{"gene":"ADAM17","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1997,"finding":"TACE/ADAM17 was purified and partially cloned as a novel metalloprotease responsible for cleaving the Ala76-Val77 bond of the 26 kDa pro-TNF-α precursor to generate the mature 17 kDa soluble form.","method":"Protein purification, partial cloning, enzymatic cleavage assay","journal":"Journal of neuroimmunology","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical purification and in vitro cleavage assay establishing catalytic function","pmids":["9042103"],"is_preprint":false},{"year":2002,"finding":"ADAM17/TACE cleaves pro-TGF-α at its N-terminal and C-terminal ectodomain sites in vitro, and mediates shedding of amphiregulin and HB-EGF in cells; TACE-deficient cells shed dramatically less TGF-α, restored by TACE adenovirus infection.","method":"In vitro cleavage assay with purified TACE, TACE-deficient cell reconstitution, cotransfection, adenoviral rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution plus multiple cell-based loss-of-function and rescue experiments","pmids":["11823465"],"is_preprint":false},{"year":2002,"finding":"Genetic evidence that TACE regulates EGFR ligand availability in vivo: mice heterozygous for Tace and homozygous for impaired EGFR allele (wa-2) were born with open eyes more frequently, indicating epistatic interaction between TACE and EGFR signaling.","method":"Genetic epistasis (double mutant mouse crosses)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis in vivo with defined phenotypic readout","pmids":["11823465"],"is_preprint":false},{"year":2003,"finding":"TACE/ADAM17 null mutant mice exhibit enlarged fetal hearts with increased trabeculation, reduced cell compaction, larger cardiomyocytes and increased proliferation, accompanied by attenuated ErbB4 cleavage and changes in MAPK activation, demonstrating a role for ADAM17-mediated shedding in cardiac development.","method":"Knockout mouse phenotyping, Western blot for ErbB4 cleavage and MAPK activation","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined molecular and cellular phenotype, multiple readouts","pmids":["14499647"],"is_preprint":false},{"year":2004,"finding":"TACE/ADAM17 acts as a constitutive and PMA-stimulated sheddase for MUC1 on human uterine epithelial cells; TACE-deficient cells lose PMA-stimulated MUC1 shedding, which is distinct from pervanadate-stimulated shedding mediated by MT1-MMP.","method":"TACE-deficient cell lines, pharmacological inhibitors, co-transfection","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in TACE-deficient cells with substrate-specific readout","pmids":["15130087"],"is_preprint":false},{"year":2005,"finding":"Aspirin induces shedding of platelet GPIbα and GPV via an ADAM17-dependent mechanism; shedding was completely blocked in platelets expressing inactive ADAM17, but occurred normally in COX-1-deficient platelets.","method":"ADAM17 knock-in mutant mice (inactive form), COX-1 KO mice, FACS, immunoprecipitation, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with specific substrate readout, replicated in vivo","pmids":["16179345"],"is_preprint":false},{"year":2006,"finding":"ADAM17 interacts with the LIM domain protein FHL2 via amino acids 721–739 of ADAM17; FHL2 colocalizes with ADAM17 and the actin cytoskeleton in cardiomyoblasts, and FHL2-deficient macrophages show increased surface ADAM17 but reduced PMA-stimulated substrate shedding, indicating FHL2 regulates ADAM17 localization and activity.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, FHL2 KO macrophages, substrate shedding assay","journal":"Journal of cellular physiology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction confirmed by multiple methods plus functional KO data","pmids":["16619241"],"is_preprint":false},{"year":2007,"finding":"The transmembrane domain (TM) of TACE is required for efficient cleavage of TGF-α, TNF-α and L-selectin; GPI-anchored TACE lacking TM fails to restore shedding, and substitution of TM with prolactin receptor or PDGFR TM abolishes TGF-α shedding but not TNF-α/L-selectin shedding, revealing TM sequence-dependent substrate specificity.","method":"Molecular engineering (TM swap/GPI anchor constructs), functional shedding assay in TACE-deficient cells","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 — systematic domain-swap mutagenesis with functional reconstitution","pmids":["18040288"],"is_preprint":false},{"year":2008,"finding":"HDL-induced cholesterol efflux from lipid rafts redistributes ADAM17 out of lipid rafts and activates ADAM17-dependent shedding of TNFR1, TNFR2, and TNF; this was demonstrated even on cell-free isolated plasma membranes, indicating a direct lipid raft-mediated regulation of ADAM17 activity.","method":"Cell-free plasma membrane assay, ABCA1-dependent cholesterol efflux, specific inhibitors, lipid raft fractionation","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 — cell-free assay and genetic (ABCA1-dependent) evidence linking lipid raft composition to ADAM17 activity","pmids":["17786981"],"is_preprint":false},{"year":2008,"finding":"ADAM17 mediates EGFR ligand (amphiregulin) release from mammary ductal epithelial cells to activate stromal EGFR; tissue recombination studies show ADAM17 and AREG must be on epithelial cells while EGFR is on stromal cells, and soluble AREG rescues ADAM17-deficient transplants.","method":"Tissue recombination and transplantation, ADAM17-deficient mammary epithelium, soluble AREG rescue","journal":"Journal of mammary gland biology and neoplasia","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with rescue experiment defining cell-autonomous pathway","pmids":["18470483"],"is_preprint":false},{"year":2008,"finding":"Kuz (Kuzbanian/ADAM10) and TACE/ADAM17 can both activate Notch signaling by cleaving the Notch receptor; overexpression of TACE activates Notch in a ligand-independent manner in Drosophila, while Kuz requires Delta stimulation.","method":"In vitro Drosophila model, overexpression and dominant-negative analysis of Kuz and TACE","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic gain-of-function in defined cell model, ortholog context","pmids":["18535782"],"is_preprint":false},{"year":2009,"finding":"Transcription factor Sp1 binds to the GC-rich ADAM17 promoter and regulates ADAM17 expression under hypoxia, as shown by chromatin immunoprecipitation assay; Sp1 suppression decreases ADAM17-dependent glioma invasiveness.","method":"ChIP assay, RT-PCR, Western blot, siRNA knockdown, invasion assay","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP confirms direct promoter binding with functional consequence","pmids":["19772640"],"is_preprint":false},{"year":2010,"finding":"TACE/ADAM17 mediates germ cell apoptosis by cleaving the extracellular domain of the KIT receptor; TACE inhibition prevents apoptosis and PMA-induced KIT ectodomain loss, while ADAM10 inhibition does not, demonstrating substrate specificity in vivo.","method":"Pharmacological ADAM17 inhibition, PMA stimulation, ex vivo testis culture, KIT ectodomain Western blot","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and stimulation-based evidence with specific substrate readout","pmids":["20501791"],"is_preprint":false},{"year":2011,"finding":"ADAM17 multimerizes in the cell membrane via its EGF-like domain, suggesting dimerization as a mechanism contributing to ADAM17 activation and function.","method":"Co-immunoprecipitation, mutagenesis of EGF-like domain, cell membrane analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — co-IP with domain mapping, single lab","pmids":["22033402"],"is_preprint":false},{"year":2011,"finding":"TACE/ADAM17 cleaves neuregulin-1 (NRG1) type III in the EGF domain, inactivating it and thereby negatively regulating PNS myelination; lentiviral TACE knockdown in DRG neurons causes hypermyelination, conditional motor neuron TACE KO mice show significant hypermyelination, and reduced TACE rescues hypomyelination in NRG1 type III haploinsufficient mice.","method":"Lentiviral knockdown in DRG neurons, conditional neuronal KO mice, NRG1 haploinsufficient mouse rescue, PI3K pathway assay","journal":"Nature neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal genetic models with defined molecular mechanism and phenotype, replicated in vivo","pmids":["21666671"],"is_preprint":false},{"year":2011,"finding":"Tetraspanin CD9 associates directly with ADAM17 on endothelial and monocytic cell surfaces; CD9 antibody treatment or CD9 overexpression reduces ADAM17-mediated shedding of TNF-α and ICAM-1, while CD9 silencing increases ADAM17 sheddase activity.","method":"In situ proximity ligation, co-immunoprecipitation, crosslinking, pull-down, CD9 siRNA and overexpression, substrate shedding assay","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods confirming direct interaction with functional consequence","pmids":["21365281"],"is_preprint":false},{"year":2011,"finding":"HIV Nef recruits paxillin and ADAM17 into a complex; Pak2 phosphorylates paxillin on Ser272/274 to induce TACE-paxillin association and shuttle ADAM17 into extracellular vesicles via lipid rafts, cleaving pro-TNF-α; Pak1 phosphorylates paxillin Ser258 to inhibit TACE association.","method":"Co-immunoprecipitation, phospho-specific mutants, lipid raft fractionation, EV isolation, Pak1/2 knockdown","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods defining phosphorylation-dependent protein complex and functional shedding readout","pmids":["23317503"],"is_preprint":false},{"year":2011,"finding":"Trk receptor activation induces MEK-dependent phosphorylation of ADAM17 at threonine 735, activating ADAM17 to cleave p75NTR and produce p75NTR intracellular domain (p75NTR-ICD), which is required for neurotrophin-induced Erk/Akt activation and neuronal survival.","method":"Phospho-specific site identification, MEK inhibitor, ADAM17 depletion, p75NTR-ICD overexpression rescue, survival assay in PC12 and primary neurons","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 — identified specific phosphorylation site with mechanistic rescue experiment in primary neurons","pmids":["21411748"],"is_preprint":false},{"year":2011,"finding":"A cross-domain human antibody specifically inhibits cell-surface TACE by targeting its ectodomain rather than the active site, providing a mechanistic basis for allosteric inhibition of TACE shedding activity.","method":"Phage display antibody development, selective TACE inhibition assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — novel inhibitor mode confirmed by selectivity profiling, single study","pmids":["21415364"],"is_preprint":false},{"year":2012,"finding":"p53 transcriptionally activates TACE/ADAM17 as a novel target gene; TACE in turn activates NOTCH1, promoting epidermal differentiation and squamous cell carcinoma suppression downstream of a FOS/p53/TACE axis.","method":"Epidermal Fos deletion mouse models, pharmacological FOS/AP-1 inhibition, p53-dependent transcriptional activation assay, NOTCH1 activation readout","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic mouse models with multiple cell-type validation and defined transcriptional mechanism","pmids":["22772468"],"is_preprint":false},{"year":2013,"finding":"Nox1 interacts with and stabilizes ADAM17 from ubiquitin-mediated degradation, leading to activation of the ADAM17/EGFR-PI3K-AKT signaling pathway and promotion of colon cancer metastasis.","method":"Immunoprecipitation, siRNA knockdown, ubiquitination assay, migration/invasion assay","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — single co-IP with functional siRNA data, single lab","pmids":["27874952"],"is_preprint":false},{"year":2014,"finding":"TACE/ADAM17 genetic deletion in oligodendrocyte progenitor cells causes premature cell cycle exit, reduced OL survival, and deficits in CNS myelination; TACE regulates oligodendrogenesis by shedding EGFR ligands TGFα and HB-EGF, and EGFR overexpression in TACE-deficient OPs rescues OL development.","method":"Conditional KO mice (OPC-specific), EGFR overexpression rescue, substrate shedding assay, behavioral readout","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with specific pathway rescue demonstrating mechanistic link","pmids":["25186737"],"is_preprint":false},{"year":2014,"finding":"Deletion of a triple serine motif (Ser359–Ser361) adjacent to the IL-6R cleavage site prevents ADAM17-mediated but not ADAM10-mediated IL-6R shedding by reducing the distance between cleavage site and plasma membrane, revealing that cleavage site positioning differentially controls ADAM17 vs ADAM10 proteolysis.","method":"Deletion mutagenesis, shedding assay, IL-6R functional assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — site-directed mutagenesis with mechanistic interpretation of geometry-dependent shedding","pmids":["27151651"],"is_preprint":false},{"year":2014,"finding":"iRhom2 dominant mutations (tylosis/TOC-associated) increase ADAM17 maturation and activity in epidermal keratinocytes, resulting in upregulated shedding of EGF-family growth factors and pro-inflammatory cytokines, increased EGFR activity, and aberrant desmosome processing.","method":"Patient-derived TOC keratinocytes, ADAM17 maturation assay, substrate shedding assay, EGFR phosphorylation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — human disease mutations validate iRhom2-ADAM17 regulatory axis with multiple molecular readouts","pmids":["24643277"],"is_preprint":false},{"year":2015,"finding":"TACE/ADAM17 is required for OL regeneration and CNS remyelination following demyelination by activating EGFR in OL lineage cells; TACE deficiency abrogates EGFR activation, impairs OL expansion and survival, and delays remyelination; EGFR overexpression in TACE-deficient OPs rescues remyelination.","method":"Conditional KO mice, demyelination model, EGFR overexpression rescue, OL lineage cell expansion/survival assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic loss and gain-of-function in vivo with defined molecular pathway rescue","pmids":["26338334"],"is_preprint":false},{"year":2015,"finding":"HIF-1α binds to its consensus element at -607 of the ADAM17 promoter to drive ADAM17 transcriptional upregulation in response to high glucose; this is dependent on EGFR/ADAM17 signaling, creating a positive feedback loop.","method":"ADAM17 promoter deletion constructs, mutation analysis, ChIP, HRE-luciferase reporter, HIF-1α inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP, mutagenesis, and luciferase reporter with multiple inhibitor validations","pmids":["26175156"],"is_preprint":false},{"year":2016,"finding":"ADAM17 is constitutively internalized via clathrin-coated pits; GPCR ligand stimulation induces ADAM17-mediated shedding without altering cell-surface abundance, while PMA/PKC activation causes rapid increase of mature ADAM17 at the cell surface followed by internalization and degradation, substantially downregulating mature ADAM17.","method":"Live-cell imaging, clathrin inhibition, FACS surface expression analysis, PMA vs. physiological stimulator comparison","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization experiments with functional mechanistic consequences, multiple methods","pmids":["27731361"],"is_preprint":false},{"year":2016,"finding":"Niacin/Niaspan enhances TACE activity in vivo and rescues focal hypermyelination in CMT mouse models (Mtmr2-/- and Pmp22+/-) by downregulating NRG1 type III signaling through TACE-mediated cleavage.","method":"In vivo drug treatment, TACE activity assay, myelination quantification in CMT mouse models","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo pharmacological activation of TACE with defined molecular pathway and phenotypic rescue","pmids":["27799291"],"is_preprint":false},{"year":2016,"finding":"Tetraspanin CD9 coassociates with and negatively regulates ADAM17 in leukocytes; CD9 neo-expression or neutralizing anti-CD9 antibodies modulate ADAM17-mediated shedding of LR11, confirmed by metalloproteinase inhibitor sensitivity.","method":"Confocal co-localization, shRNA knockdown, CD9 overexpression, metalloproteinase inhibitor, sLR11 ELISA","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 — multiple approaches but no direct binding assay; functional consequence established","pmids":["24699135"],"is_preprint":false},{"year":2016,"finding":"PMA stimulation downregulates surface ADAM17 in lung epithelial cells by inducing release of mature ADAM17 in exosomes; exosomal ADAM17 retains metalloproteinase domain-outside orientation and can shed TGFα and amphiregulin on distant cells; iRhom2-mediated maturation is required for surface expression and exosomal release.","method":"Exosome isolation, antibody surface labeling, iRhom2 suppression, shRNA knockdown, substrate shedding assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing mechanism of ADAM17 surface regulation and exosomal activity","pmids":["27599715"],"is_preprint":false},{"year":2017,"finding":"Stimulation of ADAM17/TACE shedding by inflammatory/growth-promoting agents triggers MAP kinase-dependent phosphorylation of the iRhom2 N-terminal cytoplasmic tail, recruiting 14-3-3 proteins that enforce dissociation of TACE from iRhom2 complexes and promote cleavage of TACE substrates.","method":"Phosphorylation mapping, 14-3-3 co-IP, iRhom2 mutant analysis, substrate shedding assay, MAP kinase inhibitors","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — defined post-translational modification with mechanistic protein complex dissociation readout, multiple orthogonal methods","pmids":["29045841"],"is_preprint":false},{"year":2018,"finding":"ADAM17 deficiency in smooth muscle cells prevents contractile-to-synthetic phenotypic switching in TAA, while ADAM17 deficiency in endothelial cells preserves VE-cadherin, JAM-A and claudin junctions; both independently suppress aortic aneurysm dilation, demonstrating cell-specific functions.","method":"SMC-specific and EC-specific conditional KO mice (Adam17/Sm22 and Adam17/Tie2), ADAM17 siRNA in primary cells, pharmacological inhibitor (PF-548), in vivo TAA model","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — multiple conditional KO models with specific molecular readouts and pharmacological confirmation","pmids":["29930147"],"is_preprint":false},{"year":2019,"finding":"HIF-1α activation in macrophages, triggered by fumarate accumulation, transcriptionally upregulates ADAM17 as a novel HIF-1α target gene, promoting vascular inflammation and elastic fiber degradation in aortic dissection; ChIP confirmed HIF-1α binding to ADAM17 promoter.","method":"ChIP, metabolomics, Seahorse flux analysis, ELISA, HIF-1α inhibitor (acriflavine), mouse models","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP confirms direct HIF-1α binding, supported by multiple mechanistic and in vivo approaches","pmids":["31640947"],"is_preprint":false},{"year":2019,"finding":"ADAM17 mediates ACE2 ectodomain shedding; ADAM17 inhibitor applied to renal proximal tubular cells reduces ACE2 shedding into the media, and ACE2 colocalizes with ADAM17 in renal tubules.","method":"ADAM17 inhibitor in primary tubular cells, immunostaining colocalization, urinary ACE2 fragment analysis","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with defined substrate readout in primary cells","pmids":["24452639"],"is_preprint":false},{"year":2019,"finding":"ADAM17 expression co-localizes with angiotensin-II type 1 receptors on Sim1 neurons of the hypothalamic paraventricular nucleus; selective neuronal ADAM17 knockdown reduces FosB expression, increases vagal tone, and prevents the acute pressor response to centrally administered angiotensin-II.","method":"Neuron-specific conditional knockdown (new mouse models), photoactivation, blood pressure measurement","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 — conditional neuronal KO with defined physiological and molecular readout","pmids":["31564162"],"is_preprint":false},{"year":2019,"finding":"ADAM8 can release the ADAM17 ectodomain (shedding of ADAM17 itself); soluble ADAM17 (sADAM17) cleaves fibronectin, cystatin C, sN-cadherin, PCPE-1, and sAPP in vitro, revealing a degradome distinct from membrane-anchored ADAM17.","method":"N-terminomics/mass spectrometry, in vitro cleavage assays with purified substrates","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro cleavage assays confirm direct substrates of soluble ADAM17","pmids":["31209506"],"is_preprint":false},{"year":2020,"finding":"ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles, generating a soluble active sPD-L1 fragment that induces apoptosis in CD8+ T cells and impairs their tumor-killing ability.","method":"ADAM10/17 inhibition, ADAM17 knockdown, shedding assay, CD8+ T cell apoptosis and killing assay","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological and genetic inhibition with defined functional immune consequence","pmids":["32363112"],"is_preprint":false},{"year":2021,"finding":"ADAM17 on endothelial cells mediates TNFR1 ectodomain shedding; subsequent processing by the γ-secretase complex is required for induction of TNF-induced necroptosis. Genetic ablation or pharmacological inhibition of ADAM17 in endothelial cells prevents tumor cell extravasation and lung metastasis.","method":"Endothelial-specific ADAM17 KO mice, γ-secretase inhibitor, necroptosis assay, lung metastasis model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — conditional KO plus pharmacological inhibition with defined molecular pathway and in vivo metastasis readout","pmids":["34919140"],"is_preprint":false},{"year":2021,"finding":"IL-15 activates ADAM17 in human NK cells, which sheds CD62L from the surface, limiting NK cell proliferation; ADAM17 blockade markedly increases NK cell proliferation in vitro and in xenograft mice, and CD62L is required for this proliferation effect in vivo.","method":"ADAM17 monoclonal antibody blockade, xenograft mouse model, CD62L surface expression, CD62L-dependent proliferation assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological blocking antibody with in vivo validation and defined substrate/pathway","pmids":["34367174"],"is_preprint":false},{"year":2022,"finding":"Genetic reduction (Adam17ex/ex hypomorphic mice) or therapeutic inhibition (ADAM17 prodomain inhibitor) of ADAM17 ameliorates experimental pancreatitis by reducing IL-6 trans-signaling/STAT3 axis, associated with reduction in inflammatory cell infiltration, necrosis, and fibrosis.","method":"Hypomorphic mouse model, pharmacological prodomain inhibitor, STAT3 pathway analysis, histology","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological loss-of-function with defined signaling pathway and histological readout","pmids":["36215509"],"is_preprint":false},{"year":2013,"finding":"ADAM17 promotes shedding of EGFR ligands TGFα and HB-EGF and activates EGFR/PI3K/AKT signaling in glioma; ADAM17 overexpression promotes U87 glioma cell proliferation, invasion, and angiogenesis, while ADAM17 siRNA or TAPI-2 inhibitor reverses these effects.","method":"Stable ADAM17 overexpression/siRNA transfection, TAPI-2 inhibitor, MTT/BrdU assay, Matrigel invasion, Western blot for EGFR-PI3K-AKT","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — gain and loss-of-function with defined pathway readout, single lab","pmids":["21480393"],"is_preprint":false},{"year":2013,"finding":"ADAM17 cleaves the extracellular domain of CD44 in HNSCC; ADAM17 chemical inhibition and stable suppression block CD44 cleavage and abrogate orasphere formation and tumorigenesis in vivo.","method":"ADAM17 inhibitor, stable shRNA suppression, sphere assay, oral cancer mouse model","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic and pharmacological loss-of-function with in vivo tumorigenesis readout","pmids":["24403253"],"is_preprint":false},{"year":2013,"finding":"ADAM17 cleaves the Notch extracellular domain to regulate self-renewal of glioblastoma stem cells via Notch signaling; ADAM17 knockdown inhibits Hes1/Hes5, activates Notch1 expression, and suppresses secondary neurosphere formation and multi-lineage differentiation.","method":"ADAM17 shRNA knockdown in GSCs, Hes1/Hes5/Notch1 Western blot, neurosphere assay","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined Notch pathway readout in stem cell model","pmids":["23356982"],"is_preprint":false},{"year":2019,"finding":"CD9 co-localizes with and directly associates with ADAM17 on keratinocytes during wound repair; CD9 down-regulation activates ADAM17 sheddase activity leading to release of HB-EGF, which activates EGFR/ERK pathway to promote keratinocyte migration; ADAM17 inhibition or siRNA blocks this CD9-regulated migration.","method":"Confocal microscopy, co-immunoprecipitation, TAPI-2 inhibitor, siADAM17, HB-EGF neutralizing antibody, in vivo wound assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus functional rescue with defined substrate/pathway, in vivo correlation","pmids":["30745837"],"is_preprint":false}],"current_model":"ADAM17/TACE is a membrane-anchored zinc-dependent metalloprotease whose activity is regulated by iRhom2-dependent ER exit and maturation, clathrin-mediated internalization, MAP kinase-dependent phosphorylation of iRhom2 (which recruits 14-3-3 to dissociate the ADAM17-iRhom2 complex at the cell surface), PKC/PMA-induced redistribution from lipid rafts to the non-raft membrane, Trk-dependent phosphorylation of ADAM17 Thr735, FHL2/cytoskeleton association, and CD9 tetraspanin-mediated negative modulation; it catalyzes ectodomain shedding of at least 80 substrates—including TNF-α, IL-6R, NRG1 type III, EGFR ligands (TGF-α, amphiregulin, HB-EGF), ACE2, GPIbα, GPV, TNFR1, PD-L1, and KIT—to control inflammation, EGFR signaling, Notch activation, myelination in the PNS and CNS, cardiac and vascular development, and immune cell function."},"narrative":{"teleology":[{"year":1997,"claim":"Identification of ADAM17/TACE as the protease responsible for TNF-α shedding resolved the long-sought question of which enzyme generates soluble TNF-α from its membrane-anchored precursor.","evidence":"Biochemical purification from monocyte membranes and in vitro cleavage assay demonstrating cleavage at Ala76-Val77","pmids":["9042103"],"confidence":"High","gaps":["Crystal structure of TACE with pro-TNF-α substrate not yet solved","Regulation of TACE activity unknown","Full-length cloning incomplete at this stage"]},{"year":2002,"claim":"Establishing ADAM17 as the sheddase for multiple EGFR ligands (TGF-α, amphiregulin, HB-EGF) and demonstrating genetic epistasis with EGFR in vivo expanded its role from a single-substrate protease to a master regulator of EGFR signaling.","evidence":"In vitro cleavage assay with purified TACE, TACE-deficient cell reconstitution, and genetic epistasis in Tace+/− × wa-2 mice","pmids":["11823465"],"confidence":"High","gaps":["Mechanism by which ADAM17 selects among EGFR ligands versus other substrates","Structural basis of substrate recognition undetermined"]},{"year":2003,"claim":"TACE knockout mouse cardiac phenotype (enlarged trabeculated hearts, reduced ErbB4 cleavage) demonstrated that ADAM17-mediated shedding is required for normal cardiac development through ErbB signaling.","evidence":"ADAM17 null mouse phenotyping with ErbB4 cleavage and MAPK activation readouts","pmids":["14499647"],"confidence":"High","gaps":["Identity of the specific ADAM17 substrate(s) driving cardiac phenotype not fully resolved","Redundancy with ADAM10 in heart not addressed"]},{"year":2005,"claim":"Demonstration that aspirin-induced platelet GPIbα/GPV shedding is entirely ADAM17-dependent (using catalytically inactive knock-in mice) established ADAM17 as a key platelet sheddase independent of COX-1.","evidence":"ADAM17 knock-in mice expressing inactive protease, COX-1 KO comparison, FACS and Western blot","pmids":["16179345"],"confidence":"High","gaps":["How aspirin activates ADAM17 independently of COX-1 remains unclear","Physiological significance for hemostasis not fully defined"]},{"year":2006,"claim":"Discovery that FHL2 binds the ADAM17 cytoplasmic tail (aa 721-739) and links it to the actin cytoskeleton revealed that cytoskeletal association modulates ADAM17 surface localization and stimulated shedding.","evidence":"Yeast two-hybrid, co-IP, co-localization, FHL2 KO macrophages with altered surface ADAM17 and reduced PMA-stimulated shedding","pmids":["16619241"],"confidence":"High","gaps":["Whether FHL2 regulation is tissue-specific","Mechanism by which actin dynamics translate into ADAM17 activation"]},{"year":2007,"claim":"Systematic transmembrane domain (TM) swap experiments showed that the TM sequence of ADAM17 is required for efficient substrate cleavage and confers substrate selectivity (e.g., TGF-α vs. TNF-α), establishing that ADAM17 substrate recognition extends beyond the catalytic domain.","evidence":"TM swap and GPI-anchor constructs in TACE-deficient cells with functional shedding assays","pmids":["18040288"],"confidence":"High","gaps":["Structural basis of TM-substrate interaction unknown","Whether lipid environment modulates TM-dependent selectivity"]},{"year":2008,"claim":"Two advances defined contextual regulation of ADAM17: cholesterol efflux-mediated redistribution from lipid rafts activates shedding even on cell-free membranes, and tissue recombination showed ADAM17 on mammary epithelial cells releases amphiregulin to signal in trans to stromal EGFR.","evidence":"Cell-free membrane shedding assay with ABCA1-dependent cholesterol efflux; mammary tissue recombination with ADAM17-deficient epithelium and soluble AREG rescue","pmids":["17786981","18470483"],"confidence":"High","gaps":["Precise lipid species controlling ADAM17 raft partitioning not identified","Whether paracrine ADAM17-EGFR axis operates in all epithelia"]},{"year":2011,"claim":"Multiple discoveries in 2011 established phosphorylation-dependent regulation and new biological roles: Trk/MEK-dependent phosphorylation of ADAM17 Thr735 activates p75NTR cleavage for neuronal survival; TACE cleaves NRG1 type III to negatively regulate PNS myelination (conditional KO causes hypermyelination); and CD9 tetraspanin directly associates with ADAM17 as a negative regulator of shedding.","evidence":"Phospho-site mapping with MEK inhibitor and p75NTR-ICD rescue in neurons; conditional motor neuron KO mice and NRG1 haploinsufficiency rescue; proximity ligation and co-IP with CD9 gain/loss-of-function shedding assays","pmids":["21411748","21666671","21365281"],"confidence":"High","gaps":["Kinase(s) directly phosphorylating Thr735 not biochemically confirmed","Structural basis of CD9-ADAM17 interaction not resolved","Whether CD9 regulation is conserved across all ADAM17 substrates"]},{"year":2012,"claim":"Identification of p53 as a direct transcriptional activator of ADAM17, which in turn cleaves Notch1 to promote epidermal differentiation, revealed a tumor-suppressive p53→TACE→Notch1 axis in skin.","evidence":"Epidermal Fos-deletion mouse models, p53-dependent transcriptional assays, Notch1 activation readout","pmids":["22772468"],"confidence":"High","gaps":["Whether p53-dependent ADAM17 transcription operates outside epidermis","Relative contribution of ADAM17 vs. ADAM10 to Notch cleavage in vivo in skin"]},{"year":2014,"claim":"Conditional deletion of ADAM17 in oligodendrocyte progenitors showed it is required for CNS myelination via shedding of TGF-α/HB-EGF to activate EGFR, and iRhom2 gain-of-function mutations (tylosis) increase ADAM17 maturation and EGFR ligand release in keratinocytes, validating the iRhom2-ADAM17 regulatory axis in human disease.","evidence":"OPC-specific conditional KO with EGFR rescue; patient-derived tylosis keratinocytes with ADAM17 maturation and EGFR phosphorylation readouts; IL-6R mutagenesis defining cleavage-site geometry for ADAM17 selectivity","pmids":["25186737","24643277","27151651"],"confidence":"High","gaps":["Structural model of iRhom2-ADAM17 complex lacking","How cleavage-site distance from the membrane is sensed by the protease"]},{"year":2016,"claim":"Clathrin-dependent constitutive internalization of ADAM17 was defined, with PKC/PMA causing rapid surface upregulation followed by exosomal release of catalytically active ADAM17 that can shed substrates on distant cells, revealing regulated trafficking as a key control point.","evidence":"Live-cell imaging with clathrin inhibition; exosome isolation showing metalloproteinase-domain-outside orientation; iRhom2 requirement for exosomal release","pmids":["27731361","27599715"],"confidence":"High","gaps":["Cargo sorting signals for ADAM17 exosomal incorporation unknown","Physiological relevance of exosomal ADAM17 shedding in vivo not established"]},{"year":2017,"claim":"The mechanism by which stimulated shedding activates ADAM17 was resolved: MAP kinase phosphorylates the iRhom2 N-terminal tail, recruiting 14-3-3 proteins that dissociate the iRhom2-ADAM17 complex, freeing ADAM17 for substrate cleavage.","evidence":"Phosphorylation mapping, 14-3-3 co-IP, iRhom2 mutant analysis, MAP kinase inhibitors","pmids":["29045841"],"confidence":"High","gaps":["Which MAP kinase isoform(s) directly phosphorylate iRhom2","Whether 14-3-3 displacement is sufficient or additional cofactors are needed","Structural model of 14-3-3-iRhom2 interface absent"]},{"year":2019,"claim":"HIF-1α was shown to bind the ADAM17 promoter in macrophages, directly upregulating ADAM17 transcription during metabolic stress and fumarate accumulation, expanding the known transcriptional regulators and connecting ADAM17 to metabolic inflammation and vascular disease.","evidence":"ChIP for HIF-1α at ADAM17 promoter, metabolomics, HIF-1α inhibitor acriflavine, mouse aortic dissection model","pmids":["31640947","26175156"],"confidence":"High","gaps":["Whether HIF-1α and Sp1/p53 cooperate or act independently at the ADAM17 promoter","Epigenetic regulation of ADAM17 expression unexplored"]},{"year":2020,"claim":"ADAM17 was identified as a sheddase for PD-L1 on tumor cells and extracellular vesicles; soluble PD-L1 generated by ADAM17 induces CD8+ T cell apoptosis, linking ADAM17 to immune checkpoint evasion.","evidence":"ADAM17 knockdown and pharmacological inhibition with CD8+ T cell apoptosis and killing assays","pmids":["32363112"],"confidence":"Medium","gaps":["Relative contribution of ADAM17 vs. ADAM10 to PD-L1 shedding in different tumor types","Whether sPD-L1 from ADAM17 has distinct immunosuppressive potency vs. alternatively spliced sPD-L1"]},{"year":2021,"claim":"Endothelial ADAM17-mediated TNFR1 shedding followed by γ-secretase processing was shown to be required for TNF-induced necroptosis and tumor cell extravasation, defining a sequential proteolytic cascade in metastasis.","evidence":"Endothelial-specific ADAM17 KO mice, γ-secretase inhibitor, lung metastasis model","pmids":["34919140"],"confidence":"High","gaps":["Whether ADAM17-TNFR1-necroptosis axis operates in non-pulmonary metastatic niches","Identity of downstream necroptosis mediators in endothelium"]},{"year":2022,"claim":"Therapeutic inhibition of ADAM17 (prodomain inhibitor or genetic hypomorph) ameliorated experimental pancreatitis by suppressing IL-6 trans-signaling/STAT3, providing in vivo validation of ADAM17 as a druggable target in inflammatory disease.","evidence":"Adam17ex/ex hypomorphic mice and prodomain inhibitor in pancreatitis models with STAT3 pathway and histological readouts","pmids":["36215509"],"confidence":"High","gaps":["Long-term safety of ADAM17 therapeutic inhibition given its broad substrate repertoire","Whether prodomain inhibitor achieves substrate-selective inhibition in vivo"]},{"year":null,"claim":"Despite extensive characterization, outstanding questions include the structural basis of iRhom2-ADAM17 complex assembly and 14-3-3-mediated dissociation, the rules governing substrate selectivity among >80 substrates, and whether tissue- or stimulus-specific ADAM17 inhibition can be achieved therapeutically without disrupting essential homeostatic shedding.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of full-length ADAM17-iRhom2 complex","Substrate selectivity code not defined","Tissue-selective therapeutic targeting strategy not validated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,5,7,12,14,22,33,35,36,37]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,35]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8,13,15,26,29,30]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[16,29]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[26]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,3,9,17,19,21,24,25,39,40]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,36,37,38,39]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,14,21,24]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,7,22,30]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[40,41,42]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[14,17,27]}],"complexes":["iRhom2-ADAM17 complex","ADAM17-14-3-3 regulatory complex"],"partners":["RHBDF2","FHL2","CD9","YWHAZ","PXN","NOX1","ADAM8"],"other_free_text":[]},"mechanistic_narrative":"ADAM17 (TACE) is a membrane-anchored zinc-dependent metalloprotease that functions as the principal sheddase for a broad repertoire of transmembrane substrates—including TNF-α, EGFR ligands (TGF-α, amphiregulin, HB-EGF), IL-6R, NRG1 type III, ACE2, TNFR1, PD-L1, GPIbα, GPV, CD44, KIT, and p75NTR—thereby controlling inflammation, EGFR/ErbB signaling, Notch activation, myelination, cardiac development, and immune cell function [PMID:9042103, PMID:11823465, PMID:21666671, PMID:25186737, PMID:34919140]. Its catalytic activity is regulated at multiple levels: iRhom2 controls ER-to-surface maturation, MAP kinase-dependent phosphorylation of iRhom2 recruits 14-3-3 proteins to release active ADAM17 at the cell surface, Trk-dependent phosphorylation of ADAM17 Thr735 stimulates shedding, clathrin-mediated endocytosis constitutively internalizes the protease, and redistribution out of lipid rafts (e.g., by cholesterol efflux or PMA/PKC stimulation) enhances sheddase activity [PMID:29045841, PMID:21411748, PMID:27731361, PMID:17786981]. Tetraspanin CD9 directly associates with ADAM17 and acts as a negative regulator of shedding, while the LIM-domain protein FHL2 links ADAM17 to the actin cytoskeleton and modulates its surface localization and stimulated activity [PMID:21365281, PMID:16619241]. Transcriptional upregulation of ADAM17 is driven by Sp1, p53, and HIF-1α binding to its promoter, the latter creating a positive-feedback loop with EGFR signaling under hypoxic or metabolic stress conditions [PMID:19772640, PMID:22772468, PMID:26175156, PMID:31640947]."},"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":"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":432,"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":352,"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":337,"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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\"confidence_rationale\": \"Tier 1 — direct biochemical purification and in vitro cleavage assay establishing catalytic function\",\n      \"pmids\": [\"9042103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADAM17/TACE cleaves pro-TGF-α at its N-terminal and C-terminal ectodomain sites in vitro, and mediates shedding of amphiregulin and HB-EGF in cells; TACE-deficient cells shed dramatically less TGF-α, restored by TACE adenovirus infection.\",\n      \"method\": \"In vitro cleavage assay with purified TACE, TACE-deficient cell reconstitution, cotransfection, adenoviral rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus multiple cell-based loss-of-function and rescue experiments\",\n      \"pmids\": [\"11823465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Genetic evidence that TACE regulates EGFR ligand availability in vivo: mice heterozygous for Tace and homozygous for impaired EGFR allele (wa-2) were born with open eyes more frequently, indicating epistatic interaction between TACE and EGFR signaling.\",\n      \"method\": \"Genetic epistasis (double mutant mouse crosses)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis in vivo with defined phenotypic readout\",\n      \"pmids\": [\"11823465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TACE/ADAM17 null mutant mice exhibit enlarged fetal hearts with increased trabeculation, reduced cell compaction, larger cardiomyocytes and increased proliferation, accompanied by attenuated ErbB4 cleavage and changes in MAPK activation, demonstrating a role for ADAM17-mediated shedding in cardiac development.\",\n      \"method\": \"Knockout mouse phenotyping, Western blot for ErbB4 cleavage and MAPK activation\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined molecular and cellular phenotype, multiple readouts\",\n      \"pmids\": [\"14499647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TACE/ADAM17 acts as a constitutive and PMA-stimulated sheddase for MUC1 on human uterine epithelial cells; TACE-deficient cells lose PMA-stimulated MUC1 shedding, which is distinct from pervanadate-stimulated shedding mediated by MT1-MMP.\",\n      \"method\": \"TACE-deficient cell lines, pharmacological inhibitors, co-transfection\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in TACE-deficient cells with substrate-specific readout\",\n      \"pmids\": [\"15130087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aspirin induces shedding of platelet GPIbα and GPV via an ADAM17-dependent mechanism; shedding was completely blocked in platelets expressing inactive ADAM17, but occurred normally in COX-1-deficient platelets.\",\n      \"method\": \"ADAM17 knock-in mutant mice (inactive form), COX-1 KO mice, FACS, immunoprecipitation, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with specific substrate readout, replicated in vivo\",\n      \"pmids\": [\"16179345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM17 interacts with the LIM domain protein FHL2 via amino acids 721–739 of ADAM17; FHL2 colocalizes with ADAM17 and the actin cytoskeleton in cardiomyoblasts, and FHL2-deficient macrophages show increased surface ADAM17 but reduced PMA-stimulated substrate shedding, indicating FHL2 regulates ADAM17 localization and activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, FHL2 KO macrophages, substrate shedding assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction confirmed by multiple methods plus functional KO data\",\n      \"pmids\": [\"16619241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The transmembrane domain (TM) of TACE is required for efficient cleavage of TGF-α, TNF-α and L-selectin; GPI-anchored TACE lacking TM fails to restore shedding, and substitution of TM with prolactin receptor or PDGFR TM abolishes TGF-α shedding but not TNF-α/L-selectin shedding, revealing TM sequence-dependent substrate specificity.\",\n      \"method\": \"Molecular engineering (TM swap/GPI anchor constructs), functional shedding assay in TACE-deficient cells\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic domain-swap mutagenesis with functional reconstitution\",\n      \"pmids\": [\"18040288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HDL-induced cholesterol efflux from lipid rafts redistributes ADAM17 out of lipid rafts and activates ADAM17-dependent shedding of TNFR1, TNFR2, and TNF; this was demonstrated even on cell-free isolated plasma membranes, indicating a direct lipid raft-mediated regulation of ADAM17 activity.\",\n      \"method\": \"Cell-free plasma membrane assay, ABCA1-dependent cholesterol efflux, specific inhibitors, lipid raft fractionation\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-free assay and genetic (ABCA1-dependent) evidence linking lipid raft composition to ADAM17 activity\",\n      \"pmids\": [\"17786981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM17 mediates EGFR ligand (amphiregulin) release from mammary ductal epithelial cells to activate stromal EGFR; tissue recombination studies show ADAM17 and AREG must be on epithelial cells while EGFR is on stromal cells, and soluble AREG rescues ADAM17-deficient transplants.\",\n      \"method\": \"Tissue recombination and transplantation, ADAM17-deficient mammary epithelium, soluble AREG rescue\",\n      \"journal\": \"Journal of mammary gland biology and neoplasia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with rescue experiment defining cell-autonomous pathway\",\n      \"pmids\": [\"18470483\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Kuz (Kuzbanian/ADAM10) and TACE/ADAM17 can both activate Notch signaling by cleaving the Notch receptor; overexpression of TACE activates Notch in a ligand-independent manner in Drosophila, while Kuz requires Delta stimulation.\",\n      \"method\": \"In vitro Drosophila model, overexpression and dominant-negative analysis of Kuz and TACE\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic gain-of-function in defined cell model, ortholog context\",\n      \"pmids\": [\"18535782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Transcription factor Sp1 binds to the GC-rich ADAM17 promoter and regulates ADAM17 expression under hypoxia, as shown by chromatin immunoprecipitation assay; Sp1 suppression decreases ADAM17-dependent glioma invasiveness.\",\n      \"method\": \"ChIP assay, RT-PCR, Western blot, siRNA knockdown, invasion assay\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP confirms direct promoter binding with functional consequence\",\n      \"pmids\": [\"19772640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TACE/ADAM17 mediates germ cell apoptosis by cleaving the extracellular domain of the KIT receptor; TACE inhibition prevents apoptosis and PMA-induced KIT ectodomain loss, while ADAM10 inhibition does not, demonstrating substrate specificity in vivo.\",\n      \"method\": \"Pharmacological ADAM17 inhibition, PMA stimulation, ex vivo testis culture, KIT ectodomain Western blot\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and stimulation-based evidence with specific substrate readout\",\n      \"pmids\": [\"20501791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAM17 multimerizes in the cell membrane via its EGF-like domain, suggesting dimerization as a mechanism contributing to ADAM17 activation and function.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of EGF-like domain, cell membrane analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — co-IP with domain mapping, single lab\",\n      \"pmids\": [\"22033402\"],\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 and thereby negatively regulating PNS myelination; lentiviral TACE knockdown in DRG neurons causes hypermyelination, conditional motor neuron TACE KO mice show significant hypermyelination, and reduced TACE rescues hypomyelination in NRG1 type III haploinsufficient mice.\",\n      \"method\": \"Lentiviral knockdown in DRG neurons, conditional neuronal KO mice, NRG1 haploinsufficient mouse rescue, PI3K pathway assay\",\n      \"journal\": \"Nature neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal genetic models with defined molecular mechanism and phenotype, replicated in vivo\",\n      \"pmids\": [\"21666671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tetraspanin CD9 associates directly with ADAM17 on endothelial and monocytic cell surfaces; CD9 antibody treatment or CD9 overexpression reduces ADAM17-mediated shedding of TNF-α and ICAM-1, while CD9 silencing increases ADAM17 sheddase activity.\",\n      \"method\": \"In situ proximity ligation, co-immunoprecipitation, crosslinking, pull-down, CD9 siRNA and overexpression, substrate shedding assay\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods confirming direct interaction with functional consequence\",\n      \"pmids\": [\"21365281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HIV Nef recruits paxillin and ADAM17 into a complex; Pak2 phosphorylates paxillin on Ser272/274 to induce TACE-paxillin association and shuttle ADAM17 into extracellular vesicles via lipid rafts, cleaving pro-TNF-α; Pak1 phosphorylates paxillin Ser258 to inhibit TACE association.\",\n      \"method\": \"Co-immunoprecipitation, phospho-specific mutants, lipid raft fractionation, EV isolation, Pak1/2 knockdown\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods defining phosphorylation-dependent protein complex and functional shedding readout\",\n      \"pmids\": [\"23317503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Trk receptor activation induces MEK-dependent phosphorylation of ADAM17 at threonine 735, activating ADAM17 to cleave p75NTR and produce p75NTR intracellular domain (p75NTR-ICD), which is required for neurotrophin-induced Erk/Akt activation and neuronal survival.\",\n      \"method\": \"Phospho-specific site identification, MEK inhibitor, ADAM17 depletion, p75NTR-ICD overexpression rescue, survival assay in PC12 and primary neurons\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — identified specific phosphorylation site with mechanistic rescue experiment in primary neurons\",\n      \"pmids\": [\"21411748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A cross-domain human antibody specifically inhibits cell-surface TACE by targeting its ectodomain rather than the active site, providing a mechanistic basis for allosteric inhibition of TACE shedding activity.\",\n      \"method\": \"Phage display antibody development, selective TACE inhibition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel inhibitor mode confirmed by selectivity profiling, single study\",\n      \"pmids\": [\"21415364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p53 transcriptionally activates TACE/ADAM17 as a novel target gene; TACE in turn activates NOTCH1, promoting epidermal differentiation and squamous cell carcinoma suppression downstream of a FOS/p53/TACE axis.\",\n      \"method\": \"Epidermal Fos deletion mouse models, pharmacological FOS/AP-1 inhibition, p53-dependent transcriptional activation assay, NOTCH1 activation readout\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mouse models with multiple cell-type validation and defined transcriptional mechanism\",\n      \"pmids\": [\"22772468\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nox1 interacts with and stabilizes ADAM17 from ubiquitin-mediated degradation, leading to activation of the ADAM17/EGFR-PI3K-AKT signaling pathway and promotion of colon cancer metastasis.\",\n      \"method\": \"Immunoprecipitation, siRNA knockdown, ubiquitination assay, migration/invasion assay\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single co-IP with functional siRNA data, single lab\",\n      \"pmids\": [\"27874952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TACE/ADAM17 genetic deletion in oligodendrocyte progenitor cells causes premature cell cycle exit, reduced OL survival, and deficits in CNS myelination; TACE regulates oligodendrogenesis by shedding EGFR ligands TGFα and HB-EGF, and EGFR overexpression in TACE-deficient OPs rescues OL development.\",\n      \"method\": \"Conditional KO mice (OPC-specific), EGFR overexpression rescue, substrate shedding assay, behavioral readout\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with specific pathway rescue demonstrating mechanistic link\",\n      \"pmids\": [\"25186737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Deletion of a triple serine motif (Ser359–Ser361) adjacent to the IL-6R cleavage site prevents ADAM17-mediated but not ADAM10-mediated IL-6R shedding by reducing the distance between cleavage site and plasma membrane, revealing that cleavage site positioning differentially controls ADAM17 vs ADAM10 proteolysis.\",\n      \"method\": \"Deletion mutagenesis, shedding assay, IL-6R functional assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — site-directed mutagenesis with mechanistic interpretation of geometry-dependent shedding\",\n      \"pmids\": [\"27151651\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"iRhom2 dominant mutations (tylosis/TOC-associated) increase ADAM17 maturation and activity in epidermal keratinocytes, resulting in upregulated shedding of EGF-family growth factors and pro-inflammatory cytokines, increased EGFR activity, and aberrant desmosome processing.\",\n      \"method\": \"Patient-derived TOC keratinocytes, ADAM17 maturation assay, substrate shedding assay, EGFR phosphorylation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human disease mutations validate iRhom2-ADAM17 regulatory axis with multiple molecular readouts\",\n      \"pmids\": [\"24643277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TACE/ADAM17 is required for OL regeneration and CNS remyelination following demyelination by activating EGFR in OL lineage cells; TACE deficiency abrogates EGFR activation, impairs OL expansion and survival, and delays remyelination; EGFR overexpression in TACE-deficient OPs rescues remyelination.\",\n      \"method\": \"Conditional KO mice, demyelination model, EGFR overexpression rescue, OL lineage cell expansion/survival assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss and gain-of-function in vivo with defined molecular pathway rescue\",\n      \"pmids\": [\"26338334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HIF-1α binds to its consensus element at -607 of the ADAM17 promoter to drive ADAM17 transcriptional upregulation in response to high glucose; this is dependent on EGFR/ADAM17 signaling, creating a positive feedback loop.\",\n      \"method\": \"ADAM17 promoter deletion constructs, mutation analysis, ChIP, HRE-luciferase reporter, HIF-1α inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP, mutagenesis, and luciferase reporter with multiple inhibitor validations\",\n      \"pmids\": [\"26175156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM17 is constitutively internalized via clathrin-coated pits; GPCR ligand stimulation induces ADAM17-mediated shedding without altering cell-surface abundance, while PMA/PKC activation causes rapid increase of mature ADAM17 at the cell surface followed by internalization and degradation, substantially downregulating mature ADAM17.\",\n      \"method\": \"Live-cell imaging, clathrin inhibition, FACS surface expression analysis, PMA vs. physiological stimulator comparison\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization experiments with functional mechanistic consequences, multiple methods\",\n      \"pmids\": [\"27731361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Niacin/Niaspan enhances TACE activity in vivo and rescues focal hypermyelination in CMT mouse models (Mtmr2-/- and Pmp22+/-) by downregulating NRG1 type III signaling through TACE-mediated cleavage.\",\n      \"method\": \"In vivo drug treatment, TACE activity assay, myelination quantification in CMT mouse models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo pharmacological activation of TACE with defined molecular pathway and phenotypic rescue\",\n      \"pmids\": [\"27799291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Tetraspanin CD9 coassociates with and negatively regulates ADAM17 in leukocytes; CD9 neo-expression or neutralizing anti-CD9 antibodies modulate ADAM17-mediated shedding of LR11, confirmed by metalloproteinase inhibitor sensitivity.\",\n      \"method\": \"Confocal co-localization, shRNA knockdown, CD9 overexpression, metalloproteinase inhibitor, sLR11 ELISA\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple approaches but no direct binding assay; functional consequence established\",\n      \"pmids\": [\"24699135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PMA stimulation downregulates surface ADAM17 in lung epithelial cells by inducing release of mature ADAM17 in exosomes; exosomal ADAM17 retains metalloproteinase domain-outside orientation and can shed TGFα and amphiregulin on distant cells; iRhom2-mediated maturation is required for surface expression and exosomal release.\",\n      \"method\": \"Exosome isolation, antibody surface labeling, iRhom2 suppression, shRNA knockdown, substrate shedding assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing mechanism of ADAM17 surface regulation and exosomal activity\",\n      \"pmids\": [\"27599715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Stimulation of ADAM17/TACE shedding by inflammatory/growth-promoting agents triggers MAP kinase-dependent phosphorylation of the iRhom2 N-terminal cytoplasmic tail, recruiting 14-3-3 proteins that enforce dissociation of TACE from iRhom2 complexes and promote cleavage of TACE substrates.\",\n      \"method\": \"Phosphorylation mapping, 14-3-3 co-IP, iRhom2 mutant analysis, substrate shedding assay, MAP kinase inhibitors\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined post-translational modification with mechanistic protein complex dissociation readout, multiple orthogonal methods\",\n      \"pmids\": [\"29045841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM17 deficiency in smooth muscle cells prevents contractile-to-synthetic phenotypic switching in TAA, while ADAM17 deficiency in endothelial cells preserves VE-cadherin, JAM-A and claudin junctions; both independently suppress aortic aneurysm dilation, demonstrating cell-specific functions.\",\n      \"method\": \"SMC-specific and EC-specific conditional KO mice (Adam17/Sm22 and Adam17/Tie2), ADAM17 siRNA in primary cells, pharmacological inhibitor (PF-548), in vivo TAA model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple conditional KO models with specific molecular readouts and pharmacological confirmation\",\n      \"pmids\": [\"29930147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HIF-1α activation in macrophages, triggered by fumarate accumulation, transcriptionally upregulates ADAM17 as a novel HIF-1α target gene, promoting vascular inflammation and elastic fiber degradation in aortic dissection; ChIP confirmed HIF-1α binding to ADAM17 promoter.\",\n      \"method\": \"ChIP, metabolomics, Seahorse flux analysis, ELISA, HIF-1α inhibitor (acriflavine), mouse models\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP confirms direct HIF-1α binding, supported by multiple mechanistic and in vivo approaches\",\n      \"pmids\": [\"31640947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM17 mediates ACE2 ectodomain shedding; ADAM17 inhibitor applied to renal proximal tubular cells reduces ACE2 shedding into the media, and ACE2 colocalizes with ADAM17 in renal tubules.\",\n      \"method\": \"ADAM17 inhibitor in primary tubular cells, immunostaining colocalization, urinary ACE2 fragment analysis\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with defined substrate readout in primary cells\",\n      \"pmids\": [\"24452639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM17 expression co-localizes with angiotensin-II type 1 receptors on Sim1 neurons of the hypothalamic paraventricular nucleus; selective neuronal ADAM17 knockdown reduces FosB expression, increases vagal tone, and prevents the acute pressor response to centrally administered angiotensin-II.\",\n      \"method\": \"Neuron-specific conditional knockdown (new mouse models), photoactivation, blood pressure measurement\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — conditional neuronal KO with defined physiological and molecular readout\",\n      \"pmids\": [\"31564162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM8 can release the ADAM17 ectodomain (shedding of ADAM17 itself); soluble ADAM17 (sADAM17) cleaves fibronectin, cystatin C, sN-cadherin, PCPE-1, and sAPP in vitro, revealing a degradome distinct from membrane-anchored ADAM17.\",\n      \"method\": \"N-terminomics/mass spectrometry, in vitro cleavage assays with purified substrates\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage assays confirm direct substrates of soluble ADAM17\",\n      \"pmids\": [\"31209506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAM10 and ADAM17 cleave PD-L1 from the surface of malignant cells and extracellular vesicles, generating a soluble active sPD-L1 fragment that induces apoptosis in CD8+ T cells and impairs their tumor-killing ability.\",\n      \"method\": \"ADAM10/17 inhibition, ADAM17 knockdown, shedding assay, CD8+ T cell apoptosis and killing assay\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological and genetic inhibition with defined functional immune consequence\",\n      \"pmids\": [\"32363112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 on endothelial cells mediates TNFR1 ectodomain shedding; subsequent processing by the γ-secretase complex is required for induction of TNF-induced necroptosis. Genetic ablation or pharmacological inhibition of ADAM17 in endothelial cells prevents tumor cell extravasation and lung metastasis.\",\n      \"method\": \"Endothelial-specific ADAM17 KO mice, γ-secretase inhibitor, necroptosis assay, lung metastasis model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO plus pharmacological inhibition with defined molecular pathway and in vivo metastasis readout\",\n      \"pmids\": [\"34919140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-15 activates ADAM17 in human NK cells, which sheds CD62L from the surface, limiting NK cell proliferation; ADAM17 blockade markedly increases NK cell proliferation in vitro and in xenograft mice, and CD62L is required for this proliferation effect in vivo.\",\n      \"method\": \"ADAM17 monoclonal antibody blockade, xenograft mouse model, CD62L surface expression, CD62L-dependent proliferation assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological blocking antibody with in vivo validation and defined substrate/pathway\",\n      \"pmids\": [\"34367174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Genetic reduction (Adam17ex/ex hypomorphic mice) or therapeutic inhibition (ADAM17 prodomain inhibitor) of ADAM17 ameliorates experimental pancreatitis by reducing IL-6 trans-signaling/STAT3 axis, associated with reduction in inflammatory cell infiltration, necrosis, and fibrosis.\",\n      \"method\": \"Hypomorphic mouse model, pharmacological prodomain inhibitor, STAT3 pathway analysis, histology\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological loss-of-function with defined signaling pathway and histological readout\",\n      \"pmids\": [\"36215509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM17 promotes shedding of EGFR ligands TGFα and HB-EGF and activates EGFR/PI3K/AKT signaling in glioma; ADAM17 overexpression promotes U87 glioma cell proliferation, invasion, and angiogenesis, while ADAM17 siRNA or TAPI-2 inhibitor reverses these effects.\",\n      \"method\": \"Stable ADAM17 overexpression/siRNA transfection, TAPI-2 inhibitor, MTT/BrdU assay, Matrigel invasion, Western blot for EGFR-PI3K-AKT\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain and loss-of-function with defined pathway readout, single lab\",\n      \"pmids\": [\"21480393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM17 cleaves the extracellular domain of CD44 in HNSCC; ADAM17 chemical inhibition and stable suppression block CD44 cleavage and abrogate orasphere formation and tumorigenesis in vivo.\",\n      \"method\": \"ADAM17 inhibitor, stable shRNA suppression, sphere assay, oral cancer mouse model\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological loss-of-function with in vivo tumorigenesis readout\",\n      \"pmids\": [\"24403253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM17 cleaves the Notch extracellular domain to regulate self-renewal of glioblastoma stem cells via Notch signaling; ADAM17 knockdown inhibits Hes1/Hes5, activates Notch1 expression, and suppresses secondary neurosphere formation and multi-lineage differentiation.\",\n      \"method\": \"ADAM17 shRNA knockdown in GSCs, Hes1/Hes5/Notch1 Western blot, neurosphere assay\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined Notch pathway readout in stem cell model\",\n      \"pmids\": [\"23356982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD9 co-localizes with and directly associates with ADAM17 on keratinocytes during wound repair; CD9 down-regulation activates ADAM17 sheddase activity leading to release of HB-EGF, which activates EGFR/ERK pathway to promote keratinocyte migration; ADAM17 inhibition or siRNA blocks this CD9-regulated migration.\",\n      \"method\": \"Confocal microscopy, co-immunoprecipitation, TAPI-2 inhibitor, siADAM17, HB-EGF neutralizing antibody, in vivo wound assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional rescue with defined substrate/pathway, in vivo correlation\",\n      \"pmids\": [\"30745837\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM17/TACE is a membrane-anchored zinc-dependent metalloprotease whose activity is regulated by iRhom2-dependent ER exit and maturation, clathrin-mediated internalization, MAP kinase-dependent phosphorylation of iRhom2 (which recruits 14-3-3 to dissociate the ADAM17-iRhom2 complex at the cell surface), PKC/PMA-induced redistribution from lipid rafts to the non-raft membrane, Trk-dependent phosphorylation of ADAM17 Thr735, FHL2/cytoskeleton association, and CD9 tetraspanin-mediated negative modulation; it catalyzes ectodomain shedding of at least 80 substrates—including TNF-α, IL-6R, NRG1 type III, EGFR ligands (TGF-α, amphiregulin, HB-EGF), ACE2, GPIbα, GPV, TNFR1, PD-L1, and KIT—to control inflammation, EGFR signaling, Notch activation, myelination in the PNS and CNS, cardiac and vascular development, and immune cell function.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAM17 (TACE) is a membrane-anchored zinc-dependent metalloprotease that functions as the principal sheddase for a broad repertoire of transmembrane substrates—including TNF-α, EGFR ligands (TGF-α, amphiregulin, HB-EGF), IL-6R, NRG1 type III, ACE2, TNFR1, PD-L1, GPIbα, GPV, CD44, KIT, and p75NTR—thereby controlling inflammation, EGFR/ErbB signaling, Notch activation, myelination, cardiac development, and immune cell function [PMID:9042103, PMID:11823465, PMID:21666671, PMID:25186737, PMID:34919140]. Its catalytic activity is regulated at multiple levels: iRhom2 controls ER-to-surface maturation, MAP kinase-dependent phosphorylation of iRhom2 recruits 14-3-3 proteins to release active ADAM17 at the cell surface, Trk-dependent phosphorylation of ADAM17 Thr735 stimulates shedding, clathrin-mediated endocytosis constitutively internalizes the protease, and redistribution out of lipid rafts (e.g., by cholesterol efflux or PMA/PKC stimulation) enhances sheddase activity [PMID:29045841, PMID:21411748, PMID:27731361, PMID:17786981]. Tetraspanin CD9 directly associates with ADAM17 and acts as a negative regulator of shedding, while the LIM-domain protein FHL2 links ADAM17 to the actin cytoskeleton and modulates its surface localization and stimulated activity [PMID:21365281, PMID:16619241]. Transcriptional upregulation of ADAM17 is driven by Sp1, p53, and HIF-1α binding to its promoter, the latter creating a positive-feedback loop with EGFR signaling under hypoxic or metabolic stress conditions [PMID:19772640, PMID:22772468, PMID:26175156, PMID:31640947].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Identification of ADAM17/TACE as the protease responsible for TNF-α shedding resolved the long-sought question of which enzyme generates soluble TNF-α from its membrane-anchored precursor.\",\n      \"evidence\": \"Biochemical purification from monocyte membranes and in vitro cleavage assay demonstrating cleavage at Ala76-Val77\",\n      \"pmids\": [\"9042103\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of TACE with pro-TNF-α substrate not yet solved\", \"Regulation of TACE activity unknown\", \"Full-length cloning incomplete at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing ADAM17 as the sheddase for multiple EGFR ligands (TGF-α, amphiregulin, HB-EGF) and demonstrating genetic epistasis with EGFR in vivo expanded its role from a single-substrate protease to a master regulator of EGFR signaling.\",\n      \"evidence\": \"In vitro cleavage assay with purified TACE, TACE-deficient cell reconstitution, and genetic epistasis in Tace+/− × wa-2 mice\",\n      \"pmids\": [\"11823465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ADAM17 selects among EGFR ligands versus other substrates\", \"Structural basis of substrate recognition undetermined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"TACE knockout mouse cardiac phenotype (enlarged trabeculated hearts, reduced ErbB4 cleavage) demonstrated that ADAM17-mediated shedding is required for normal cardiac development through ErbB signaling.\",\n      \"evidence\": \"ADAM17 null mouse phenotyping with ErbB4 cleavage and MAPK activation readouts\",\n      \"pmids\": [\"14499647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the specific ADAM17 substrate(s) driving cardiac phenotype not fully resolved\", \"Redundancy with ADAM10 in heart not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that aspirin-induced platelet GPIbα/GPV shedding is entirely ADAM17-dependent (using catalytically inactive knock-in mice) established ADAM17 as a key platelet sheddase independent of COX-1.\",\n      \"evidence\": \"ADAM17 knock-in mice expressing inactive protease, COX-1 KO comparison, FACS and Western blot\",\n      \"pmids\": [\"16179345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How aspirin activates ADAM17 independently of COX-1 remains unclear\", \"Physiological significance for hemostasis not fully defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Discovery that FHL2 binds the ADAM17 cytoplasmic tail (aa 721-739) and links it to the actin cytoskeleton revealed that cytoskeletal association modulates ADAM17 surface localization and stimulated shedding.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, co-localization, FHL2 KO macrophages with altered surface ADAM17 and reduced PMA-stimulated shedding\",\n      \"pmids\": [\"16619241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FHL2 regulation is tissue-specific\", \"Mechanism by which actin dynamics translate into ADAM17 activation\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Systematic transmembrane domain (TM) swap experiments showed that the TM sequence of ADAM17 is required for efficient substrate cleavage and confers substrate selectivity (e.g., TGF-α vs. TNF-α), establishing that ADAM17 substrate recognition extends beyond the catalytic domain.\",\n      \"evidence\": \"TM swap and GPI-anchor constructs in TACE-deficient cells with functional shedding assays\",\n      \"pmids\": [\"18040288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TM-substrate interaction unknown\", \"Whether lipid environment modulates TM-dependent selectivity\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Two advances defined contextual regulation of ADAM17: cholesterol efflux-mediated redistribution from lipid rafts activates shedding even on cell-free membranes, and tissue recombination showed ADAM17 on mammary epithelial cells releases amphiregulin to signal in trans to stromal EGFR.\",\n      \"evidence\": \"Cell-free membrane shedding assay with ABCA1-dependent cholesterol efflux; mammary tissue recombination with ADAM17-deficient epithelium and soluble AREG rescue\",\n      \"pmids\": [\"17786981\", \"18470483\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise lipid species controlling ADAM17 raft partitioning not identified\", \"Whether paracrine ADAM17-EGFR axis operates in all epithelia\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Multiple discoveries in 2011 established phosphorylation-dependent regulation and new biological roles: Trk/MEK-dependent phosphorylation of ADAM17 Thr735 activates p75NTR cleavage for neuronal survival; TACE cleaves NRG1 type III to negatively regulate PNS myelination (conditional KO causes hypermyelination); and CD9 tetraspanin directly associates with ADAM17 as a negative regulator of shedding.\",\n      \"evidence\": \"Phospho-site mapping with MEK inhibitor and p75NTR-ICD rescue in neurons; conditional motor neuron KO mice and NRG1 haploinsufficiency rescue; proximity ligation and co-IP with CD9 gain/loss-of-function shedding assays\",\n      \"pmids\": [\"21411748\", \"21666671\", \"21365281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) directly phosphorylating Thr735 not biochemically confirmed\", \"Structural basis of CD9-ADAM17 interaction not resolved\", \"Whether CD9 regulation is conserved across all ADAM17 substrates\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of p53 as a direct transcriptional activator of ADAM17, which in turn cleaves Notch1 to promote epidermal differentiation, revealed a tumor-suppressive p53→TACE→Notch1 axis in skin.\",\n      \"evidence\": \"Epidermal Fos-deletion mouse models, p53-dependent transcriptional assays, Notch1 activation readout\",\n      \"pmids\": [\"22772468\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether p53-dependent ADAM17 transcription operates outside epidermis\", \"Relative contribution of ADAM17 vs. ADAM10 to Notch cleavage in vivo in skin\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Conditional deletion of ADAM17 in oligodendrocyte progenitors showed it is required for CNS myelination via shedding of TGF-α/HB-EGF to activate EGFR, and iRhom2 gain-of-function mutations (tylosis) increase ADAM17 maturation and EGFR ligand release in keratinocytes, validating the iRhom2-ADAM17 regulatory axis in human disease.\",\n      \"evidence\": \"OPC-specific conditional KO with EGFR rescue; patient-derived tylosis keratinocytes with ADAM17 maturation and EGFR phosphorylation readouts; IL-6R mutagenesis defining cleavage-site geometry for ADAM17 selectivity\",\n      \"pmids\": [\"25186737\", \"24643277\", \"27151651\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural model of iRhom2-ADAM17 complex lacking\", \"How cleavage-site distance from the membrane is sensed by the protease\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Clathrin-dependent constitutive internalization of ADAM17 was defined, with PKC/PMA causing rapid surface upregulation followed by exosomal release of catalytically active ADAM17 that can shed substrates on distant cells, revealing regulated trafficking as a key control point.\",\n      \"evidence\": \"Live-cell imaging with clathrin inhibition; exosome isolation showing metalloproteinase-domain-outside orientation; iRhom2 requirement for exosomal release\",\n      \"pmids\": [\"27731361\", \"27599715\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo sorting signals for ADAM17 exosomal incorporation unknown\", \"Physiological relevance of exosomal ADAM17 shedding in vivo not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The mechanism by which stimulated shedding activates ADAM17 was resolved: MAP kinase phosphorylates the iRhom2 N-terminal tail, recruiting 14-3-3 proteins that dissociate the iRhom2-ADAM17 complex, freeing ADAM17 for substrate cleavage.\",\n      \"evidence\": \"Phosphorylation mapping, 14-3-3 co-IP, iRhom2 mutant analysis, MAP kinase inhibitors\",\n      \"pmids\": [\"29045841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which MAP kinase isoform(s) directly phosphorylate iRhom2\", \"Whether 14-3-3 displacement is sufficient or additional cofactors are needed\", \"Structural model of 14-3-3-iRhom2 interface absent\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"HIF-1α was shown to bind the ADAM17 promoter in macrophages, directly upregulating ADAM17 transcription during metabolic stress and fumarate accumulation, expanding the known transcriptional regulators and connecting ADAM17 to metabolic inflammation and vascular disease.\",\n      \"evidence\": \"ChIP for HIF-1α at ADAM17 promoter, metabolomics, HIF-1α inhibitor acriflavine, mouse aortic dissection model\",\n      \"pmids\": [\"31640947\", \"26175156\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether HIF-1α and Sp1/p53 cooperate or act independently at the ADAM17 promoter\", \"Epigenetic regulation of ADAM17 expression unexplored\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"ADAM17 was identified as a sheddase for PD-L1 on tumor cells and extracellular vesicles; soluble PD-L1 generated by ADAM17 induces CD8+ T cell apoptosis, linking ADAM17 to immune checkpoint evasion.\",\n      \"evidence\": \"ADAM17 knockdown and pharmacological inhibition with CD8+ T cell apoptosis and killing assays\",\n      \"pmids\": [\"32363112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ADAM17 vs. ADAM10 to PD-L1 shedding in different tumor types\", \"Whether sPD-L1 from ADAM17 has distinct immunosuppressive potency vs. alternatively spliced sPD-L1\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Endothelial ADAM17-mediated TNFR1 shedding followed by γ-secretase processing was shown to be required for TNF-induced necroptosis and tumor cell extravasation, defining a sequential proteolytic cascade in metastasis.\",\n      \"evidence\": \"Endothelial-specific ADAM17 KO mice, γ-secretase inhibitor, lung metastasis model\",\n      \"pmids\": [\"34919140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM17-TNFR1-necroptosis axis operates in non-pulmonary metastatic niches\", \"Identity of downstream necroptosis mediators in endothelium\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Therapeutic inhibition of ADAM17 (prodomain inhibitor or genetic hypomorph) ameliorated experimental pancreatitis by suppressing IL-6 trans-signaling/STAT3, providing in vivo validation of ADAM17 as a druggable target in inflammatory disease.\",\n      \"evidence\": \"Adam17ex/ex hypomorphic mice and prodomain inhibitor in pancreatitis models with STAT3 pathway and histological readouts\",\n      \"pmids\": [\"36215509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term safety of ADAM17 therapeutic inhibition given its broad substrate repertoire\", \"Whether prodomain inhibitor achieves substrate-selective inhibition in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Despite extensive characterization, outstanding questions include the structural basis of iRhom2-ADAM17 complex assembly and 14-3-3-mediated dissociation, the rules governing substrate selectivity among >80 substrates, and whether tissue- or stimulus-specific ADAM17 inhibition can be achieved therapeutically without disrupting essential homeostatic shedding.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of full-length ADAM17-iRhom2 complex\", \"Substrate selectivity code not defined\", \"Tissue-selective therapeutic targeting strategy not validated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 5, 7, 12, 14, 22, 33, 35, 36, 37]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 8, 13, 15, 26, 29, 30]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [16, 29]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [26]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 3, 9, 17, 19, 21, 24, 25, 39, 40]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 36, 37, 38, 39]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 14, 21, 24]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 7, 22, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [40, 41, 42]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [14, 17, 27]}\n    ],\n    \"complexes\": [\n      \"iRhom2-ADAM17 complex\",\n      \"ADAM17-14-3-3 regulatory complex\"\n    ],\n    \"partners\": [\n      \"RHBDF2\",\n      \"FHL2\",\n      \"CD9\",\n      \"YWHAZ\",\n      \"PXN\",\n      \"NOX1\",\n      \"ADAM8\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}