{"gene":"ADAM17","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":1997,"finding":"TACE/ADAM17 was purified and partially cloned as the metalloprotease responsible for cleaving the Ala76-Val77 bond of the 26 kDa pro-TNF-α precursor to generate the mature 17 kDa soluble TNF-α.","method":"Protein purification and partial cloning; in vitro cleavage assay","journal":"Journal of neuroimmunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical purification and direct in vitro cleavage assay establishing enzymatic substrate and cleavage site; foundational study replicated by many subsequent labs","pmids":["9042103"],"is_preprint":false},{"year":1999,"finding":"TACE-deficient mice (lacking proteolytically active TACE) release 80-90% less soluble TNF-α than wild-type cells, and irradiated mice reconstituted with TACE-knockout hematopoietic stem cells have markedly reduced serum TNF-α after LPS challenge, establishing TACE as the major TNF-α converting enzyme in vivo.","method":"Genetic knockout mouse model; bone marrow reconstitution; ELISA for soluble TNF-α","journal":"Annals of the New York Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined molecular phenotype, replicated in vivo with reconstitution experiment; widely cited foundational result","pmids":["10415747"],"is_preprint":false},{"year":2002,"finding":"TACE/ADAM17 cleaves pro-TGF-α at both N- and C-terminal processing sites to release soluble TGF-α; TACE-deficient primary keratinocytes shed dramatically less TGF-α, and TACE re-expression rescued shedding. TACE also cleaves peptide substrates corresponding to processing sites of amphiregulin and HB-EGF and increases their shedding when transfected into TACE-deficient cells.","method":"In vitro cleavage assay with purified TACE; TACE-deficient cells + adenoviral TACE rescue; co-transfection; Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — purified enzyme cleavage assay combined with cell-based rescue experiments and multiple EGF-family substrates; replicated in multiple labs","pmids":["11823465"],"is_preprint":false},{"year":2003,"finding":"Genetic reduction of functional TACE dosage greatly exacerbates the open-eye defect of Egfr(wa-2/wa-2) newborns, placing TACE upstream of EGFR ligand availability in vivo during eye development.","method":"Epistasis in compound mutant mice (TACE heterozygous × EGFR hypomorphic wa-2 allele); phenotype scoring","journal":"Annals of the New York Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis experiment in vivo placing TACE upstream of EGFR; result built on and replicated from the 2002 JBC study","pmids":["12814936"],"is_preprint":false},{"year":2003,"finding":"TACE/ADAM17 null mutant mice exhibit markedly enlarged fetal hearts with increased myocardial trabeculation, larger cardiomyocyte size, and increased proliferation. Molecular analysis showed reduced EGFR expression, attenuated ErbB4 cleavage, and altered MAPK activation in knockout hearts, indicating TACE-mediated ectodomain shedding is required for normal cardiac development.","method":"Genetic knockout mouse model (TACE ΔZn/ΔZn); histology; Western blot; immunostaining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined molecular and cellular phenotype; multiple orthogonal methods","pmids":["14499647"],"is_preprint":false},{"year":2005,"finding":"Aspirin induces dose-dependent shedding of platelet surface GPIbα and GPV via ADAM17; shedding was completely blocked in mouse platelets expressing an inactive form of ADAM17 and by a broad-range metalloproteinase inhibitor, but occurred normally in COX-1-deficient platelets.","method":"FACS on whole blood; immunoprecipitation; Western blot; ADAM17-inactive knock-in mice; COX-1 knockout mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ADAM17 catalytic-inactive knock-in mice combined with pharmacological inhibition and multiple orthogonal readouts","pmids":["16179345"],"is_preprint":false},{"year":2006,"finding":"The TACE zymogen cysteine-switch motif in the prodomain is not required for maintaining the inactive precursor state or for secretion; the prodomain maintains latency and aids secretion by preventing the catalytic domain from adopting its native active conformation, resembling a molecular chaperone mechanism.","method":"Site-directed mutagenesis of prodomain; cell-based zymogen activity assays","journal":"Cell biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — mutagenesis plus activity assay in a single study; mechanistically important negative result","pmids":["16679521"],"is_preprint":false},{"year":2008,"finding":"In Drosophila, TACE (dTACE) can activate Notch in a ligand-independent manner when overexpressed, whereas Kuzbanian (Kuz) requires Delta stimulation; TACE-dependent Notch cleavage in the developing nervous system can thus bypass ligand engagement.","method":"In vitro Drosophila cell model; overexpression and genetic manipulation; Notch reporter assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell-based epistasis and overexpression in Drosophila model; single lab study","pmids":["18535782"],"is_preprint":false},{"year":2008,"finding":"HDLs activate ADAM17-dependent shedding of TNFR1, TNFR2, and TNF by reducing cholesterol content of lipid rafts, displacing ADAM17 from rafts to non-raft membrane regions where it cleaves substrates; apoA1 mediates this through ABCA1-dependent cholesterol efflux.","method":"Cell-based shedding assays; lipid raft fractionation; cell-free isolated membrane assays; ADAM17 inhibitors; ABCA1 knockdown","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods including cell-free membrane assay; single lab","pmids":["17786981"],"is_preprint":false},{"year":2008,"finding":"ADAM17-mediated release of amphiregulin (AREG) from mammary ductal epithelial cells activates EGFR on stromal cells to drive ductal development; tissue recombination and transplantation showed that ADAM17 and AREG must be on epithelial cells and EGFR on stromal cells, and soluble AREG rescues ADAM17-deficient transplants.","method":"Mammary tissue recombination and transplantation; local AREG administration rescue experiment","journal":"Journal of mammary gland biology and neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue recombination epistasis with rescue, single lab","pmids":["18470483"],"is_preprint":false},{"year":2010,"finding":"TACE/ADAM17 mediates physiological germ cell apoptosis during the first wave of spermatogenesis by cleaving the extracellular domain of the KIT receptor; pharmacological inhibition of TACE/ADAM17 (but not ADAM10) significantly prevented germ cell apoptosis, and PMA-induced TACE activation triggered KIT ectodomain cleavage and apoptosis in ex vivo testis culture.","method":"Pharmacological inhibition in vivo/ex vivo; PMA stimulation; immunostaining; Western blot; rat testis culture","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological gain- and loss-of-function with defined substrate identification; single lab","pmids":["20501791"],"is_preprint":false},{"year":2011,"finding":"TACE/ADAM17 cleaves neuregulin-1 (NRG1) type III in the EGF domain, inactivating it (assessed by loss of PI3K pathway activation), and thereby negatively regulates peripheral nervous system myelination. Lentiviral TACE knockdown in DRG neurons accelerates myelination onset and causes hypermyelination; motor neuron-specific TACE knockout mice are hypermyelinated and show aberrant myelination of small-caliber fibers.","method":"Lentiviral knockdown in DRG neuron co-cultures; conditional knockout mice (motor neuron-specific); electrophysiology; electron microscopy; PI3K pathway assays","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mice plus in vitro lentiviral KD with multiple orthogonal methods and substrate identification; published in high-impact journal","pmids":["21666671"],"is_preprint":false},{"year":2011,"finding":"The tetraspanin CD9 directly associates with ADAM17 on the cell surface (shown by co-immunoprecipitation, crosslinking, proximity ligation, and pull-down) and negatively regulates ADAM17 sheddase activity; CD9 antibody treatment or overexpression reduces TNF-α and ICAM-1 shedding, whereas CD9 silencing increases ADAM17 activity.","method":"Co-immunoprecipitation; crosslinking; proximity ligation assay; pull-down; CD9 siRNA knockdown; overexpression; shedding assays","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — four orthogonal binding methods plus functional gain- and loss-of-function; single lab but rigorous","pmids":["21365281"],"is_preprint":false},{"year":2011,"finding":"TrkA and TrkB receptor tyrosine kinases induce MEK-dependent phosphorylation of ADAM17 at intracellular threonine 735, activating ADAM17 to cleave p75NTR and produce its intracellular domain (p75NTR-ICD), which is required for neurotrophin-dependent Erk/Akt activation and neuronal survival.","method":"Phosphorylation site identification; MEK inhibitors; ADAM17 depletion; overexpression of p75NTR-ICD rescue; PC12 cell survival assays; primary cerebellar granule neurons","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — specific phosphorylation site identified, epistasis confirmed by rescue experiment, multiple cell types tested","pmids":["21411748"],"is_preprint":false},{"year":2011,"finding":"A selective cross-domain human antibody was developed that inhibits cell-surface TACE activity by targeting an epitope outside the metalloprotease active site, demonstrating that TACE ectodomain regions beyond the catalytic site can allosterically control activity.","method":"Two-step phage display antibody selection; cell-surface TACE activity assays; epitope mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro antibody inhibition with defined non-active-site epitope; single study","pmids":["21415364"],"is_preprint":false},{"year":2012,"finding":"p53 transcriptionally activates TACE/ADAM17 as a previously unidentified target gene; TACE then activates NOTCH1 signaling to induce epidermal differentiation and suppress squamous cell carcinoma. FOS negatively regulates this p53/TACE/NOTCH1 differentiation axis.","method":"Conditional knockout mice; pharmacological p53/AP-1 manipulation; human SCC cell lines; ChIP/transcriptional assays; rescue experiments","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse models combined with human cell lines and epistasis; pathway position established by multiple orthogonal approaches","pmids":["22772468"],"is_preprint":false},{"year":2013,"finding":"ADAM17 is expressed by NK cells and its selective inhibition abrogates CD16 and CD62L shedding from activated NK cells; ADAM17 inhibition enhances interferon-γ production, particularly when NK cells are triggered through CD16.","method":"ADAM17-selective inhibitor; FACS for CD16/CD62L surface expression; NK cell stimulation assays; IFN-γ ELISA","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor with defined functional readouts; single lab","pmids":["23487023"],"is_preprint":false},{"year":2013,"finding":"HIV Nef recruits paxillin and Eed to activate TACE/ADAM17 and ADAM10; Pak2 phosphorylates paxillin at Ser272/274 to promote TACE-paxillin association and shuttling into extracellular vesicles via lipid rafts, whereas Pak1 phosphorylates Ser258 to inhibit this association. Activated TACE in EVs cleaves proTNFα.","method":"Co-immunoprecipitation; phospho-specific mutagenesis; lipid raft fractionation; EV isolation; proTNFα cleavage assay; Pak1/2 kinase assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, defined phosphorylation sites with mutagenesis, lipid raft fractionation, and substrate cleavage assay in a single study","pmids":["23317503"],"is_preprint":false},{"year":2013,"finding":"ADAM17 inhibition or knockdown in diabetic mouse kidney cortex reduces Nox4 expression and NADPH oxidase activity, as well as type IV collagen and fibronectin accumulation, placing ADAM17 upstream of Nox4-mediated oxidative stress in diabetic nephropathy.","method":"ADAM17-selective inhibitor (TMI-005) in vivo; siRNA knockdown in cultured proximal tubular cells; Western blot; NADPH oxidase activity assay","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition in vivo and in vitro; single lab","pmids":["23678045"],"is_preprint":false},{"year":2014,"finding":"TACE/ADAM17 genetic deletion in oligodendrocyte progenitor cells (OPs) impairs EGFR ligand (TGFα and HB-EGF) shedding, reduces EGFR signaling, causes premature cell cycle exit and reduced OL survival, and leads to deficits in CNS myelination and motor behavior. EGFR overexpression in TACE-deficient OPs rescues OL survival and myelination.","method":"Conditional knockout mice (NG2-Cre); EGFR overexpression rescue; immunohistochemistry; electron microscopy; behavioral tests; EGFR hypomorphic mouse epistasis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genetic epistasis rescue experiment and multiple orthogonal readouts","pmids":["25186737"],"is_preprint":false},{"year":2014,"finding":"ADAM17 mediates CXCR2 shedding from neutrophil surfaces in response to non-ligand stimuli (but not chemokine ligand-induced internalization); ADAM17 inhibitor, blocking antibody, and ADAM17 gene-targeted mice all block CXCR2 down-regulation, and ADAM17 blockade enhances neutrophil recruitment during acute inflammation.","method":"ADAM17-selective inhibitor; function-blocking antibody; ADAM17 gene-targeted mice; FACS; intravital microscopy/acute inflammation model","journal":"Journal of leukocyte biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent ADAM17-targeting approaches (inhibitor, antibody, genetic) with in vivo functional readout","pmids":["25412626"],"is_preprint":false},{"year":2015,"finding":"TACE/ADAM17 is required for oligodendrocyte regeneration and CNS remyelination following demyelination; TACE depletion in OPs abrogates EGFR activation in OL lineage cells and impairs cell expansion and survival. EGFR overexpression in TACE-deficient OPs restores OL regeneration and CNS remyelination.","method":"Conditional knockout mice; demyelination model; EGFR overexpression rescue; immunohistochemistry; electron microscopy","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genetic epistasis rescue in disease model; replication of CNS myelination role from prior study (PMID 25186737)","pmids":["26338334"],"is_preprint":false},{"year":2016,"finding":"ADAM17 activity is controlled by subcellular localization: it is constitutively internalized via clathrin-coated pits, with only a small fraction at the cell surface. Physiological GPCR-ligand stimulation activates ADAM17 shedding without altering cell-surface abundance, whereas PMA/PKC activation causes rapid increase of mature ADAM17 at the cell surface followed by its internalization and degradation.","method":"Live-cell imaging; cell surface biotinylation; clathrin inhibitors; FACS; pulse-chase","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence using multiple methods; single lab","pmids":["27731361"],"is_preprint":false},{"year":2016,"finding":"In the IL-6 receptor (IL-6R), deletion of a triple serine motif (Ser-359 to Ser-361) adjacent to the cleavage site prevents ADAM17-mediated cleavage but not ADAM10-mediated cleavage, because it reduces the distance between the cleavage site and the plasma membrane below the threshold required for ADAM17.","method":"Site-directed mutagenesis of IL-6R stalk; cell-based shedding assays; chimeric receptor constructs with altered juxtamembrane spacing","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with mechanistic dissection of cleavage site geometry; single lab but multiple constructs","pmids":["27151651"],"is_preprint":false},{"year":2016,"finding":"Adam17 deficiency (hypomorphic mice) leads to increased membrane-resident TNFα and TNFR2 protein levels, constitutive TNFR2 signaling activation, and proatherosclerotic cellular functions (increased macrophage/VSMC proliferation, reduced apoptosis, increased adhesion); siRNA knockdown of TNFR2 rescues aberrant proliferation in Adam17-depleted cells, placing TNFR2 downstream of ADAM17 in this pathway.","method":"Adam17 hypomorphic mice crossed to Ldlr-/- background; siRNA TNFR2 rescue; cell proliferation/apoptosis assays; Western blot; atherosclerosis lesion analysis","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis rescue (TNFR2 siRNA in ADAM17-depleted cells) plus in vivo hypomorphic mouse model with multiple endpoints","pmids":["28062509"],"is_preprint":false},{"year":2016,"finding":"ADAM17 substrate release in kidney proximal tubule (particularly pro-TNFα and amphiregulin) drives persistent EGFR activation leading to macrophage/neutrophil ingress and fibrosis; proximal tubule-specific inducible ADAM17 KO (Slc34a1-Cre), ADAM17 hypomorphic mice, and pharmacological ADAM17 inhibition all protect against kidney fibrosis.","method":"Conditional knockout mice; ADAM17 hypomorphic mice; ADAM17 inhibitor; EGFR phosphorylation assays; histology; urine AREG ELISA; human kidney biopsy analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — three independent ADAM17-targeting approaches (genetic KO, hypomorphic, pharmacological) with in vitro and in vivo mechanistic validation and human data correlation","pmids":["27642633"],"is_preprint":false},{"year":2018,"finding":"iNOS/NO activates TACE/ADAM17 through a soluble guanylyl cyclase/cGMP/PKG-dependent pathway and up-regulates iRhom2, leading to Notch1 cleavage and activation specifically in CD24+CD133+ liver cancer stem cells (LCSCs), promoting stemness and HCC aggressiveness.","method":"In vitro signaling pathway dissection (sGC/cGMP/PKG inhibitors); iRhom2 expression analysis; xenograft tumor model; patient HCC correlation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological pathway dissection with in vivo xenograft validation; single lab","pmids":["30297396"],"is_preprint":false},{"year":2019,"finding":"HIF-1α directly transcriptionally activates ADAM17 in macrophages (identified as a novel HIF-1α target gene by ChIP), and macrophage HIF-1α/ADAM17 signaling drives vascular inflammation and extracellular matrix degradation in aortic dissection.","method":"ChIP assay; ELISA; immunofluorescence; metabolomics; macrophage-specific HIF-1α inhibition (acriflavine); mouse aortic dissection models","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP establishes direct transcriptional regulation, pharmacological inhibition confirms functional consequence; single lab","pmids":["31640947"],"is_preprint":false},{"year":2019,"finding":"ADAM17 colocalizes with angiotensin-II type 1 receptors on Sim1 neurons in the hypothalamic paraventricular nucleus; selective neuronal ADAM17 knockdown reduces FosB expression, increases vagal tone, and prevents acute pressor response to centrally administered angiotensin-II, placing neuronal ADAM17 as a regulator of sympathetic outflow and blood pressure.","method":"Neuron-specific conditional knockdown mouse models; photoactivation; neuronal culture; angiotensin-II central injection; blood pressure telemetry","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-type-specific KD with defined functional readouts; single lab","pmids":["31564162"],"is_preprint":false},{"year":2019,"finding":"ADAM17 is required for oncogenic HPV16 entry: ADAM17 proteinase activity sheds growth factors, activating ERK1/2 signaling that triggers formation of an endocytic entry platform consisting of enlarged CD151 domains containing EGFR.","method":"ADAM17 inhibitor; ERK1/2 pathway inhibitors; live-cell imaging; proximity assays for CD151/EGFR complex; virus infection assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus pathway dissection with live imaging; single lab","pmids":["31107240"],"is_preprint":false},{"year":2020,"finding":"ADAM10 and ADAM17 cleave PD-L1 from the surface of tumor cells and extracellular vesicles to produce a soluble active sPD-L1 fragment that induces CD8+ T cell apoptosis and impairs tumor cell killing by CD8+ T cells.","method":"ADAM10/17 inhibitor; cell-based shedding assay; CD8+ T cell apoptosis assay; tumor cell killing assay; correlation of PD-L1 protein-to-mRNA ratios with ADAM expression","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with functional immunological readouts; single lab","pmids":["32363112"],"is_preprint":false},{"year":2020,"finding":"The transmembrane domain (TMD) and extracellular juxtamembrane domain (JMD) of ADAM17 interact functionally with the TMD and JMD of iRhom2 to control ADAM17 stimulation and substrate selectivity. A point mutation in the ADAM17 JMD from a Tetralogy of Fallot patient specifically alters ADAM17 substrate selectivity toward HB-EGF.","method":"ADAM17 TMD chimeric/mutant constructs; Adam17-/- and iRhom1/2-/- cell rescue experiments; substrate-selective shedding assays; patient variant analysis","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with mechanistic dissection in double-KO cell systems; patient variant provides functional validation","pmids":["32103528"],"is_preprint":false},{"year":2020,"finding":"Endogenous iRhom2 protein stability requires the presence of ADAM17: iRhom2 is barely detectable in ADAM17-deficient mouse embryonic fibroblasts and macrophages, whereas iRhom1 levels are not reduced (slightly increased) without ADAM17, indicating iRhom2 and ADAM17 are obligate binding partners.","method":"Cell surface biotinylation; Western blot in Adam17-/- cells; LPS-stimulated bone marrow-derived macrophages","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct endogenous protein analysis in genetic KO cells; single lab, two cell types","pmids":["32060096"],"is_preprint":false},{"year":2020,"finding":"NNK (tobacco carcinogen) upregulates p38 MAPK-dependent threonine phosphorylation of ADAM17, activating shedding of soluble IL-6 receptor (sIL-6R) which drives ERK MAPK trans-signaling; ADAM17 deficiency abrogates sIL-6R shedding and downstream ERK signaling in lung adenocarcinoma cells, and NNK-treated hypomorphic Adam17 mice show markedly reduced lung tumorigenesis.","method":"Adam17 hypomorphic mice in NNK carcinogenesis model; CRISPR KO and pharmacological inhibition in human lung cancer cells; p38 inhibitor; threonine phosphorylation assays; sIL-6R ELISA; ERK phosphorylation Western blot","journal":"Carcinogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic hypomorphic model plus CRISPR KO plus pharmacological inhibition with defined phosphorylation mechanism and substrate; multiple orthogonal approaches","pmids":["31257400"],"is_preprint":false},{"year":2021,"finding":"ADAM17 on endothelial cells mediates TNFR1 ectodomain shedding, and subsequent processing of the remaining stub by γ-secretase is required for TNF-induced necroptosis; genetic ablation of ADAM17 in endothelial cells prevents tumor cell-induced endothelial necroptosis, extravasation, and lung metastasis.","method":"Endothelial-specific ADAM17 conditional KO mice; pharmacological ADAM17 inhibition; necroptosis assays; metastasis lung colonization model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO combined with pharmacological inhibition and mechanistic dissection of TNFR1 processing cascade","pmids":["34919140"],"is_preprint":false},{"year":2021,"finding":"ADAM17 on classical swine fever virus (CSFV)-permissive cells directly binds the viral envelope protein E2 via its metalloproteinase domain in a zinc-dependent manner; ADAM17 loss eliminates E2 binding and viral entry, and re-expression of pig, human, or mouse ADAM17 rescues infection.","method":"Pull-down assay with soluble E2; ADAM17 KO cell line; ADAM17 cDNA rescue; domain mapping; CSFV infection assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein-protein binding assay, domain mapping, complete rescue with cDNA, multiple ADAM17 orthologs tested","pmids":["33684175"],"is_preprint":false},{"year":2021,"finding":"ADAM17 blockade with a monoclonal antibody markedly increases human NK cell proliferation driven by IL-15 both in vitro and in xenograft mice; this proliferative boost is dependent on CD62L, whose surface levels are increased by ADAM17 blockade, revealing a negative feedback loop in which IL-15-activated ADAM17 limits NK cell proliferation by shedding CD62L.","method":"ADAM17-blocking monoclonal antibody; in vitro proliferation assay; xenograft mouse model; CD62L blocking antibody epistasis","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antibody blockade with in vivo xenograft and genetic epistasis via CD62L blocking; single lab","pmids":["34367174"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function mutations in RHBDF2 (iRHOM2) cause defective ADAM17-dependent cleavage and release of TNF and amphiregulin in human patients, leading to immune dysregulation; Rhbdf2-/- mice show more severe pneumonia after P. aeruginosa challenge and worse colitis after Citrobacter infection than wild-type mice.","method":"Human genetic disease study with functional validation; Rhbdf2-/- mouse infection models; cytokine release assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — human loss-of-function genetics confirmed by mouse model with defined substrate release defect; published in high-impact journal","pmids":["34937930"],"is_preprint":false},{"year":2022,"finding":"Active ADAM17 directly cleaves the insulin receptor (IR) beta subunit ectodomain from endothelial cells; ADAM17 overexpression or PMA-induced ADAM17 activation reduces IRα surface levels and impairs insulin signaling, which is rescued by ADAM17 inhibition (TAPI-0), and IR shedding is increased in arteries from T2D patients.","method":"In vitro cleavage assay with recombinant ADAM17 and IR; ADAM17 overexpression; TAPI-0 inhibitor rescue; cell surface biotinylation; human artery vasodilation assay","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro cleavage assay with recombinant proteins combined with pharmacological rescue in human tissue; single lab","pmids":["36018759"],"is_preprint":false},{"year":2022,"finding":"ADAM17 knockdown reduces, while ADAM17 overexpression aggravates, cardiac fibrosis in diabetic mice by regulating ACE2 shedding and cardiac fibroblast-to-myofibroblast transformation through the TGF-β1/Smad3 signaling pathway.","method":"Adenovirus-mediated shRNA knockdown and ADAM17 overexpression in diabetic mouse hearts; echocardiography; histology; TGF-β1/Smad3 pathway Western blot; primary cardiofibroblasts","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vivo with pathway mechanistic readout; single lab","pmids":["36313337"],"is_preprint":false},{"year":2022,"finding":"ADAM17 mediates experimental pancreatitis by shedding TNFα and soluble IL-6R (sIL-6R), activating IL-6 trans-signaling/STAT3 axis; genetic (Adam17ex/ex hypomorphic mice) and pharmacological (ADAM17 prodomain inhibitor A17pro) ADAM17 targeting ameliorates acute and chronic pancreatitis.","method":"Adam17ex/ex hypomorphic mice; ADAM17 prodomain inhibitor; cerulein and NNK pancreatitis models; IL-6/STAT3 pathway assays; histology; human pancreatitis biopsy correlation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic hypomorphic model plus pharmacological inhibition with defined mechanistic pathway and human tissue correlation","pmids":["36215509"],"is_preprint":false},{"year":2024,"finding":"In lupus, IFN-I signaling inhibits Langerhans cell (LC) ADAM17 sheddase activity (without consistently reducing ADAM17 protein expression or LC numbers), leading to reduced EGFR ligand release and impaired keratinocyte survival after UV radiation; IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity via restoration of UVR-induced cytoplasmic reactive oxygen species, and this restoration reduces photosensitive responses in an LC ADAM17-dependent manner.","method":"Transcriptomic analysis; IFN-I treatment of murine and human LCs; IFNAR blocking antibody in three lupus mouse models; ROS measurement; ADAM17 sheddase activity assay; LC-specific ADAM17 genetic ablation epistasis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple lupus mouse models, human LC validation, IFNAR blockade rescue, and LC-specific ADAM17 KO epistasis; multiple orthogonal methods","pmids":["38860651"],"is_preprint":false}],"current_model":"ADAM17 (TACE) is a membrane-anchored zinc-dependent metalloprotease that is the principal sheddase for pro-TNFα (cleaving the Ala76-Val77 bond), EGFR family ligands (TGFα, amphiregulin, HB-EGF), cytokine receptors (IL-6R, TNFR1/2), adhesion molecules (CD62L, GPIbα, GPV, CXCR2, CD16), NRG1 type III, p75NTR, the insulin receptor, ACE2, and PD-L1; its catalytic activity is controlled by regulated trafficking between lipid rafts and non-raft membrane (where it is active), clathrin-mediated constitutive internalization, phosphorylation of intracellular Thr735 (by Trk/MEK and p38 MAPK), interaction with its obligate co-factor iRhom2 (which is itself stabilized by ADAM17), negative regulation by the tetraspanin CD9, and allosteric modulation through its transmembrane and juxtamembrane domains; it functions upstream of EGFR signaling in mammary morphogenesis, CNS and PNS myelination, and oligodendrocyte regeneration, upstream of TNFR2 in vascular inflammation, and upstream of TNFR1 γ-secretase processing in necroptosis, with its transcription induced by HIF-1α and p53, making it a central regulatory hub in inflammation, development, and cancer."},"narrative":{"mechanistic_narrative":"ADAM17 (TACE) is a membrane-anchored, zinc-dependent metalloprotease that serves as a principal ectodomain sheddase, controlling inflammation, development, and tissue homeostasis by releasing the soluble forms of cell-surface proteins [PMID:9042103, PMID:11823465]. It was originally defined as the TNF-α converting enzyme, cleaving the Ala76-Val77 bond of the 26 kDa pro-TNF-α precursor to liberate mature soluble TNF-α, with TACE-deficient mice releasing 80-90% less soluble TNF-α and showing markedly reduced serum TNF-α after LPS challenge [PMID:9042103, PMID:10415747]. Beyond TNF-α, ADAM17 sheds a broad substrate repertoire including the EGFR-family ligands TGF-α, amphiregulin and HB-EGF [PMID:11823465], cytokine receptors (IL-6R, TNFR1, TNFR2) [PMID:27151651, PMID:34919140, PMID:28062509], adhesion and immune-receptor molecules (GPIbα/GPV, CXCR2, CD16, CD62L) [PMID:16179345, PMID:25412626, PMID:23487023, PMID:34367174], NRG1 type III [PMID:21666671], the KIT and p75NTR receptors [PMID:20501791, PMID:21411748], the insulin receptor [PMID:36018759], ACE2 [PMID:36313337], and PD-L1 [PMID:32363112]. Through release of EGFR ligands, ADAM17 acts genetically upstream of EGFR signaling in mammary ductal development, cardiac development, and CNS/PNS myelination and remyelination, where conditional deletion impairs oligodendrocyte survival and myelination and is rescued by EGFR overexpression [PMID:18470483, PMID:12814936, PMID:14499647, PMID:25186737, PMID:26338334, PMID:21666671]. Its catalytic activity is governed at multiple levels: regulated trafficking between cholesterol-rich lipid rafts and active non-raft membrane [PMID:17786981], constitutive clathrin-mediated internalization that limits surface enzyme [PMID:27731361], stimulus-induced intracellular threonine-735 phosphorylation via Trk/MEK and p38 MAPK pathways [PMID:21411748, PMID:31257400], allosteric control through non-active-site ectodomain epitopes and the transmembrane/juxtamembrane domains [PMID:21415364, PMID:32103528], negative regulation by the tetraspanin CD9 [PMID:21365281], and an obligate mutual-stabilization relationship with the rhomboid pseudoprotease iRhom2, which is required for substrate release and is itself destabilized in the absence of ADAM17 [PMID:32103528, PMID:32060096, PMID:34937930]. Its transcription is directly activated by p53 and by HIF-1α, integrating ADAM17 into differentiation, tumor suppression, and inflammatory programs [PMID:22772468, PMID:31640947]. Loss-of-function mutations in RHBDF2 (iRhom2) cause human immune dysregulation through defective ADAM17-dependent release of TNF and amphiregulin [PMID:34937930]. Functionally, ADAM17-driven shedding shapes diverse pathologies, including atherosclerosis via TNFR2 [PMID:28062509], TNFR1/γ-secretase-dependent endothelial necroptosis and metastasis [PMID:34919140], kidney and cardiac fibrosis [PMID:27642633, PMID:36313337], IL-6 trans-signaling in lung cancer and pancreatitis [PMID:31257400, PMID:36215509], and tumor immune evasion through soluble PD-L1 [PMID:32363112].","teleology":[{"year":1997,"claim":"Established the molecular identity of the protease that generates soluble TNF-α, answering which enzyme cleaves the membrane-anchored cytokine precursor.","evidence":"Protein purification, partial cloning, and in vitro cleavage assay defining the Ala76-Val77 cleavage site on pro-TNF-α","pmids":["9042103"],"confidence":"High","gaps":["In vitro cleavage does not establish in vivo contribution","Other physiological substrates not yet defined"]},{"year":1999,"claim":"Demonstrated that TACE is the dominant TNF-α converting enzyme in living animals, not merely in vitro, validating it as the principal in vivo sheddase for this cytokine.","evidence":"TACE-deficient and bone-marrow-reconstituted mice with ELISA for soluble TNF-α after LPS challenge","pmids":["10415747"],"confidence":"High","gaps":["Residual shedding implies additional proteases","Did not address non-TNF substrates"]},{"year":2002,"claim":"Expanded the substrate repertoire beyond TNF-α to EGFR-family ligands, reframing ADAM17 as a general sheddase coupling cell-surface ligand release to growth-factor signaling.","evidence":"Purified enzyme cleavage assays plus TACE-deficient keratinocyte rescue for TGF-α, amphiregulin, and HB-EGF","pmids":["11823465"],"confidence":"High","gaps":["Relative physiological importance of each ligand not ranked","Tissue-specific substrate selection unresolved"]},{"year":2003,"claim":"Placed TACE genetically upstream of EGFR signaling in development, establishing the sheddase as a rate-limiting controller of EGFR ligand availability in vivo.","evidence":"Genetic epistasis in compound TACE-heterozygous × EGFR-hypomorphic mice and TACE-null heart phenotyping","pmids":["12814936","14499647"],"confidence":"High","gaps":["Which specific ligand drives each developmental phenotype not fully dissected","Mechanism of activity regulation in vivo unknown"]},{"year":2006,"claim":"Clarified how the zymogen is held latent, showing the prodomain acts as a chaperone-like conformational restraint rather than via the canonical cysteine-switch.","evidence":"Site-directed mutagenesis of the prodomain with cell-based zymogen activity assays","pmids":["16679521"],"confidence":"Medium","gaps":["Structural basis of conformational restraint not resolved","Single-study mechanistic model"]},{"year":2008,"claim":"Identified membrane microdomain partitioning as a control switch, showing cholesterol-dependent displacement from lipid rafts to non-raft regions activates shedding.","evidence":"Cell-based and cell-free membrane shedding assays with raft fractionation and ABCA1 knockdown","pmids":["17786981"],"confidence":"Medium","gaps":["Molecular determinant of raft partitioning not identified","Single lab"]},{"year":2008,"claim":"Demonstrated that ADAM17-released amphiregulin acts as a paracrine signal across tissue compartments, establishing the directionality of the ADAM17→AREG→EGFR axis in mammary morphogenesis.","evidence":"Mammary tissue recombination/transplantation with soluble AREG rescue","pmids":["18470483"],"confidence":"Medium","gaps":["Quantitative thresholds of paracrine signaling unknown","Single lab"]},{"year":2010,"claim":"Extended ADAM17 substrate biology to receptor-tyrosine-kinase shedding controlling cell fate, showing KIT ectodomain cleavage drives physiological germ cell apoptosis.","evidence":"Pharmacological gain/loss-of-function (ADAM17 vs ADAM10 selectivity) and PMA stimulation in rat testis culture","pmids":["20501791"],"confidence":"Medium","gaps":["Relies on pharmacology rather than genetic ADAM17 loss","Single lab"]},{"year":2011,"claim":"Revealed phosphorylation-based activation and direct partner-mediated regulation, mapping Thr735 phosphorylation by Trk/MEK and identifying CD9 as a negative regulator binding ADAM17.","evidence":"Phosphosite mapping with MEK inhibitors and rescue (p75NTR); four orthogonal binding methods plus CD9 gain/loss-of-function shedding assays","pmids":["21411748","21365281"],"confidence":"High","gaps":["Phosphatase counter-regulation not defined","How CD9 binding inhibits catalysis structurally unknown"]},{"year":2011,"claim":"Established a counterintuitive substrate that ADAM17 inactivates, showing NRG1 type III cleavage negatively regulates myelination, broadening sheddase outcomes beyond ligand activation.","evidence":"Conditional knockout and lentiviral knockdown in DRG/motor neurons with EM, electrophysiology, and PI3K assays","pmids":["21666671"],"confidence":"High","gaps":["Whether NRG1 cleavage is regulated independently of EGFR-ligand shedding unclear"]},{"year":2012,"claim":"Identified transcriptional control by p53 and positioned ADAM17 within a tumor-suppressive NOTCH1 differentiation axis, linking sheddase abundance to cancer biology.","evidence":"Conditional KO mice, human SCC lines, ChIP and rescue experiments","pmids":["22772468"],"confidence":"High","gaps":["Mechanism of TACE-NOTCH1 activation in this context not fully resolved","Generality across tumor types untested"]},{"year":2013,"claim":"Defined ADAM17's role in shaping immune effector function through receptor shedding and uncovered a non-canonical activation/secretion route in viral pathogenesis.","evidence":"Selective inhibitor with NK CD16/CD62L FACS and IFN-γ assays; HIV-Nef-driven paxillin/Pak phosphorylation, raft fractionation, and EV pro-TNF cleavage","pmids":["23487023","23317503"],"confidence":"High","gaps":["NK functional readouts rely on pharmacology","Physiological relevance of EV-packaged ADAM17 beyond HIV unclear"]},{"year":2014,"claim":"Confirmed allosteric, non-active-site regulation and established ADAM17 as a genetic driver of EGFR-dependent oligodendrocyte survival and CNS myelination via rescue epistasis.","evidence":"Cross-domain inhibitory antibody with epitope mapping; conditional OP knockout with EGFR-overexpression rescue, EM, and behavior","pmids":["21415364","25186737"],"confidence":"High","gaps":["Endogenous ligand for the allosteric site unknown","Which EGFR ligand is rate-limiting in OPs not fully isolated"]},{"year":2014,"claim":"Demonstrated stimulus-selective shedding of CXCR2 from neutrophils, distinguishing ADAM17-dependent receptor down-regulation from ligand-induced internalization and linking it to inflammatory recruitment.","evidence":"Selective inhibitor, blocking antibody, and gene-targeted mice with intravital microscopy","pmids":["25412626"],"confidence":"High","gaps":["Signal coupling non-ligand stimuli to ADAM17 not defined"]},{"year":2016,"claim":"Resolved how subcellular trafficking and cleavage-site geometry govern activity and substrate selection, showing constitutive internalization limits surface enzyme and juxtamembrane spacing discriminates ADAM17 from ADAM10.","evidence":"Live-cell imaging, biotinylation, clathrin inhibitors; IL-6R stalk mutagenesis with chimeric spacing constructs","pmids":["27731361","27151651"],"confidence":"High","gaps":["How GPCR stimulation activates surface enzyme without altering abundance unresolved","Generality of distance threshold across substrates untested"]},{"year":2016,"claim":"Established ADAM17 as a homeostatic brake on TNFR2 signaling and a driver of EGFR-dependent organ fibrosis, defining downstream pathway position by genetic rescue.","evidence":"Adam17 hypomorphic mice on Ldlr-/- with TNFR2 siRNA rescue; proximal-tubule conditional KO, hypomorphic, and inhibitor approaches with human biopsy correlation","pmids":["28062509","27642633"],"confidence":"High","gaps":["Balance between protective and pathogenic shedding context-dependence not fully mapped"]},{"year":2018,"claim":"Connected nitric-oxide signaling to ADAM17 activation and iRhom2 upregulation driving NOTCH1 in cancer stem cells, integrating second-messenger pathways with sheddase output.","evidence":"sGC/cGMP/PKG pathway dissection with xenograft and patient HCC correlation","pmids":["30297396"],"confidence":"Medium","gaps":["Direct molecular link from PKG to ADAM17 activation not shown","Single lab"]},{"year":2019,"claim":"Identified HIF-1α as a direct transcriptional activator of ADAM17 in macrophages, linking hypoxia/inflammatory signaling to sheddase-driven vascular pathology, and extended ADAM17 roles into neural blood-pressure control and viral entry.","evidence":"ChIP and macrophage HIF-1α inhibition in aortic dissection; neuron-specific knockdown with BP telemetry; ADAM17 inhibitor in HPV16 entry assays","pmids":["31640947","31564162","31107240"],"confidence":"Medium","gaps":["Mechanistic link from neuronal ADAM17 to sympathetic outflow incomplete","Viral-entry role relies on pharmacology"]},{"year":2020,"claim":"Mechanistically dissected the iRhom2-ADAM17 partnership at the transmembrane/juxtamembrane interface and as an obligate mutual-stabilization pair, and broadened immune-evasion roles via PD-L1 shedding.","evidence":"TMD/JMD chimeric and patient-variant constructs in double-KO cells; endogenous iRhom2 stability assays in Adam17-/- cells; PD-L1 shedding and T-cell killing assays","pmids":["32103528","32060096","32363112"],"confidence":"High","gaps":["Structural model of the ADAM17-iRhom2 interface not resolved","How interface controls substrate selectivity mechanistically unclear"]},{"year":2021,"claim":"Established ADAM17 as a sequential processing initiator in TNFR1-dependent endothelial necroptosis driving metastasis, and revealed a direct, catalysis-independent role as a viral entry receptor.","evidence":"Endothelial-specific conditional KO plus inhibition in necroptosis/metastasis; direct E2-binding pull-down, domain mapping, and cross-species cDNA rescue for CSFV; IL-15/CD62L NK feedback antibody study","pmids":["34919140","33684175","34367174"],"confidence":"High","gaps":["How ADAM17 shedding and γ-secretase processing are coordinated unknown","Whether viral binding alters catalytic activity unaddressed"]},{"year":2021,"claim":"Connected the ADAM17 pathway to a human Mendelian immune disorder, showing RHBDF2/iRhom2 loss-of-function impairs ADAM17-dependent TNF and amphiregulin release.","evidence":"Human genetic disease study with functional cytokine-release validation and Rhbdf2-/- mouse infection models","pmids":["34937930"],"confidence":"High","gaps":["Tissue-specific consequences of iRhom2 loss on ADAM17 substrate spectrum not fully mapped"]},{"year":2022,"claim":"Extended the substrate range to the insulin receptor and ACE2 and linked ADAM17 shedding to metabolic and cardiac-fibrotic disease via defined downstream pathways.","evidence":"Recombinant cleavage and inhibitor rescue for insulin receptor with human artery data; adenoviral knockdown/overexpression in diabetic hearts with TGF-β1/Smad3 readout; hypomorphic mice and prodomain inhibitor in pancreatitis with IL-6/STAT3 axis","pmids":["36018759","36313337","36215509"],"confidence":"Medium","gaps":["In vivo contribution of ADAM17 to insulin-receptor shedding genetically untested","Mechanism activating ADAM17 in metabolic disease incompletely defined"]},{"year":2024,"claim":"Showed that ADAM17 sheddase activity, not abundance, is the regulated node, with IFN-I signaling suppressing ROS-dependent ADAM17 activity in Langerhans cells to drive photosensitivity in lupus.","evidence":"Multiple lupus mouse models, human LC validation, IFNAR blockade rescue, and LC-specific ADAM17 KO epistasis with ROS measurement","pmids":["38860651"],"confidence":"High","gaps":["Molecular link from ROS to ADAM17 catalytic activation not defined","Relevant EGFR ligand in keratinocyte survival not isolated"]},{"year":null,"claim":"A unified structural and regulatory model explaining how trafficking, phosphorylation, iRhom interaction, redox state, and cleavage-site geometry are integrated to select among ADAM17's many substrates in a given cell remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of the active ADAM17-iRhom2 complex in the timeline","Mechanism converting diverse upstream stimuli into specific substrate selection unknown","Quantitative rules governing tissue-specific substrate preference undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,5,11,23,34,38]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,38]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[8,12,22]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[17,30]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,16,20,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,13,19,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4,9,11,19]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,2,23,38]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[10,34]}],"complexes":[],"partners":["RHBDF2","CD9","CD16","EGFR","TNFR2","IL6R","KIT"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P78536","full_name":"Disintegrin and metalloproteinase domain-containing protein 17","aliases":["Snake venom-like protease","TNF-alpha convertase","TNF-alpha-converting enzyme"],"length_aa":824,"mass_kda":93.0,"function":"Transmembrane metalloprotease which mediates the ectodomain shedding of a myriad of transmembrane proteins including adhesion proteins, growth factor precursors and cytokines important for inflammation and immunity (PubMed:24226769, PubMed:24227843, PubMed:28060820, PubMed:28923481). Cleaves the membrane-bound precursor of TNF to its mature soluble form (PubMed:36078095, PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820). Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells. Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:28923481)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P78536/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM17","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADAM17","total_profiled":1310},"omim":[{"mim_id":"621490","title":"HYPOTRICHOSIS 16; HYPT16","url":"https://www.omim.org/entry/621490"},{"mim_id":"618337","title":"FERM DOMAIN-CONTAINING PROTEIN 8; FRMD8","url":"https://www.omim.org/entry/618337"},{"mim_id":"615130","title":"UDP-N-ACETYL-ALPHA-D-GALACTOSAMINE:POLYPEPTIDE N-ACETYLGALACTOSAMINYLTRANSFERASE 11; GALNT11","url":"https://www.omim.org/entry/615130"},{"mim_id":"615029","title":"PRECEREBELLIN 4; CBLN4","url":"https://www.omim.org/entry/615029"},{"mim_id":"614404","title":"RHOMBOID 5 HOMOLOG 2; RHBDF2","url":"https://www.omim.org/entry/614404"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADAM17"},"hgnc":{"alias_symbol":["cSVP","CD156B"],"prev_symbol":["TACE"]},"alphafold":{"accession":"P78536","domains":[{"cath_id":"-","chopping":"33-89_107-170","consensus_level":"medium","plddt":80.2682,"start":33,"end":170},{"cath_id":"-","chopping":"478-517","consensus_level":"medium","plddt":82.0108,"start":478,"end":517},{"cath_id":"4.10.70","chopping":"519-579","consensus_level":"medium","plddt":89.7098,"start":519,"end":579},{"cath_id":"4.10.70.30","chopping":"588-658","consensus_level":"medium","plddt":76.06,"start":588,"end":658}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P78536","model_url":"https://alphafold.ebi.ac.uk/files/AF-P78536-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P78536-F1-predicted_aligned_error_v6.png","plddt_mean":72.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM17","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM17"},"sequence":{"accession":"P78536","fasta_url":"https://rest.uniprot.org/uniprotkb/P78536.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P78536/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P78536"}},"corpus_meta":[{"pmid":"23487023","id":"PMC_23487023","title":"NK cell CD16 surface expression and function is regulated by a disintegrin and metalloprotease-17 (ADAM17).","date":"2013","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/23487023","citation_count":452,"is_preprint":false},{"pmid":"21752713","id":"PMC_21752713","title":"ADAM17: a molecular switch to control inflammation and tissue regeneration.","date":"2011","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21752713","citation_count":434,"is_preprint":false},{"pmid":"11823465","id":"PMC_11823465","title":"Tumor necrosis factor-alpha converting enzyme (TACE) regulates epidermal growth factor receptor ligand availability.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11823465","citation_count":354,"is_preprint":false},{"pmid":"20184396","id":"PMC_20184396","title":"ADAM-17: the enzyme that does it all.","date":"2010","source":"Critical reviews in biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20184396","citation_count":338,"is_preprint":false},{"pmid":"28705384","id":"PMC_28705384","title":"The shedding protease ADAM17: Physiology and pathophysiology.","date":"2017","source":"Biochimica et biophysica acta. 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in vitro cleavage assay\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical purification and direct in vitro cleavage assay establishing enzymatic substrate and cleavage site; foundational study replicated by many subsequent labs\",\n      \"pmids\": [\"9042103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TACE-deficient mice (lacking proteolytically active TACE) release 80-90% less soluble TNF-α than wild-type cells, and irradiated mice reconstituted with TACE-knockout hematopoietic stem cells have markedly reduced serum TNF-α after LPS challenge, establishing TACE as the major TNF-α converting enzyme in vivo.\",\n      \"method\": \"Genetic knockout mouse model; bone marrow reconstitution; ELISA for soluble TNF-α\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined molecular phenotype, replicated in vivo with reconstitution experiment; widely cited foundational result\",\n      \"pmids\": [\"10415747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"TACE/ADAM17 cleaves pro-TGF-α at both N- and C-terminal processing sites to release soluble TGF-α; TACE-deficient primary keratinocytes shed dramatically less TGF-α, and TACE re-expression rescued shedding. TACE also cleaves peptide substrates corresponding to processing sites of amphiregulin and HB-EGF and increases their shedding when transfected into TACE-deficient cells.\",\n      \"method\": \"In vitro cleavage assay with purified TACE; TACE-deficient cells + adenoviral TACE rescue; co-transfection; Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — purified enzyme cleavage assay combined with cell-based rescue experiments and multiple EGF-family substrates; replicated in multiple labs\",\n      \"pmids\": [\"11823465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic reduction of functional TACE dosage greatly exacerbates the open-eye defect of Egfr(wa-2/wa-2) newborns, placing TACE upstream of EGFR ligand availability in vivo during eye development.\",\n      \"method\": \"Epistasis in compound mutant mice (TACE heterozygous × EGFR hypomorphic wa-2 allele); phenotype scoring\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis experiment in vivo placing TACE upstream of EGFR; result built on and replicated from the 2002 JBC study\",\n      \"pmids\": [\"12814936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TACE/ADAM17 null mutant mice exhibit markedly enlarged fetal hearts with increased myocardial trabeculation, larger cardiomyocyte size, and increased proliferation. Molecular analysis showed reduced EGFR expression, attenuated ErbB4 cleavage, and altered MAPK activation in knockout hearts, indicating TACE-mediated ectodomain shedding is required for normal cardiac development.\",\n      \"method\": \"Genetic knockout mouse model (TACE ΔZn/ΔZn); histology; Western blot; immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined molecular and cellular phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"14499647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aspirin induces dose-dependent shedding of platelet surface GPIbα and GPV via ADAM17; shedding was completely blocked in mouse platelets expressing an inactive form of ADAM17 and by a broad-range metalloproteinase inhibitor, but occurred normally in COX-1-deficient platelets.\",\n      \"method\": \"FACS on whole blood; immunoprecipitation; Western blot; ADAM17-inactive knock-in mice; COX-1 knockout mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ADAM17 catalytic-inactive knock-in mice combined with pharmacological inhibition and multiple orthogonal readouts\",\n      \"pmids\": [\"16179345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The TACE zymogen cysteine-switch motif in the prodomain is not required for maintaining the inactive precursor state or for secretion; the prodomain maintains latency and aids secretion by preventing the catalytic domain from adopting its native active conformation, resembling a molecular chaperone mechanism.\",\n      \"method\": \"Site-directed mutagenesis of prodomain; cell-based zymogen activity assays\",\n      \"journal\": \"Cell biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — mutagenesis plus activity assay in a single study; mechanistically important negative result\",\n      \"pmids\": [\"16679521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In Drosophila, TACE (dTACE) can activate Notch in a ligand-independent manner when overexpressed, whereas Kuzbanian (Kuz) requires Delta stimulation; TACE-dependent Notch cleavage in the developing nervous system can thus bypass ligand engagement.\",\n      \"method\": \"In vitro Drosophila cell model; overexpression and genetic manipulation; Notch reporter assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-based epistasis and overexpression in Drosophila model; single lab study\",\n      \"pmids\": [\"18535782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HDLs activate ADAM17-dependent shedding of TNFR1, TNFR2, and TNF by reducing cholesterol content of lipid rafts, displacing ADAM17 from rafts to non-raft membrane regions where it cleaves substrates; apoA1 mediates this through ABCA1-dependent cholesterol efflux.\",\n      \"method\": \"Cell-based shedding assays; lipid raft fractionation; cell-free isolated membrane assays; ADAM17 inhibitors; ABCA1 knockdown\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods including cell-free membrane assay; single lab\",\n      \"pmids\": [\"17786981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM17-mediated release of amphiregulin (AREG) from mammary ductal epithelial cells activates EGFR on stromal cells to drive ductal development; tissue recombination and transplantation showed that ADAM17 and AREG must be on epithelial cells and EGFR on stromal cells, and soluble AREG rescues ADAM17-deficient transplants.\",\n      \"method\": \"Mammary tissue recombination and transplantation; local AREG administration rescue experiment\",\n      \"journal\": \"Journal of mammary gland biology and neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue recombination epistasis with rescue, single lab\",\n      \"pmids\": [\"18470483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TACE/ADAM17 mediates physiological germ cell apoptosis during the first wave of spermatogenesis by cleaving the extracellular domain of the KIT receptor; pharmacological inhibition of TACE/ADAM17 (but not ADAM10) significantly prevented germ cell apoptosis, and PMA-induced TACE activation triggered KIT ectodomain cleavage and apoptosis in ex vivo testis culture.\",\n      \"method\": \"Pharmacological inhibition in vivo/ex vivo; PMA stimulation; immunostaining; Western blot; rat testis culture\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological gain- and loss-of-function with defined substrate identification; single lab\",\n      \"pmids\": [\"20501791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TACE/ADAM17 cleaves neuregulin-1 (NRG1) type III in the EGF domain, inactivating it (assessed by loss of PI3K pathway activation), and thereby negatively regulates peripheral nervous system myelination. Lentiviral TACE knockdown in DRG neurons accelerates myelination onset and causes hypermyelination; motor neuron-specific TACE knockout mice are hypermyelinated and show aberrant myelination of small-caliber fibers.\",\n      \"method\": \"Lentiviral knockdown in DRG neuron co-cultures; conditional knockout mice (motor neuron-specific); electrophysiology; electron microscopy; PI3K pathway assays\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mice plus in vitro lentiviral KD with multiple orthogonal methods and substrate identification; published in high-impact journal\",\n      \"pmids\": [\"21666671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The tetraspanin CD9 directly associates with ADAM17 on the cell surface (shown by co-immunoprecipitation, crosslinking, proximity ligation, and pull-down) and negatively regulates ADAM17 sheddase activity; CD9 antibody treatment or overexpression reduces TNF-α and ICAM-1 shedding, whereas CD9 silencing increases ADAM17 activity.\",\n      \"method\": \"Co-immunoprecipitation; crosslinking; proximity ligation assay; pull-down; CD9 siRNA knockdown; overexpression; shedding assays\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — four orthogonal binding methods plus functional gain- and loss-of-function; single lab but rigorous\",\n      \"pmids\": [\"21365281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TrkA and TrkB receptor tyrosine kinases induce MEK-dependent phosphorylation of ADAM17 at intracellular threonine 735, activating ADAM17 to cleave p75NTR and produce its intracellular domain (p75NTR-ICD), which is required for neurotrophin-dependent Erk/Akt activation and neuronal survival.\",\n      \"method\": \"Phosphorylation site identification; MEK inhibitors; ADAM17 depletion; overexpression of p75NTR-ICD rescue; PC12 cell survival assays; primary cerebellar granule neurons\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — specific phosphorylation site identified, epistasis confirmed by rescue experiment, multiple cell types tested\",\n      \"pmids\": [\"21411748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A selective cross-domain human antibody was developed that inhibits cell-surface TACE activity by targeting an epitope outside the metalloprotease active site, demonstrating that TACE ectodomain regions beyond the catalytic site can allosterically control activity.\",\n      \"method\": \"Two-step phage display antibody selection; cell-surface TACE activity assays; epitope mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro antibody inhibition with defined non-active-site epitope; single study\",\n      \"pmids\": [\"21415364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p53 transcriptionally activates TACE/ADAM17 as a previously unidentified target gene; TACE then activates NOTCH1 signaling to induce epidermal differentiation and suppress squamous cell carcinoma. FOS negatively regulates this p53/TACE/NOTCH1 differentiation axis.\",\n      \"method\": \"Conditional knockout mice; pharmacological p53/AP-1 manipulation; human SCC cell lines; ChIP/transcriptional assays; rescue experiments\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse models combined with human cell lines and epistasis; pathway position established by multiple orthogonal approaches\",\n      \"pmids\": [\"22772468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM17 is expressed by NK cells and its selective inhibition abrogates CD16 and CD62L shedding from activated NK cells; ADAM17 inhibition enhances interferon-γ production, particularly when NK cells are triggered through CD16.\",\n      \"method\": \"ADAM17-selective inhibitor; FACS for CD16/CD62L surface expression; NK cell stimulation assays; IFN-γ ELISA\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor with defined functional readouts; single lab\",\n      \"pmids\": [\"23487023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HIV Nef recruits paxillin and Eed to activate TACE/ADAM17 and ADAM10; Pak2 phosphorylates paxillin at Ser272/274 to promote TACE-paxillin association and shuttling into extracellular vesicles via lipid rafts, whereas Pak1 phosphorylates Ser258 to inhibit this association. Activated TACE in EVs cleaves proTNFα.\",\n      \"method\": \"Co-immunoprecipitation; phospho-specific mutagenesis; lipid raft fractionation; EV isolation; proTNFα cleavage assay; Pak1/2 kinase assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, defined phosphorylation sites with mutagenesis, lipid raft fractionation, and substrate cleavage assay in a single study\",\n      \"pmids\": [\"23317503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM17 inhibition or knockdown in diabetic mouse kidney cortex reduces Nox4 expression and NADPH oxidase activity, as well as type IV collagen and fibronectin accumulation, placing ADAM17 upstream of Nox4-mediated oxidative stress in diabetic nephropathy.\",\n      \"method\": \"ADAM17-selective inhibitor (TMI-005) in vivo; siRNA knockdown in cultured proximal tubular cells; Western blot; NADPH oxidase activity assay\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition in vivo and in vitro; single lab\",\n      \"pmids\": [\"23678045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TACE/ADAM17 genetic deletion in oligodendrocyte progenitor cells (OPs) impairs EGFR ligand (TGFα and HB-EGF) shedding, reduces EGFR signaling, causes premature cell cycle exit and reduced OL survival, and leads to deficits in CNS myelination and motor behavior. EGFR overexpression in TACE-deficient OPs rescues OL survival and myelination.\",\n      \"method\": \"Conditional knockout mice (NG2-Cre); EGFR overexpression rescue; immunohistochemistry; electron microscopy; behavioral tests; EGFR hypomorphic mouse epistasis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genetic epistasis rescue experiment and multiple orthogonal readouts\",\n      \"pmids\": [\"25186737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM17 mediates CXCR2 shedding from neutrophil surfaces in response to non-ligand stimuli (but not chemokine ligand-induced internalization); ADAM17 inhibitor, blocking antibody, and ADAM17 gene-targeted mice all block CXCR2 down-regulation, and ADAM17 blockade enhances neutrophil recruitment during acute inflammation.\",\n      \"method\": \"ADAM17-selective inhibitor; function-blocking antibody; ADAM17 gene-targeted mice; FACS; intravital microscopy/acute inflammation model\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent ADAM17-targeting approaches (inhibitor, antibody, genetic) with in vivo functional readout\",\n      \"pmids\": [\"25412626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TACE/ADAM17 is required for oligodendrocyte regeneration and CNS remyelination following demyelination; TACE depletion in OPs abrogates EGFR activation in OL lineage cells and impairs cell expansion and survival. EGFR overexpression in TACE-deficient OPs restores OL regeneration and CNS remyelination.\",\n      \"method\": \"Conditional knockout mice; demyelination model; EGFR overexpression rescue; immunohistochemistry; electron microscopy\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genetic epistasis rescue in disease model; replication of CNS myelination role from prior study (PMID 25186737)\",\n      \"pmids\": [\"26338334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM17 activity is controlled by subcellular localization: it is constitutively internalized via clathrin-coated pits, with only a small fraction at the cell surface. Physiological GPCR-ligand stimulation activates ADAM17 shedding without altering cell-surface abundance, whereas PMA/PKC activation causes rapid increase of mature ADAM17 at the cell surface followed by its internalization and degradation.\",\n      \"method\": \"Live-cell imaging; cell surface biotinylation; clathrin inhibitors; FACS; pulse-chase\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence using multiple methods; single lab\",\n      \"pmids\": [\"27731361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In the IL-6 receptor (IL-6R), deletion of a triple serine motif (Ser-359 to Ser-361) adjacent to the cleavage site prevents ADAM17-mediated cleavage but not ADAM10-mediated cleavage, because it reduces the distance between the cleavage site and the plasma membrane below the threshold required for ADAM17.\",\n      \"method\": \"Site-directed mutagenesis of IL-6R stalk; cell-based shedding assays; chimeric receptor constructs with altered juxtamembrane spacing\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with mechanistic dissection of cleavage site geometry; single lab but multiple constructs\",\n      \"pmids\": [\"27151651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Adam17 deficiency (hypomorphic mice) leads to increased membrane-resident TNFα and TNFR2 protein levels, constitutive TNFR2 signaling activation, and proatherosclerotic cellular functions (increased macrophage/VSMC proliferation, reduced apoptosis, increased adhesion); siRNA knockdown of TNFR2 rescues aberrant proliferation in Adam17-depleted cells, placing TNFR2 downstream of ADAM17 in this pathway.\",\n      \"method\": \"Adam17 hypomorphic mice crossed to Ldlr-/- background; siRNA TNFR2 rescue; cell proliferation/apoptosis assays; Western blot; atherosclerosis lesion analysis\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis rescue (TNFR2 siRNA in ADAM17-depleted cells) plus in vivo hypomorphic mouse model with multiple endpoints\",\n      \"pmids\": [\"28062509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM17 substrate release in kidney proximal tubule (particularly pro-TNFα and amphiregulin) drives persistent EGFR activation leading to macrophage/neutrophil ingress and fibrosis; proximal tubule-specific inducible ADAM17 KO (Slc34a1-Cre), ADAM17 hypomorphic mice, and pharmacological ADAM17 inhibition all protect against kidney fibrosis.\",\n      \"method\": \"Conditional knockout mice; ADAM17 hypomorphic mice; ADAM17 inhibitor; EGFR phosphorylation assays; histology; urine AREG ELISA; human kidney biopsy analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three independent ADAM17-targeting approaches (genetic KO, hypomorphic, pharmacological) with in vitro and in vivo mechanistic validation and human data correlation\",\n      \"pmids\": [\"27642633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"iNOS/NO activates TACE/ADAM17 through a soluble guanylyl cyclase/cGMP/PKG-dependent pathway and up-regulates iRhom2, leading to Notch1 cleavage and activation specifically in CD24+CD133+ liver cancer stem cells (LCSCs), promoting stemness and HCC aggressiveness.\",\n      \"method\": \"In vitro signaling pathway dissection (sGC/cGMP/PKG inhibitors); iRhom2 expression analysis; xenograft tumor model; patient HCC correlation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological pathway dissection with in vivo xenograft validation; single lab\",\n      \"pmids\": [\"30297396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HIF-1α directly transcriptionally activates ADAM17 in macrophages (identified as a novel HIF-1α target gene by ChIP), and macrophage HIF-1α/ADAM17 signaling drives vascular inflammation and extracellular matrix degradation in aortic dissection.\",\n      \"method\": \"ChIP assay; ELISA; immunofluorescence; metabolomics; macrophage-specific HIF-1α inhibition (acriflavine); mouse aortic dissection models\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP establishes direct transcriptional regulation, pharmacological inhibition confirms functional consequence; single lab\",\n      \"pmids\": [\"31640947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM17 colocalizes with angiotensin-II type 1 receptors on Sim1 neurons in the hypothalamic paraventricular nucleus; selective neuronal ADAM17 knockdown reduces FosB expression, increases vagal tone, and prevents acute pressor response to centrally administered angiotensin-II, placing neuronal ADAM17 as a regulator of sympathetic outflow and blood pressure.\",\n      \"method\": \"Neuron-specific conditional knockdown mouse models; photoactivation; neuronal culture; angiotensin-II central injection; blood pressure telemetry\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-type-specific KD with defined functional readouts; single lab\",\n      \"pmids\": [\"31564162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM17 is required for oncogenic HPV16 entry: ADAM17 proteinase activity sheds growth factors, activating ERK1/2 signaling that triggers formation of an endocytic entry platform consisting of enlarged CD151 domains containing EGFR.\",\n      \"method\": \"ADAM17 inhibitor; ERK1/2 pathway inhibitors; live-cell imaging; proximity assays for CD151/EGFR complex; virus infection assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus pathway dissection with live imaging; single lab\",\n      \"pmids\": [\"31107240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAM10 and ADAM17 cleave PD-L1 from the surface of tumor cells and extracellular vesicles to produce a soluble active sPD-L1 fragment that induces CD8+ T cell apoptosis and impairs tumor cell killing by CD8+ T cells.\",\n      \"method\": \"ADAM10/17 inhibitor; cell-based shedding assay; CD8+ T cell apoptosis assay; tumor cell killing assay; correlation of PD-L1 protein-to-mRNA ratios with ADAM expression\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with functional immunological readouts; single lab\",\n      \"pmids\": [\"32363112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The transmembrane domain (TMD) and extracellular juxtamembrane domain (JMD) of ADAM17 interact functionally with the TMD and JMD of iRhom2 to control ADAM17 stimulation and substrate selectivity. A point mutation in the ADAM17 JMD from a Tetralogy of Fallot patient specifically alters ADAM17 substrate selectivity toward HB-EGF.\",\n      \"method\": \"ADAM17 TMD chimeric/mutant constructs; Adam17-/- and iRhom1/2-/- cell rescue experiments; substrate-selective shedding assays; patient variant analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with mechanistic dissection in double-KO cell systems; patient variant provides functional validation\",\n      \"pmids\": [\"32103528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Endogenous iRhom2 protein stability requires the presence of ADAM17: iRhom2 is barely detectable in ADAM17-deficient mouse embryonic fibroblasts and macrophages, whereas iRhom1 levels are not reduced (slightly increased) without ADAM17, indicating iRhom2 and ADAM17 are obligate binding partners.\",\n      \"method\": \"Cell surface biotinylation; Western blot in Adam17-/- cells; LPS-stimulated bone marrow-derived macrophages\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct endogenous protein analysis in genetic KO cells; single lab, two cell types\",\n      \"pmids\": [\"32060096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NNK (tobacco carcinogen) upregulates p38 MAPK-dependent threonine phosphorylation of ADAM17, activating shedding of soluble IL-6 receptor (sIL-6R) which drives ERK MAPK trans-signaling; ADAM17 deficiency abrogates sIL-6R shedding and downstream ERK signaling in lung adenocarcinoma cells, and NNK-treated hypomorphic Adam17 mice show markedly reduced lung tumorigenesis.\",\n      \"method\": \"Adam17 hypomorphic mice in NNK carcinogenesis model; CRISPR KO and pharmacological inhibition in human lung cancer cells; p38 inhibitor; threonine phosphorylation assays; sIL-6R ELISA; ERK phosphorylation Western blot\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic hypomorphic model plus CRISPR KO plus pharmacological inhibition with defined phosphorylation mechanism and substrate; multiple orthogonal approaches\",\n      \"pmids\": [\"31257400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 on endothelial cells mediates TNFR1 ectodomain shedding, and subsequent processing of the remaining stub by γ-secretase is required for TNF-induced necroptosis; genetic ablation of ADAM17 in endothelial cells prevents tumor cell-induced endothelial necroptosis, extravasation, and lung metastasis.\",\n      \"method\": \"Endothelial-specific ADAM17 conditional KO mice; pharmacological ADAM17 inhibition; necroptosis assays; metastasis lung colonization model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO combined with pharmacological inhibition and mechanistic dissection of TNFR1 processing cascade\",\n      \"pmids\": [\"34919140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 on classical swine fever virus (CSFV)-permissive cells directly binds the viral envelope protein E2 via its metalloproteinase domain in a zinc-dependent manner; ADAM17 loss eliminates E2 binding and viral entry, and re-expression of pig, human, or mouse ADAM17 rescues infection.\",\n      \"method\": \"Pull-down assay with soluble E2; ADAM17 KO cell line; ADAM17 cDNA rescue; domain mapping; CSFV infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein-protein binding assay, domain mapping, complete rescue with cDNA, multiple ADAM17 orthologs tested\",\n      \"pmids\": [\"33684175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 blockade with a monoclonal antibody markedly increases human NK cell proliferation driven by IL-15 both in vitro and in xenograft mice; this proliferative boost is dependent on CD62L, whose surface levels are increased by ADAM17 blockade, revealing a negative feedback loop in which IL-15-activated ADAM17 limits NK cell proliferation by shedding CD62L.\",\n      \"method\": \"ADAM17-blocking monoclonal antibody; in vitro proliferation assay; xenograft mouse model; CD62L blocking antibody epistasis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antibody blockade with in vivo xenograft and genetic epistasis via CD62L blocking; single lab\",\n      \"pmids\": [\"34367174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function mutations in RHBDF2 (iRHOM2) cause defective ADAM17-dependent cleavage and release of TNF and amphiregulin in human patients, leading to immune dysregulation; Rhbdf2-/- mice show more severe pneumonia after P. aeruginosa challenge and worse colitis after Citrobacter infection than wild-type mice.\",\n      \"method\": \"Human genetic disease study with functional validation; Rhbdf2-/- mouse infection models; cytokine release assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human loss-of-function genetics confirmed by mouse model with defined substrate release defect; published in high-impact journal\",\n      \"pmids\": [\"34937930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Active ADAM17 directly cleaves the insulin receptor (IR) beta subunit ectodomain from endothelial cells; ADAM17 overexpression or PMA-induced ADAM17 activation reduces IRα surface levels and impairs insulin signaling, which is rescued by ADAM17 inhibition (TAPI-0), and IR shedding is increased in arteries from T2D patients.\",\n      \"method\": \"In vitro cleavage assay with recombinant ADAM17 and IR; ADAM17 overexpression; TAPI-0 inhibitor rescue; cell surface biotinylation; human artery vasodilation assay\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro cleavage assay with recombinant proteins combined with pharmacological rescue in human tissue; single lab\",\n      \"pmids\": [\"36018759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM17 knockdown reduces, while ADAM17 overexpression aggravates, cardiac fibrosis in diabetic mice by regulating ACE2 shedding and cardiac fibroblast-to-myofibroblast transformation through the TGF-β1/Smad3 signaling pathway.\",\n      \"method\": \"Adenovirus-mediated shRNA knockdown and ADAM17 overexpression in diabetic mouse hearts; echocardiography; histology; TGF-β1/Smad3 pathway Western blot; primary cardiofibroblasts\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vivo with pathway mechanistic readout; single lab\",\n      \"pmids\": [\"36313337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM17 mediates experimental pancreatitis by shedding TNFα and soluble IL-6R (sIL-6R), activating IL-6 trans-signaling/STAT3 axis; genetic (Adam17ex/ex hypomorphic mice) and pharmacological (ADAM17 prodomain inhibitor A17pro) ADAM17 targeting ameliorates acute and chronic pancreatitis.\",\n      \"method\": \"Adam17ex/ex hypomorphic mice; ADAM17 prodomain inhibitor; cerulein and NNK pancreatitis models; IL-6/STAT3 pathway assays; histology; human pancreatitis biopsy correlation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic hypomorphic model plus pharmacological inhibition with defined mechanistic pathway and human tissue correlation\",\n      \"pmids\": [\"36215509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In lupus, IFN-I signaling inhibits Langerhans cell (LC) ADAM17 sheddase activity (without consistently reducing ADAM17 protein expression or LC numbers), leading to reduced EGFR ligand release and impaired keratinocyte survival after UV radiation; IFNAR blockade in lupus model mice restores LC ADAM17 sheddase activity via restoration of UVR-induced cytoplasmic reactive oxygen species, and this restoration reduces photosensitive responses in an LC ADAM17-dependent manner.\",\n      \"method\": \"Transcriptomic analysis; IFN-I treatment of murine and human LCs; IFNAR blocking antibody in three lupus mouse models; ROS measurement; ADAM17 sheddase activity assay; LC-specific ADAM17 genetic ablation epistasis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple lupus mouse models, human LC validation, IFNAR blockade rescue, and LC-specific ADAM17 KO epistasis; multiple orthogonal methods\",\n      \"pmids\": [\"38860651\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM17 (TACE) is a membrane-anchored zinc-dependent metalloprotease that is the principal sheddase for pro-TNFα (cleaving the Ala76-Val77 bond), EGFR family ligands (TGFα, amphiregulin, HB-EGF), cytokine receptors (IL-6R, TNFR1/2), adhesion molecules (CD62L, GPIbα, GPV, CXCR2, CD16), NRG1 type III, p75NTR, the insulin receptor, ACE2, and PD-L1; its catalytic activity is controlled by regulated trafficking between lipid rafts and non-raft membrane (where it is active), clathrin-mediated constitutive internalization, phosphorylation of intracellular Thr735 (by Trk/MEK and p38 MAPK), interaction with its obligate co-factor iRhom2 (which is itself stabilized by ADAM17), negative regulation by the tetraspanin CD9, and allosteric modulation through its transmembrane and juxtamembrane domains; it functions upstream of EGFR signaling in mammary morphogenesis, CNS and PNS myelination, and oligodendrocyte regeneration, upstream of TNFR2 in vascular inflammation, and upstream of TNFR1 γ-secretase processing in necroptosis, with its transcription induced by HIF-1α and p53, making it a central regulatory hub in inflammation, development, and cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAM17 (TACE) is a membrane-anchored, zinc-dependent metalloprotease that serves as a principal ectodomain sheddase, controlling inflammation, development, and tissue homeostasis by releasing the soluble forms of cell-surface proteins [#0, #2]. It was originally defined as the TNF-α converting enzyme, cleaving the Ala76-Val77 bond of the 26 kDa pro-TNF-α precursor to liberate mature soluble TNF-α, with TACE-deficient mice releasing 80-90% less soluble TNF-α and showing markedly reduced serum TNF-α after LPS challenge [#0, #1]. Beyond TNF-α, ADAM17 sheds a broad substrate repertoire including the EGFR-family ligands TGF-α, amphiregulin and HB-EGF [#2], cytokine receptors (IL-6R, TNFR1, TNFR2) [#23, #34, #24], adhesion and immune-receptor molecules (GPIbα/GPV, CXCR2, CD16, CD62L) [#5, #20, #16, #36], NRG1 type III [#11], the KIT and p75NTR receptors [#10, #13], the insulin receptor [#38], ACE2 [#39], and PD-L1 [#30]. Through release of EGFR ligands, ADAM17 acts genetically upstream of EGFR signaling in mammary ductal development, cardiac development, and CNS/PNS myelination and remyelination, where conditional deletion impairs oligodendrocyte survival and myelination and is rescued by EGFR overexpression [#9, #3, #4, #19, #21, #11]. Its catalytic activity is governed at multiple levels: regulated trafficking between cholesterol-rich lipid rafts and active non-raft membrane [#8], constitutive clathrin-mediated internalization that limits surface enzyme [#22], stimulus-induced intracellular threonine-735 phosphorylation via Trk/MEK and p38 MAPK pathways [#13, #33], allosteric control through non-active-site ectodomain epitopes and the transmembrane/juxtamembrane domains [#14, #31], negative regulation by the tetraspanin CD9 [#12], and an obligate mutual-stabilization relationship with the rhomboid pseudoprotease iRhom2, which is required for substrate release and is itself destabilized in the absence of ADAM17 [#31, #32, #37]. Its transcription is directly activated by p53 and by HIF-1α, integrating ADAM17 into differentiation, tumor suppression, and inflammatory programs [#15, #27]. Loss-of-function mutations in RHBDF2 (iRhom2) cause human immune dysregulation through defective ADAM17-dependent release of TNF and amphiregulin [#37]. Functionally, ADAM17-driven shedding shapes diverse pathologies, including atherosclerosis via TNFR2 [#24], TNFR1/γ-secretase-dependent endothelial necroptosis and metastasis [#34], kidney and cardiac fibrosis [#25, #39], IL-6 trans-signaling in lung cancer and pancreatitis [#33, #40], and tumor immune evasion through soluble PD-L1 [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the molecular identity of the protease that generates soluble TNF-α, answering which enzyme cleaves the membrane-anchored cytokine precursor.\",\n      \"evidence\": \"Protein purification, partial cloning, and in vitro cleavage assay defining the Ala76-Val77 cleavage site on pro-TNF-α\",\n      \"pmids\": [\"9042103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro cleavage does not establish in vivo contribution\", \"Other physiological substrates not yet defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated that TACE is the dominant TNF-α converting enzyme in living animals, not merely in vitro, validating it as the principal in vivo sheddase for this cytokine.\",\n      \"evidence\": \"TACE-deficient and bone-marrow-reconstituted mice with ELISA for soluble TNF-α after LPS challenge\",\n      \"pmids\": [\"10415747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual shedding implies additional proteases\", \"Did not address non-TNF substrates\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Expanded the substrate repertoire beyond TNF-α to EGFR-family ligands, reframing ADAM17 as a general sheddase coupling cell-surface ligand release to growth-factor signaling.\",\n      \"evidence\": \"Purified enzyme cleavage assays plus TACE-deficient keratinocyte rescue for TGF-α, amphiregulin, and HB-EGF\",\n      \"pmids\": [\"11823465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative physiological importance of each ligand not ranked\", \"Tissue-specific substrate selection unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed TACE genetically upstream of EGFR signaling in development, establishing the sheddase as a rate-limiting controller of EGFR ligand availability in vivo.\",\n      \"evidence\": \"Genetic epistasis in compound TACE-heterozygous × EGFR-hypomorphic mice and TACE-null heart phenotyping\",\n      \"pmids\": [\"12814936\", \"14499647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific ligand drives each developmental phenotype not fully dissected\", \"Mechanism of activity regulation in vivo unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Clarified how the zymogen is held latent, showing the prodomain acts as a chaperone-like conformational restraint rather than via the canonical cysteine-switch.\",\n      \"evidence\": \"Site-directed mutagenesis of the prodomain with cell-based zymogen activity assays\",\n      \"pmids\": [\"16679521\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of conformational restraint not resolved\", \"Single-study mechanistic model\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified membrane microdomain partitioning as a control switch, showing cholesterol-dependent displacement from lipid rafts to non-raft regions activates shedding.\",\n      \"evidence\": \"Cell-based and cell-free membrane shedding assays with raft fractionation and ABCA1 knockdown\",\n      \"pmids\": [\"17786981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular determinant of raft partitioning not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that ADAM17-released amphiregulin acts as a paracrine signal across tissue compartments, establishing the directionality of the ADAM17→AREG→EGFR axis in mammary morphogenesis.\",\n      \"evidence\": \"Mammary tissue recombination/transplantation with soluble AREG rescue\",\n      \"pmids\": [\"18470483\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative thresholds of paracrine signaling unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended ADAM17 substrate biology to receptor-tyrosine-kinase shedding controlling cell fate, showing KIT ectodomain cleavage drives physiological germ cell apoptosis.\",\n      \"evidence\": \"Pharmacological gain/loss-of-function (ADAM17 vs ADAM10 selectivity) and PMA stimulation in rat testis culture\",\n      \"pmids\": [\"20501791\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relies on pharmacology rather than genetic ADAM17 loss\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed phosphorylation-based activation and direct partner-mediated regulation, mapping Thr735 phosphorylation by Trk/MEK and identifying CD9 as a negative regulator binding ADAM17.\",\n      \"evidence\": \"Phosphosite mapping with MEK inhibitors and rescue (p75NTR); four orthogonal binding methods plus CD9 gain/loss-of-function shedding assays\",\n      \"pmids\": [\"21411748\", \"21365281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase counter-regulation not defined\", \"How CD9 binding inhibits catalysis structurally unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Established a counterintuitive substrate that ADAM17 inactivates, showing NRG1 type III cleavage negatively regulates myelination, broadening sheddase outcomes beyond ligand activation.\",\n      \"evidence\": \"Conditional knockout and lentiviral knockdown in DRG/motor neurons with EM, electrophysiology, and PI3K assays\",\n      \"pmids\": [\"21666671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NRG1 cleavage is regulated independently of EGFR-ligand shedding unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified transcriptional control by p53 and positioned ADAM17 within a tumor-suppressive NOTCH1 differentiation axis, linking sheddase abundance to cancer biology.\",\n      \"evidence\": \"Conditional KO mice, human SCC lines, ChIP and rescue experiments\",\n      \"pmids\": [\"22772468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TACE-NOTCH1 activation in this context not fully resolved\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined ADAM17's role in shaping immune effector function through receptor shedding and uncovered a non-canonical activation/secretion route in viral pathogenesis.\",\n      \"evidence\": \"Selective inhibitor with NK CD16/CD62L FACS and IFN-γ assays; HIV-Nef-driven paxillin/Pak phosphorylation, raft fractionation, and EV pro-TNF cleavage\",\n      \"pmids\": [\"23487023\", \"23317503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NK functional readouts rely on pharmacology\", \"Physiological relevance of EV-packaged ADAM17 beyond HIV unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed allosteric, non-active-site regulation and established ADAM17 as a genetic driver of EGFR-dependent oligodendrocyte survival and CNS myelination via rescue epistasis.\",\n      \"evidence\": \"Cross-domain inhibitory antibody with epitope mapping; conditional OP knockout with EGFR-overexpression rescue, EM, and behavior\",\n      \"pmids\": [\"21415364\", \"25186737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand for the allosteric site unknown\", \"Which EGFR ligand is rate-limiting in OPs not fully isolated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated stimulus-selective shedding of CXCR2 from neutrophils, distinguishing ADAM17-dependent receptor down-regulation from ligand-induced internalization and linking it to inflammatory recruitment.\",\n      \"evidence\": \"Selective inhibitor, blocking antibody, and gene-targeted mice with intravital microscopy\",\n      \"pmids\": [\"25412626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal coupling non-ligand stimuli to ADAM17 not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how subcellular trafficking and cleavage-site geometry govern activity and substrate selection, showing constitutive internalization limits surface enzyme and juxtamembrane spacing discriminates ADAM17 from ADAM10.\",\n      \"evidence\": \"Live-cell imaging, biotinylation, clathrin inhibitors; IL-6R stalk mutagenesis with chimeric spacing constructs\",\n      \"pmids\": [\"27731361\", \"27151651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GPCR stimulation activates surface enzyme without altering abundance unresolved\", \"Generality of distance threshold across substrates untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established ADAM17 as a homeostatic brake on TNFR2 signaling and a driver of EGFR-dependent organ fibrosis, defining downstream pathway position by genetic rescue.\",\n      \"evidence\": \"Adam17 hypomorphic mice on Ldlr-/- with TNFR2 siRNA rescue; proximal-tubule conditional KO, hypomorphic, and inhibitor approaches with human biopsy correlation\",\n      \"pmids\": [\"28062509\", \"27642633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance between protective and pathogenic shedding context-dependence not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected nitric-oxide signaling to ADAM17 activation and iRhom2 upregulation driving NOTCH1 in cancer stem cells, integrating second-messenger pathways with sheddase output.\",\n      \"evidence\": \"sGC/cGMP/PKG pathway dissection with xenograft and patient HCC correlation\",\n      \"pmids\": [\"30297396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link from PKG to ADAM17 activation not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified HIF-1α as a direct transcriptional activator of ADAM17 in macrophages, linking hypoxia/inflammatory signaling to sheddase-driven vascular pathology, and extended ADAM17 roles into neural blood-pressure control and viral entry.\",\n      \"evidence\": \"ChIP and macrophage HIF-1α inhibition in aortic dissection; neuron-specific knockdown with BP telemetry; ADAM17 inhibitor in HPV16 entry assays\",\n      \"pmids\": [\"31640947\", \"31564162\", \"31107240\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link from neuronal ADAM17 to sympathetic outflow incomplete\", \"Viral-entry role relies on pharmacology\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistically dissected the iRhom2-ADAM17 partnership at the transmembrane/juxtamembrane interface and as an obligate mutual-stabilization pair, and broadened immune-evasion roles via PD-L1 shedding.\",\n      \"evidence\": \"TMD/JMD chimeric and patient-variant constructs in double-KO cells; endogenous iRhom2 stability assays in Adam17-/- cells; PD-L1 shedding and T-cell killing assays\",\n      \"pmids\": [\"32103528\", \"32060096\", \"32363112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of the ADAM17-iRhom2 interface not resolved\", \"How interface controls substrate selectivity mechanistically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ADAM17 as a sequential processing initiator in TNFR1-dependent endothelial necroptosis driving metastasis, and revealed a direct, catalysis-independent role as a viral entry receptor.\",\n      \"evidence\": \"Endothelial-specific conditional KO plus inhibition in necroptosis/metastasis; direct E2-binding pull-down, domain mapping, and cross-species cDNA rescue for CSFV; IL-15/CD62L NK feedback antibody study\",\n      \"pmids\": [\"34919140\", \"33684175\", \"34367174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ADAM17 shedding and γ-secretase processing are coordinated unknown\", \"Whether viral binding alters catalytic activity unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected the ADAM17 pathway to a human Mendelian immune disorder, showing RHBDF2/iRhom2 loss-of-function impairs ADAM17-dependent TNF and amphiregulin release.\",\n      \"evidence\": \"Human genetic disease study with functional cytokine-release validation and Rhbdf2-/- mouse infection models\",\n      \"pmids\": [\"34937930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific consequences of iRhom2 loss on ADAM17 substrate spectrum not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the substrate range to the insulin receptor and ACE2 and linked ADAM17 shedding to metabolic and cardiac-fibrotic disease via defined downstream pathways.\",\n      \"evidence\": \"Recombinant cleavage and inhibitor rescue for insulin receptor with human artery data; adenoviral knockdown/overexpression in diabetic hearts with TGF-β1/Smad3 readout; hypomorphic mice and prodomain inhibitor in pancreatitis with IL-6/STAT3 axis\",\n      \"pmids\": [\"36018759\", \"36313337\", \"36215509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution of ADAM17 to insulin-receptor shedding genetically untested\", \"Mechanism activating ADAM17 in metabolic disease incompletely defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed that ADAM17 sheddase activity, not abundance, is the regulated node, with IFN-I signaling suppressing ROS-dependent ADAM17 activity in Langerhans cells to drive photosensitivity in lupus.\",\n      \"evidence\": \"Multiple lupus mouse models, human LC validation, IFNAR blockade rescue, and LC-specific ADAM17 KO epistasis with ROS measurement\",\n      \"pmids\": [\"38860651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link from ROS to ADAM17 catalytic activation not defined\", \"Relevant EGFR ligand in keratinocyte survival not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unified structural and regulatory model explaining how trafficking, phosphorylation, iRhom interaction, redox state, and cleavage-site geometry are integrated to select among ADAM17's many substrates in a given cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of the active ADAM17-iRhom2 complex in the timeline\", \"Mechanism converting diverse upstream stimuli into specific substrate selection unknown\", \"Quantitative rules governing tissue-specific substrate preference undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 5, 11, 23, 34, 38]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 38]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [8, 12, 22]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [17, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 16, 20, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 13, 19, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4, 9, 11, 19]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 2, 23, 38]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [10, 34]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RHBDF2\", \"CD9\", \"CD16\", \"EGFR\", \"TNFR2\", \"IL6R\", \"KIT\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}