direct lipid raft-mediated regulation of ADAM17 activity. Cell-free plasma membrane assay, ABCA1-dependent cholesterol efflux, specific inhibitors, lipid raft fractionation Journal of cellular physiology Medium 17786981
2008 ADAM17 mediates EGFR ligand (amphiregulin) release from mammary ductal epithelial cells to activate stromal EGFR; tissue recombination studies show ADAM17 and AREG must be on epithelial cells while EGFR is on stromal cells, and soluble AREG rescues ADAM17-deficient transplants. Tissue recombination and transplantation, ADAM17-deficient mammary epithelium, soluble AREG rescue Journal of mammary gland biology and neoplasia High 18470483
2008 Kuz (Kuzbanian/ADAM10) and TACE/ADAM17 can both activate Notch signaling by cleaving the Notch receptor; overexpression of TACE activates Notch in a ligand-independent manner in Drosophila, while Kuz requires Delta stimulation. In vitro Drosophila model, overexpression and dominant-negative analysis of Kuz and TACE Cellular and molecular life sciences : CMLS Medium 18535782
2009 Transcription factor Sp1 binds to the GC-rich ADAM17 promoter and regulates ADAM17 expression under hypoxia, as shown by chromatin immunoprecipitation assay; Sp1 suppression decreases ADAM17-dependent glioma invasiveness. ChIP assay, RT-PCR, Western blot, siRNA knockdown, invasion assay Journal of experimental & clinical cancer research Medium 19772640
2010 TACE/ADAM17 mediates germ cell apoptosis by cleaving the extracellular domain of the KIT receptor; TACE inhibition prevents apoptosis and PMA-induced KIT ectodomain loss, while ADAM10 inhibition does not, demonstrating substrate specificity in vivo. Pharmacological ADAM17 inhibition, PMA stimulation, ex vivo testis culture, KIT ectodomain Western blot Reproduction (Cambridge, England) Medium 20501791
2011 ADAM17 multimerizes in the cell membrane via its EGF-like domain, suggesting dimerization as a mechanism contributing to ADAM17 activation and function. Co-immunoprecipitation, mutagenesis of EGF-like domain, cell membrane analysis Biochemical and biophysical research communications Medium 22033402
2011 TACE/ADAM17 cleaves neuregulin-1 (NRG1) type III in the EGF domain, inactivating it and thereby negatively regulating PNS myelination; lentiviral TACE knockdown in DRG neurons causes hypermyelination, conditional motor neuron TACE KO mice show significant hypermyelination, and reduced TACE rescues hypomyelination in NRG1 type III haploinsufficient mice. Lentiviral knockdown in DRG neurons, conditional neuronal KO mice, NRG1 haploinsufficient mouse rescue, PI3K pathway assay Nature neuroscience High 21666671
2011 Tetraspanin CD9 associates directly with ADAM17 on endothelial and monocytic cell surfaces; CD9 antibody treatment or CD9 overexpression reduces ADAM17-mediated shedding of TNF-α and ICAM-1, while CD9 silencing increases ADAM17 sheddase activity. In situ proximity ligation, co-immunoprecipitation, crosslinking, pull-down, CD9 siRNA and overexpression, substrate shedding assay Cellular and molecular life sciences : CMLS High 21365281
2011 HIV Nef recruits paxillin and ADAM17 into a complex; Pak2 phosphorylates paxillin on Ser272/274 to induce TACE-paxillin association and shuttle ADAM17 into extracellular vesicles via lipid rafts, cleaving pro-TNF-α; Pak1 phosphorylates paxillin Ser258 to inhibit TACE association. Co-immunoprecipitation, phospho-specific mutants, lipid raft fractionation, EV isolation, Pak1/2 knockdown Molecular cell High 23317503
2011 Trk receptor activation induces MEK-dependent phosphorylation of ADAM17 at threonine 735, activating ADAM17 to cleave p75NTR and produce p75NTR intracellular domain (p75NTR-ICD), which is required for neurotrophin-induced Erk/Akt activation and neuronal survival. Phospho-specific site identification, MEK inhibitor, ADAM17 depletion, p75NTR-ICD overexpression rescue, survival assay in PC12 and primary neurons FASEB journal High 21411748
2011 A cross-domain human antibody specifically inhibits cell-surface TACE by targeting its ectodomain rather than the active site, providing a mechanistic basis for allosteric inhibition of TACE shedding activity. Phage display antibody development, selective TACE inhibition assay Proceedings of the National Academy of Sciences of the United States of America Medium 21415364
2012 p53 transcriptionally activates TACE/ADAM17 as a novel target gene; TACE in turn activates NOTCH1, promoting epidermal differentiation and squamous cell carcinoma suppression downstream of a FOS/p53/TACE axis. Epidermal Fos deletion mouse models, pharmacological FOS/AP-1 inhibition, p53-dependent transcriptional activation assay, NOTCH1 activation readout The Journal of clinical investigation High 22772468
2013 Nox1 interacts with and stabilizes ADAM17 from ubiquitin-mediated degradation, leading to activation of the ADAM17/EGFR-PI3K-AKT signaling pathway and promotion of colon cancer metastasis. Immunoprecipitation, siRNA knockdown, ubiquitination assay, migration/invasion assay European review for medical and pharmacological sciences Medium 27874952
2014 TACE/ADAM17 genetic deletion in oligodendrocyte progenitor cells causes premature cell cycle exit, reduced OL survival, and deficits in CNS myelination; TACE regulates oligodendrogenesis by shedding EGFR ligands TGFα and HB-EGF, and EGFR overexpression in TACE-deficient OPs rescues OL development. Conditional KO mice (OPC-specific), EGFR overexpression rescue, substrate shedding assay, behavioral readout The Journal of neuroscience High 25186737
2014 Deletion of a triple serine motif (Ser359–Ser361) adjacent to the IL-6R cleavage site prevents ADAM17-mediated but not ADAM10-mediated IL-6R shedding by reducing the distance between cleavage site and plasma membrane, revealing that cleavage site positioning differentially controls ADAM17 vs ADAM10 proteolysis. Deletion mutagenesis, shedding assay, IL-6R functional assay Scientific reports High 27151651
2014 iRhom2 dominant mutations (tylosis/TOC-associated) increase ADAM17 maturation and activity in epidermal keratinocytes, resulting in upregulated shedding of EGF-family growth factors and pro-inflammatory cytokines, increased EGFR activity, and aberrant desmosome processing. Patient-derived TOC keratinocytes, ADAM17 maturation assay, substrate shedding assay, EGFR phosphorylation Human molecular genetics High 24643277
2015 TACE/ADAM17 is required for OL regeneration and CNS remyelination following demyelination by activating EGFR in OL lineage cells; TACE deficiency abrogates EGFR activation, impairs OL expansion and survival, and delays remyelination; EGFR overexpression in TACE-deficient OPs rescues remyelination. Conditional KO mice, demyelination model, EGFR overexpression rescue, OL lineage cell expansion/survival assay The Journal of neuroscience High 26338334
2015 HIF-1α binds to its consensus element at -607 of the ADAM17 promoter to drive ADAM17 transcriptional upregulation in response to high glucose; this is dependent on EGFR/ADAM17 signaling, creating a positive feedback loop. ADAM17 promoter deletion constructs, mutation analysis, ChIP, HRE-luciferase reporter, HIF-1α inhibition The Journal of biological chemistry High 26175156
2016 ADAM17 is constitutively internalized via clathrin-coated pits; GPCR ligand stimulation induces ADAM17-mediated shedding without altering cell-surface abundance, while PMA/PKC activation causes rapid increase of mature ADAM17 at the cell surface followed by internalization and degradation, substantially downregulating mature ADAM17. Live-cell imaging, clathrin inhibition, FACS surface expression analysis, PMA vs. physiological stimulator comparison Scientific reports High 27731361
2016 Niacin/Niaspan enhances TACE activity in vivo and rescues focal hypermyelination in CMT mouse models (Mtmr2-/- and Pmp22+/-) by downregulating NRG1 type III signaling through TACE-mediated cleavage. In vivo drug treatment, TACE activity assay, myelination quantification in CMT mouse models EMBO molecular medicine Medium 27799291
2016 Tetraspanin CD9 coassociates with and negatively regulates ADAM17 in leukocytes; CD9 neo-expression or neutralizing anti-CD9 antibodies modulate ADAM17-mediated shedding of LR11, confirmed by metalloproteinase inhibitor sensitivity. Confocal co-localization, shRNA knockdown, CD9 overexpression, metalloproteinase inhibitor, sLR11 ELISA Experimental & molecular medicine Medium 24699135
2016 PMA stimulation downregulates surface ADAM17 in lung epithelial cells by inducing release of mature ADAM17 in exosomes; exosomal ADAM17 retains metalloproteinase domain-outside orientation and can shed TGFα and amphiregulin on distant cells; iRhom2-mediated maturation is required for surface expression and exosomal release. Exosome isolation, antibody surface labeling, iRhom2 suppression, shRNA knockdown, substrate shedding assay Biochimica et biophysica acta Medium 27599715
2017 Stimulation of ADAM17/TACE shedding by inflammatory/growth-promoting agents triggers MAP kinase-dependent phosphorylation of the iRhom2 N-terminal cytoplasmic tail, recruiting 14-3-3 proteins that enforce dissociation of TACE from iRhom2 complexes and promote cleavage of TACE substrates. Phosphorylation mapping, 14-3-3 co-IP, iRhom2 mutant analysis, substrate shedding assay, MAP kinase inhibitors Cell reports High 29045841
2018 ADAM17 deficiency in smooth muscle cells prevents contractile-to-synthetic phenotypic switching in TAA, while ADAM17 deficiency in endothelial cells preserves VE-cadherin, JAM-A and claudin junctions; both independently suppress aortic aneurysm dilation, demonstrating cell-specific functions. SMC-specific and EC-specific conditional KO mice (Adam17/Sm22 and Adam17/Tie2), ADAM17 siRNA in primary cells, pharmacological inhibitor (PF-548), in vivo TAA model Circulation research High 29930147
2019 HIF-1α activation in macrophages, triggered by fumarate accumulation, transcriptionally upregulates ADAM17 as a novel HIF-1α target gene, promoting vascular inflammation and elastic fiber degradation in aortic dissection; ChIP confirmed HIF-1α binding to ADAM17 promoter. ChIP, metabolomics, Seahorse flux analysis, ELISA, HIF-1α inhibitor (acriflavine), mouse models EBioMedicine High 31640947
2019 ADAM17 mediates ACE2 ectodomain shedding; ADAM17 inhibitor applied to renal proximal tubular cells reduces ACE2 shedding into the media, and ACE2 colocalizes with ADAM17 in renal tubules. ADAM17 inhibitor in primary tubular cells, immunostaining colocalization, urinary ACE2 fragment analysis American journal of physiology. Renal physiology Medium 24452639
2019 ADAM17 expression co-localizes with angiotensin-II type 1 receptors on Sim1 neurons of the hypothalamic paraventricular nucleus; selective neuronal ADAM17 knockdown reduces FosB expression, increases vagal tone, and prevents the acute pressor response to centrally administered angiotensin-II. Neuron-specific conditional knockdown (new mouse models), photoactivation, blood pressure measurement Hypertension Medium 31564162
2019 ADAM8 can release the ADAM17 ectodomain (shedding of ADAM17 itself); soluble ADAM17 (sADAM17) cleaves fibronectin, cystatin C, sN-cadherin, PCPE-1, and sAPP in vitro, revealing a degradome distinct from membrane-anchored ADAM17. N-terminomics/mass spectrometry, in vitro cleavage assays with purified substrates Cellular and molecular life sciences : CMLS Medium 31209506
2020 ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles, generating a soluble active sPD-L1 fragment that induces apoptosis in CD8+ T cells and impairs their tumor-killing ability. ADAM10/17 inhibition, ADAM17 knockdown, shedding assay, CD8+ T cell apoptosis and killing assay Oncoimmunology Medium 32363112
2021 ADAM17 on endothelial cells mediates TNFR1 ectodomain shedding; subsequent processing by the γ-secretase complex is required for induction of TNF-induced necroptosis. Genetic ablation or pharmacological inhibition of ADAM17 in endothelial cells prevents tumor cell extravasation and lung metastasis. Endothelial-specific ADAM17 KO mice, γ-secretase inhibitor, necroptosis assay, lung metastasis model The Journal of experimental medicine High 34919140
2021 IL-15 activates ADAM17 in human NK cells, which sheds CD62L from the surface, limiting NK cell proliferation; ADAM17 blockade markedly increases NK cell proliferation in vitro and in xenograft mice, and CD62L is required for this proliferation effect in vivo. ADAM17 monoclonal antibody blockade, xenograft mouse model, CD62L surface expression, CD62L-dependent proliferation assay Frontiers in immunology Medium 34367174
2022 Genetic reduction (Adam17ex/ex hypomorphic mice) or therapeutic inhibition (ADAM17 prodomain inhibitor) of ADAM17 ameliorates experimental pancreatitis by reducing IL-6 trans-signaling/STAT3 axis, associated with reduction in inflammatory cell infiltration, necrosis, and fibrosis. Hypomorphic mouse model, pharmacological prodomain inhibitor, STAT3 pathway analysis, histology Proceedings of the National Academy of Sciences of the United States of America High 36215509
2013 ADAM17 promotes shedding of EGFR ligands TGFα and HB-EGF and activates EGFR/PI3K/AKT signaling in glioma; ADAM17 overexpression promotes U87 glioma cell proliferation, invasion, and angiogenesis, while ADAM17 siRNA or TAPI-2 inhibitor reverses these effects. Stable ADAM17 overexpression/siRNA transfection, TAPI-2 inhibitor, MTT/BrdU assay, Matrigel invasion, Western blot for EGFR-PI3K-AKT Molecular carcinogenesis Medium 21480393
2013 ADAM17 cleaves the extracellular domain of CD44 in HNSCC; ADAM17 chemical inhibition and stable suppression block CD44 cleavage and abrogate orasphere formation and tumorigenesis in vivo. ADAM17 inhibitor, stable shRNA suppression, sphere assay, oral cancer mouse model Cancer medicine Medium 24403253
2013 ADAM17 cleaves the Notch extracellular domain to regulate self-renewal of glioblastoma stem cells via Notch signaling; ADAM17 knockdown inhibits Hes1/Hes5, activates Notch1 expression, and suppresses secondary neurosphere formation and multi-lineage differentiation. ADAM17 shRNA knockdown in GSCs, Hes1/Hes5/Notch1 Western blot, neurosphere assay Neuroscience letters Medium 23356982
2019 CD9 co-localizes with and directly associates with ADAM17 on keratinocytes during wound repair; CD9 down-regulation activates ADAM17 sheddase activity leading to release of HB-EGF, which activates EGFR/ERK pathway to promote keratinocyte migration; ADAM17 inhibition or siRNA blocks this CD9-regulated migration. Confocal microscopy, co-immunoprecipitation, TAPI-2 inhibitor, siADAM17, HB-EGF neutralizing antibody, in vivo wound assay International journal of biological sciences Medium 30745837

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends in immunology 432 21752713
2002 Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability. The Journal of biological chemistry 352 11823465
2010 ADAM-17: the enzyme that does it all. Critical reviews in biochemistry and molecular biology 337 20184396
2017 The shedding protease ADAM17: Physiology and pathophysiology. Biochimica et biophysica acta. Molecular cell research 270 28705384
2010 The "A Disintegrin And Metalloproteases" ADAM10 and ADAM17: novel drug targets with therapeutic potential? European journal of cell biology 254 21194787
2004 MT1-MMP mediates MUC1 shedding independent of TACE/ADAM17. The Biochemical journal 128 15130087
2019 Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway✰. EBioMedicine 120 31640947
2011 TACE (ADAM17) inhibits Schwann cell myelination. Nature neuroscience 120 21666671
2020 ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance. Oncoimmunology 105 32363112
2011 Cross-domain inhibition of TACE ectodomain. Proceedings of the National Academy of Sciences of the United States of America 104 21415364
2013 The role of ADAM17 in metabolic inflammation. Atherosclerosis 98 23384719
1999 Adamalysins. A family of metzincins including TNF-alpha converting enzyme (TACE). Annals of the New York Academy of Sciences 96 10415747
2016 Control of ADAM17 activity by regulation of its cellular localisation. Scientific reports 94 27731361
2014 Insulin treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice. American journal of physiology. Renal physiology 92 24452639
2019 The metalloprotease ADAM17 in inflammation and cancer. Pathology, research and practice 89 30992230
1997 Structural features and biochemical properties of TNF-alpha converting enzyme (TACE). Journal of neuroimmunology 89 9042103
2003 TACE is required for fetal murine cardiac development and modeling. Developmental biology 87 14499647
2017 Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE. Cell reports 86 29045841
2013 HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases. Molecular cell 85 23317503
2016 Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17. Scientific reports 83 27151651
2011 The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9. Cellular and molecular life sciences : CMLS 81 21365281
2007 Inhibition of ADAM17 reduces hypoxia-induced brain tumor cell invasiveness. Cancer science 81 17355261
2008 The ADAM17-amphiregulin-EGFR axis in mammary development and cancer. Journal of mammary gland biology and neoplasia 76 18470483
2019 ACE2 and ADAM17 Interaction Regulates the Activity of Presympathetic Neurons. Hypertension (Dallas, Tex. : 1979) 75 31564162
2015 High Glucose Up-regulates ADAM17 through HIF-1α in Mesangial Cells. The Journal of biological chemistry 70 26175156
2014 ADAM17 at the interface between inflammation and autoimmunity. Immunology letters 70 25171914
2014 iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function. Human molecular genetics 66 24643277
2004 ADAM17 mRNA expression and pathological features of hepatocellular carcinoma. World journal of gastroenterology 66 15309730
2008 Deficiency of TNFalpha converting enzyme (TACE/ADAM17) causes a lean, hypermetabolic phenotype in mice. Endocrinology 64 18687778
2011 ADAM17 promotes glioma cell malignant phenotype. Molecular carcinogenesis 61 21480393
2012 Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17. The Journal of clinical investigation 59 22772468
2018 Cell-Specific Functions of ADAM17 Regulate the Progression of Thoracic Aortic Aneurysm. Circulation research 57 29930147
2016 Stimulated release and functional activity of surface expressed metalloproteinase ADAM17 in exosomes. Biochimica et biophysica acta 57 27599715
2009 Transcription factor Sp1 induces ADAM17 and contributes to tumor cell invasiveness under hypoxia. Journal of experimental & clinical cancer research : CR 57 19772640
2001 Design of selective and soluble inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). Journal of medicinal chemistry 57 11708926
2005 Aspirin induces platelet receptor shedding via ADAM17 (TACE). The Journal of biological chemistry 56 16179345
2015 Paricalcitol modulates ACE2 shedding and renal ADAM17 in NOD mice beyond proteinuria. American journal of physiology. Renal physiology 55 26697977
2021 Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis. The Journal of experimental medicine 52 34919140
2019 Degradome of soluble ADAM10 and ADAM17 metalloproteases. Cellular and molecular life sciences : CMLS 51 31209506
2006 ADAM17 activity during human neutrophil activation and apoptosis. European journal of immunology 47 16541467
2016 Niacin-mediated Tace activation ameliorates CMT neuropathies with focal hypermyelination. EMBO molecular medicine 46 27799291
2019 Role of ADAM17 in kidney disease. American journal of physiology. Renal physiology 45 31141400
2014 ADAM10 and ADAM17 have opposite roles during sprouting angiogenesis. Angiogenesis 45 25218057
2008 Tumor necrosis factor-alpha-converting enzyme (TACE) levels in periodontal diseases. Journal of dental research 45 18296613
2005 Inhibitors of TACE and Caspase-1 as anti-inflammatory drugs. Current medicinal chemistry 45 16378499
2019 Status update on iRhom and ADAM17: It's still complicated. Biochimica et biophysica acta. Molecular cell research 44 31330158
2013 ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice. American journal of physiology. Renal physiology 44 23678045
2021 Contribution of ADAM17 and related ADAMs in cardiovascular diseases. Cellular and molecular life sciences : CMLS 43 33575814
2014 Deciphering the role of the ADAM17-dependent secretome in cell signaling. Journal of proteome research 41 24625128
2014 TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination. The Journal of neuroscience : the official journal of the Society for Neuroscience 39 25186737
2018 FoxM1 drives ADAM17/EGFR activation loop to promote mesenchymal transition in glioblastoma. Cell death & disease 38 29700308
2011 Multimerisation of A disintegrin and metalloprotease protein-17 (ADAM17) is mediated by its EGF-like domain. Biochemical and biophysical research communications 38 22033402
2008 HDLs activate ADAM17-dependent shedding. Journal of cellular physiology 38 17786981
2023 The protease ADAM17 at the crossroads of disease: revisiting its significance in inflammation, cancer, and beyond. The FEBS journal 35 37540030
2017 Cezanne predicts progression and adjuvant TACE response in hepatocellular carcinoma. Cell death & disease 35 28880268
2014 MicroRNA-145 inhibits cell proliferation by directly targeting ADAM17 in hepatocellular carcinoma. Oncology reports 35 25174729
2013 ADAM17 promotes U87 glioblastoma stem cell migration and invasion. Brain research 35 23470260
2007 Hydantoins, triazolones, and imidazolones as selective non-hydroxamate inhibitors of tumor necrosis factor-alpha converting enzyme (TACE). Bioorganic & medicinal chemistry letters 35 17368021
2020 Blocking glycine receptors reduces neuroinflammation and restores neurotransmission in cerebellum through ADAM17-TNFR1-NF-κβ pathway. Journal of neuroinflammation 34 32917219
2011 Trk-dependent ADAM17 activation facilitates neurotrophin survival signaling. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 21411748
2006 FHL2 interacts with both ADAM-17 and the cytoskeleton and regulates ADAM-17 localization and activity. Journal of cellular physiology 34 16619241
2022 Immunomodulatory role of metalloproteinase ADAM17 in tumor development. Frontiers in immunology 32 36466812
2016 The role of ADAM17 in tumorigenesis and progression of breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 30 27658778
2016 Nox1 promotes colon cancer cell metastasis via activation of the ADAM17 pathway. European review for medical and pharmacological sciences 30 27874952
2008 Kuz and TACE can activate Notch independent of ligand. Cellular and molecular life sciences : CMLS 30 18535782
2016 Metalloproteinases ADAM10 and ADAM17 Mediate Migration and Differentiation in Glioblastoma Sphere-Forming Cells. Molecular neurobiology 29 27541285
2014 Dihydroartemisinin suppresses glioma proliferation and invasion via inhibition of the ADAM17 pathway. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 28 25301262
2013 Effects of tetrandrine on glioma cell malignant phenotype via inhibition of ADAM17. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 28 24185966
2020 Shedding Light on COVID-19: ADAM17 the Missing Link? American journal of therapeutics 27 32769398
2021 Abnormal ADAM17 expression causes airway fibrosis in chronic obstructive asthma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 26 34051616
2020 Recent developments and strategies for the discovery of TACE inhibitors. Expert opinion on drug discovery 26 32281878
2018 Specific inhibition of ADAM17/TACE promotes neurogenesis in the injured motor cortex. Cell death & disease 26 30154402
2016 Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 26 27607600
2013 ADAM17 regulates self-renewal and differentiation of U87 glioblastoma stem cells. Neuroscience letters 26 23356982
2013 ADAM17-mediated CD44 cleavage promotes orasphere formation or stemness and tumorigenesis in HNSCC. Cancer medicine 26 24403253
2019 NOTCH2/NOTCH3/DLL3/MAML1/ADAM17 signaling network is associated with ovarian cancer. Oncology letters 25 31186700
2016 Targeting ADAM17 in leukocytes increases neutrophil recruitment and reduces bacterial spread during polymicrobial sepsis. Journal of leukocyte biology 25 27059842
2009 The discovery of novel tartrate-based TNF-alpha converting enzyme (TACE) inhibitors. Bioorganic & medicinal chemistry letters 25 20022498
2007 Tackling EGFR signaling with TACE antagonists: a rational target for metalloprotease inhibitors in cancer. Expert opinion on therapeutic targets 25 17907959
2021 Role of ADAM10 and ADAM17 in Regulating CD137 Function. International journal of molecular sciences 24 33800462
2018 Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4-ROS-ADAM17 pathway. Journal of cellular and molecular medicine 24 30953402
2014 The role of metalloproteinase ADAM17 in regulating ICOS ligand-mediated humoral immune responses. Journal of immunology (Baltimore, Md. : 1950) 24 25108021
2014 Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes. Experimental & molecular medicine 23 24699135
2022 Blockade of the protease ADAM17 ameliorates experimental pancreatitis. Proceedings of the National Academy of Sciences of the United States of America 22 36215509
2015 Oligodendrocyte Regeneration and CNS Remyelination Require TACE/ADAM17. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 26338334
2014 Upregulation of APP, ADAM10 and ADAM17 in the denervated mouse dentate gyrus. PloS one 22 24404197
2010 TACE/ADAM17 is involved in germ cell apoptosis during rat spermatogenesis. Reproduction (Cambridge, England) 22 20501791
2009 TNF-alpha-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species. Leukemia 22 19890373
2019 CD9 regulates keratinocyte migration by negatively modulating the sheddase activity of ADAM17. International journal of biological sciences 21 30745837
2007 Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation. Bioorganic & medicinal chemistry 21 17936631
2007 The transmembrane domain of TACE regulates protein ectodomain shedding. Cell research 21 18040288
2021 Activation of ADAM17 by IL-15 Limits Human NK Cell Proliferation. Frontiers in immunology 20 34367174
2021 MiR-26a-5p alleviates cardiac hypertrophy and dysfunction via targeting ADAM17. Cell biology international 20 34370360
2021 A model for COVID-19-induced dysregulation of ACE2 shedding by ADAM17. Biochemical and biophysical research communications 20 34416436
2020 HNF-4α inhibits hepatocellular carcinoma cell proliferation through mir-122-adam17 pathway. PloS one 20 32210451
2012 Novel methods and strategies in the discovery of TACE inhibitors. Expert opinion on drug discovery 20 23231541
2009 Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-alpha converting enzyme (TACE) inhibitors. Bioorganic & medicinal chemistry 20 19410464
2020 Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons. International journal of molecular sciences 19 33375653
2023 Efficacy and safety analysis of TACE + Donafenib + Toripalimab versus TACE + Sorafenib in the treatment of unresectable hepatocellular carcinoma: a retrospective study. BMC cancer 18 37880661
2010 Ectodomain shedding of Fcalpha receptor is mediated by ADAM10 and ADAM17. Immunology 18 20059578