ADAM17 (TACE, TNF-alpha converting enzyme) is a zinc-dependent, single-pass type I transmembrane metalloendopeptidase of the ADAM/adamalysin family and one of the two principal mammalian sheddases. After furin-type removal of its inhibitory pro-domain during transit through the Golgi, the mature enzyme reaches the plasma membrane, where it cleaves the juxtamembrane stalks of many transmembrane proteins and so releases their ectodomains. Its best-established substrates include the membrane-anchored precursor of TNF (which it converts to the soluble cytokine), the EGF-receptor ligands amphiregulin, TGF-alpha, HB-EGF, epigen and epiregulin, the interleukin-6 receptor alpha chain, TNF receptors 1 and 2, L-selectin, KIT, platelet glycoprotein V, FcgammaRIIIA/CD16A, MICA, CXCL16, vasorin, ACE2, TREM2, the DCC guidance receptor and the amyloid precursor protein. Through these cleavages ADAM17 governs the availability of soluble cytokines, growth factors and receptor ectodomains, and thereby acts upstream of EGFR, TNF-receptor, IL-6 trans-signalling, TGF-beta and Notch signalling. Its activity is tightly controlled rather than constitutive: trafficking and activation require an iRhom (RHBDF1/RHBDF2) partner with FRMD8, the enzyme is restrained by the tissue inhibitor TIMP3 and by integrin alpha5beta1 binding to its disintegrin domain, and substrate access is set by lipid-raft partitioning and tetraspanin association. ADAM17 also has a non-proteolytic role as an integrin alpha5beta1 ligand. Loss of activity in mouse is perinatally lethal with epithelial and immune defects and a lean, hypermetabolic phenotype, and a human CANDIS-domain variant that destabilises the protein causes hypotrichosis with woolly hair.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9662747 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the Golgi membrane in the context of iRHOM2-dependent ER-to-Golgi transport. Reason: ADAM17 traverses the Golgi, where the furin-type convertase removes its inhibitory pro-domain; Golgi membrane is therefore a genuine (transient) location of the protein, though not the compartment where it acts on substrates. Direct experimental support exists independently of the Reactome assertion: furin cleavage of the ADAM17 pro-domain was localised to Golgi-derived cholesterol-rich microdomains. Supporting Evidence: PMID:17010968 during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9662773 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the Golgi membrane in the context of Zn2+ cofactor loading. Reason: ADAM17 traverses the Golgi, where the furin-type convertase removes its inhibitory pro-domain; Golgi membrane is therefore a genuine (transient) location of the protein, though not the compartment where it acts on substrates. Direct experimental support exists independently of the Reactome assertion: furin cleavage of the ADAM17 pro-domain was localised to Golgi-derived cholesterol-rich microdomains. Supporting Evidence: PMID:17010968 during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9662786 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the Golgi membrane in the context of FURIN-mediated pro-domain removal. Reason: ADAM17 traverses the Golgi, where the furin-type convertase removes its inhibitory pro-domain; Golgi membrane is therefore a genuine (transient) location of the protein, though not the compartment where it acts on substrates. Direct experimental support exists independently of the Reactome assertion: furin cleavage of the ADAM17 pro-domain was localised to Golgi-derived cholesterol-rich microdomains. Supporting Evidence: PMID:17010968 during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin |
| GO:0000139 Golgi membrane | TAS Reactome:R-HSA-9662818 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the Golgi membrane in the context of iRHOM2-dependent Golgi-to-plasma-membrane transport. Reason: ADAM17 traverses the Golgi, where the furin-type convertase removes its inhibitory pro-domain; Golgi membrane is therefore a genuine (transient) location of the protein, though not the compartment where it acts on substrates. Direct experimental support exists independently of the Reactome assertion: furin cleavage of the ADAM17 pro-domain was localised to Golgi-derived cholesterol-rich microdomains. Supporting Evidence: PMID:17010968 during its transport through the Golgi apparatus, ADAM17 is included in cholesterol-rich membrane microdomains (lipid rafts) where its prodomain is cleaved by furin |
| GO:0001666 response to hypoxia | IDA PMID:18276953 Tumor necrosis factor-alpha converting enzyme in the human p... | KEEP AS NON CORE | Summary: Hypoxia (2% O2) raises TACE/ADAM17 mRNA and protein in placental villous explants and cytotrophoblasts, and TACE inhibition or knockdown reduces HB-EGF and amphiregulin shedding there. Reason: ADAM17 is a target of hypoxic regulation rather than an executor of a hypoxia-response programme: the measured effect is increased ADAM17 expression. The annotation is a fair record of the experiment but describes a condition that modulates the sheddase, not a core ADAM17 function. Supporting Evidence: PMID:18276953 Moreover, hypoxia (2% O(2)) caused an increase in the levels of TACE mRNA and protein in villous explants and primary cytotrophoblastic cells in vitro. PMID:18276953 Preadministration of a TACE inhibitor in villous explant cultures or transfection of cytotrophoblastic cells with TACE-specific small interference RNA decreased the shedding of HBEGF and AREG. |
| GO:0002446 neutrophil mediated immunity | IC PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | MARK AS OVER ANNOTATED | Summary: Curator-inferred (IC) annotation from the airway-epithelium study, in which bacteria induce TACE and IL-6R alpha shedding, with downstream consequences for polymorphonuclear-cell recruitment. Reason: The experiments measure epithelial TACE induction, IL-6R alpha shedding and IL-6 trans-signalling; neutrophil-mediated immunity is two steps downstream and is not an activity ADAM17 itself executes. The sheddase step is already captured by GO:0006509 and the trans-signalling consequence by the chemokine-production annotation from the same paper. Supporting Evidence: PMID:16034137 By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. PMID:16034137 Epithelial IL-6 and soluble IL-6Ralpha were shown to participate in trans-signaling, interacting with membrane-associated gp130 to activate CCL-2 expression and inhibit additional CXCL8 production. |
| GO:0002467 germinal center formation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Germinal centre formation, propagated electronically from the mouse ortholog. Reason: A downstream organismal phenotype of ADAM17 loss in mouse (ADAM17 sheds TNF, TNF receptors and Notch ligands that shape B-cell responses). ADAM17 does not execute a step of germinal-centre formation itself, so it is kept as non-core rather than accepted as a core function. Supporting Evidence: PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0002467 germinal center formation | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | KEEP AS NON CORE | Summary: Germinal centre formation, transferred by sequence similarity from mouse Adam17. Reason: The ISS source (PMID:10433800) is a mouse cDNA/gene-structure and chromosomal-mapping paper; it establishes 92% identity between mouse and human ADAM17 and TNF-precursor cleavage, but contains none of the immunological or developmental phenotype data the term describes. The underlying mouse knockout biology is real, so the annotation is retained rather than removed, but it cannot be treated as a core human ADAM17 function. Supporting Evidence: PMID:10433800 Mouse TACE/ADAM17 has a 92% amino-acid identity with the human protein and was ubiquitously expressed. |
| GO:0002532 production of molecular mediator involved in inflammatory response | IEA GO_REF:0000107 | ACCEPT | Summary: Production of molecular mediators of the inflammatory response, by electronic transfer. Reason: This is a direct and accurate process-level statement of ADAM17's founding activity: it converts the membrane TNF precursor into the soluble pro-inflammatory cytokine, and likewise releases IL-6R, TNFR1/2 and chemokines. Supporting Evidence: PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. PMID:18355445 The TNF-alpha-converting enzyme (TACE/ADAM17) is the major sheddase for ectodomain shedding of TNF-alpha. |
| GO:0002690 positive regulation of leukocyte chemotaxis | IC PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | KEEP AS NON CORE | Summary: Curator-inferred positive regulation of leukocyte chemotaxis, from the airway bacterial-infection study. Reason: ADAM17 does catalyse the release of chemoattractants and chemokine receptors (CXCL16 shedding by ADAM10/ADAM17 reduces T-cell chemotaxis when blocked), so the regulation claim has a mechanism. It is nevertheless a consequence of the sheddase step rather than a core function, and the IC evidence here is indirect. Supporting Evidence: PMID:18373975 Notably, targeting ADAM10 and ADAM17 in hMCs decreased the chemotaxis of T-Jurkat cells, whereas the inhibition of CXCL16 had no significant influence. |
| GO:0004175 endopeptidase activity | IEA GO_REF:0000107 | MODIFY | Summary: Endopeptidase activity by electronic transfer from the mouse ortholog. Reason: Correct but less specific than GO:0004222 metalloendopeptidase activity, which the extensive direct evidence supports: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc site. Replacing the generic parent also keeps the review consistent across the rows annotated to this term. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0004175 endopeptidase activity | IMP PMID:24990881 TREM2 mutations implicated in neurodegeneration impair cell ... | MODIFY | Summary: Loss-of-function evidence that ADAM proteases cleave TREM2: FTD-associated TREM2 missense variants abolish ectodomain shedding, and soluble TREM2 is near-absent from patient CSF and plasma. Reason: The cited paper attributes TREM2 shedding to "ADAM proteases" without naming ADAM17, and its authors later summarise it as showing ADAM10 (see source_defects), so this row does not itself show ADAM17 activity. The activity is true of ADAM17 from other papers, and the term is the generic endopeptidase parent. The informative term for this gene product is GO:0004222 metalloendopeptidase activity: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc-binding site, and the metal dependence is what the inhibitor and DeltaZn-mutant experiments actually report. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:24990881 missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells PMID:28855300 MALDIβTOF MS determination of the ectodomain cleavage site upon ADAM17 stimulation using PMA |
| GO:0004175 endopeptidase activity | IMP PMID:25049354 Matrix metalloproteinase-8 plays a pivotal role in neuroinfl... | MODIFY | Summary: TACE/ADAM17 activity used as the reference TNF-converting activity against which MMP-8 prodomain cleavage of TNF-alpha was benchmarked. Reason: The assayed activity is TNF-precursor cleavage, i.e. zinc metalloendopeptidase activity, so the generic endopeptidase parent understates it. The informative term for this gene product is GO:0004222 metalloendopeptidase activity: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc-binding site, and the metal dependence is what the inhibitor and DeltaZn-mutant experiments actually report. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:25049354 Subsequent experiments showed that MMP-8 exhibits TNF-Ξ±-converting enzyme (TACE) activity by cleaving the prodomain of TNF-Ξ± (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. |
| GO:0004222 metalloendopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred metalloendopeptidase activity (PAINT/IBA). Reason: This is ADAM17's core molecular function and the IBA sits at the right level of specificity: the catalytic metalloprotease domain and its zinc site are conserved across the ADAM17 clade, and the human gene carries abundant direct experimental support for the same activity. Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:14625290 Tumor necrosis factor-alpha-converting enzyme controls surfa... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: KIT (c-Kit) ectodomain release, lost in TACE DeltaZn/DeltaZn cells. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:14625290 PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (DeltaZn/DeltaZn), confirming the role of TACE in PMA-induced c-Kit shedding. PMID:14625290 we report that tumor necrosis factor alpha-converting enzyme (TACE; ADAM-17) mediates shedding of c-Kit |
| GO:0004222 metalloendopeptidase activity | IDA PMID:15691827 Evidence for a role of ADAM17 (TACE) in the regulation of pl... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: platelet glycoprotein V release by recombinant ADAM17 ectodomain. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:15691827 we show that recombinant ADAM17 ectodomain efficiently releases GPV from the platelet surface PMID:15691827 This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 |
| GO:0004222 metalloendopeptidase activity | IDA PMID:17010968 The shedding activity of ADAM17 is sequestered in lipid raft... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: cleavage of TNF, TNFR1 and TNFR2 under raft-dependent control. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:17010968 Membrane cholesterol depletion increases the ADAM17-dependent shedding of these substrates demonstrating the importance of lipid rafts in the control of this process. PMID:17010968 Consequently, ADAM17 shedding activity is sequestered in lipid rafts |
| GO:0004222 metalloendopeptidase activity | IDA PMID:18355445 Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: in vitro TNF-alpha peptide cleavage, enhanced by nardilysin. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:18355445 A peptide cleavage assay in vitro showed that recombinant NRDc enhances the cleavage of TNF-alpha induced by TACE. PMID:18355445 In a cell-based shedding assay, expression of NRDc synergistically enhanced TACE-induced TNF-alpha shedding. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:24226769 The heterotaxy gene GALNT11 glycosylates Notch to orchestrat... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: in vitro cleavage of the NOTCH1 juxtamembrane peptide. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:24226769 GALNT11 O-glycosylation enhanced cleavage of the juxtamembrane peptide by ADAM 17 |
| GO:0004222 metalloendopeptidase activity | IDA PMID:24337742 ADAM17-mediated shedding of FcΞ³RIIIA on human NK cells: iden... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: cleavage of the FcgammaRIIIA/CD16A stalk, mapped between Ala195 and Val196. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:24337742 We found that recombinant a disintegrin and metalloprotease (ADAM) 17 cleaved the ectodomain of FcΞ³RIIIA/CD16A and a peptide for which the sequence encompasses aa 191-201 of the FcΞ³RIIIA/CD16A stalk region but not ADAM10. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:36476876 Tace/ADAM17 is a bi-directional regulator of axon guidance t... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: cleavage of the DCC/Frazzled receptor ectodomain. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:36476876 Here we establish a conserved and essential role for Tace and ADAM17 in cleaving Fra and Dcc and demonstrate that this proteolysis bi-directionally regulates axon guidance at the midline. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:9774383 Evidence that tumor necrosis factor alpha converting enzyme ... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: regulated alpha-secretase cleavage of APP. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:9774383 we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. PMID:9774383 Furthermore, we show that inhibiting this enzyme affects both APP secretion and Abeta formation in cultured cells. |
| GO:0004222 metalloendopeptidase activity | IDA PMID:9920899 Metalloprotease-disintegrin MDC9: intracellular maturation a... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: comparative peptide-substrate specificity of recombinant TACE. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:9920899 Soluble MDC9 appears to have distinct specificities for cleaving candidate substrate peptides compared with the TNF-alpha convertase (TACE/ADAM17). |
| GO:0004222 metalloendopeptidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Metalloendopeptidase activity from combined automated annotation methods. Reason: The automated assignment matches the extensive direct evidence for ADAM17 zinc-metalloendopeptidase activity and is at the appropriate level of specificity. Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0004222 metalloendopeptidase activity | IMP PMID:9034190 A metalloproteinase disintegrin that releases tumour-necrosi... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: TNF-precursor cleavage, with loss of soluble TNF on gene inactivation. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:9034190 Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. |
| GO:0004222 metalloendopeptidase activity | IMP PMID:9034191 Cloning of a disintegrin metalloproteinase that processes pr... | ACCEPT | Summary: Direct assay of ADAM17 catalysis: recombinant TACE processing pro-TNF to the mature cytokine. Reason: Direct demonstration of ADAM17's core zinc-metalloendopeptidase activity on a transmembrane substrate. Multiple independent substrates and assay formats converge on the same activity, which is the gene's defining function. Supporting Evidence: PMID:9034191 The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-alpha to the mature form. |
| GO:0004222 metalloendopeptidase activity | TAS Reactome:R-NUL-5362792 | ACCEPT | Summary: Reactome TAS annotation of ADAM17 metalloendopeptidase activity in the context of releasing Shh from the plasma membrane. Reason: The molecular function asserted (metalloendopeptidase activity) is correct and abundantly supported. Note the specific Shh-release reaction is a non-human (R-NUL) Reactome inference, so only the activity, not that substrate assignment, is endorsed here. Supporting Evidence: PMID:9034191 The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-alpha to the mature form. |
| GO:0005112 Notch binding | IDA PMID:24226769 The heterotaxy gene GALNT11 glycosylates Notch to orchestrat... | ACCEPT | Summary: In vitro binding and cleavage of a NOTCH1 juxtamembrane glycopeptide by recombinant ADAM17, enhanced by GALNT11 O-glycosylation adjacent to the ADAM site. Reason: Notch binding is an informative substrate-recognition statement and is directly supported: ADAM17 engages and cleaves the NOTCH1 juxtamembrane region in vitro. It is retained as a substrate-binding function rather than as the gene's core activity. Supporting Evidence: PMID:24226769 GALNT11 O-glycosylation enhanced cleavage of the juxtamembrane peptide by ADAM 17 PMID:24226769 We thus propose a model where site-specific GALNT11 glycosylation of NOTCH1 adjacent to the ADAM cleavage site facilitates shedding and activates the pathway by increasing the amount of NICD. |
| GO:0005112 Notch binding | IMP PMID:38771644 ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-... | MARK AS OVER ANNOTATED | Summary: Notch binding inferred from a human ADAM17 CANDIS-domain variant that destabilises the protein and lowers Notch target-gene expression in patient and knock-in mouse skin. Reason: The experiments measure NICD abundance and Notch target transcription after loss of ADAM17 protein; no ADAM17-Notch binding assay is reported, and the same paper states that ADAM17 activates Notch only under non-physiological in vitro conditions (ADAM10 is the physiological S2 protease). The binding claim therefore exceeds the evidence in this reference, although the in vitro interaction is independently supported (PMID:24226769). Supporting Evidence: PMID:38771644 Conversely, ADAM17 can only activate Notch signaling under nonphysiological conditions in vitro (62β66). |
| GO:0005138 interleukin-6 receptor binding | IPI PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | ACCEPT | Summary: IL-6 receptor alpha (IL6R) is an ADAM17 substrate: bacterial exposure drives TACE to the apical surface where it colocalises with IL-6R alpha, and soluble IL-6R alpha accumulates. Reason: An informative substrate-binding molecular function, consistent with the well-established role of ADAM17 in generating soluble IL-6R for IL-6 trans-signalling. Supporting Evidence: PMID:16034137 By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. PMID:16034137 Epithelial IL-6 and soluble IL-6Ralpha were shown to participate in trans-signaling, interacting with membrane-associated gp130 to activate CCL-2 expression and inhibit additional CXCL8 production. |
| GO:0005178 integrin binding | IPI PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | ACCEPT | Summary: Trans interaction between the ADAM17 disintegrin/cysteine-rich region and integrin alpha5beta1, shown by adhesion assays with recombinant ADAM17 fragments. Reason: A specific, informative molecular function supported by domain mapping: the integrin binds the disintegrin domain in a ligand-receptor manner. This non-proteolytic activity also feeds back on catalysis, since alpha5beta1 engagement restrains ADAM17 sheddase activity. Supporting Evidence: PMID:14970227 we now demonstrate a functional interaction between ADAM-17 and alpha(5)beta(1) integrin in a trans orientation PMID:14970227 Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the alpha(5)beta(1) ligand binding pocket. |
| GO:0005178 integrin binding | IPI PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | ACCEPT | Summary: Second integrin-binding annotation from the same study (ADAM17 disintegrin domain and alpha5beta1). Reason: Duplicate annotations of the same informative function from one reference are acceptable. The interaction is independently corroborated, including evidence that alpha5beta1 binding inhibits ADAM17 catalytic activity. Supporting Evidence: PMID:14970227 Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the alpha(5)beta(1) ligand binding pocket. PMID:30455686 the interaction between integrin Ξ±5Ξ²1 and the disintegrin domain of ADAM17 has been shown to cause the inhibition of both the adhesive capacity of the integrin |
| GO:0005515 protein binding | IPI PMID:10527948 Evidence for an interaction of the metalloprotease-disintegr... | REMOVE | Summary: Yeast two-hybrid and biochemical interaction between the ADAM17 cytoplasmic tail and MAD2 (MAD2L1). Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. No downstream function for the ADAM17-MAD2 interaction has been established, so no informative replacement term can be justified from this reference. Supporting Evidence: PMID:10527948 We have identified mitotic arrest deficient 2 (MAD2) as a binding partner of the TACE cytoplasmic domain, and a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain. |
| GO:0005515 protein binding | IPI PMID:10527948 Evidence for an interaction of the metalloprotease-disintegr... | REMOVE | Summary: Second generic protein-binding row from the same MAD2/MAD2beta two-hybrid study. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The interaction is a cytoplasmic-tail two-hybrid hit without an assigned molecular consequence for ADAM17. Supporting Evidence: PMID:10527948 We have identified mitotic arrest deficient 2 (MAD2) as a binding partner of the TACE cytoplasmic domain, and a novel MAD2-related protein, MAD2beta, as a binding partner of the MDC9 cytoplasmic domain. |
| GO:0005515 protein binding | IPI PMID:12668732 Identification of SAP97 as an intracellular binding partner ... | MODIFY | Summary: Interaction of the extreme C-terminus of TACE with the PDZ3 domain of SAP97/DLG1, mapped by deletion and site-directed mutagenesis, affecting substrate release. Reason: The evidence identifies a specific interaction module - the ADAM17 C-terminal group-I PDZ-binding motif engaging a PDZ domain - so the uninformative parent should be replaced by GO:0030165 PDZ domain binding, which the gene already carries from the PTPH1 study. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12668732 By deletions and site-directed mutagenesis, we demonstrated that this interaction involved the PDZ3 domain of SAP97 and the extreme C-terminal amino-acid sequence of TACE. PMID:12668732 Furthermore, overexpression of SAP97, unlike that of a mutant form of SAP97 deleted for its PDZ3 domain, altered the ability of TACE to release its substrates. |
| GO:0005515 protein binding | IPI PMID:15280379 ADAM binding protein Eve-1 is required for ectodomain sheddi... | REMOVE | Summary: Interaction with the SH3-domain adaptor Eve-1/SH3D19, whose knockdown reduces ADAM-dependent shedding of EGFR ligand precursors. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The functional readout in this paper is reduced EGFR-ligand shedding, which is already annotated for ADAM17 (GO:0006509, GO:0045742); the interaction itself supports no more specific ADAM17 molecular function here. Supporting Evidence: PMID:15280379 Knockdown of Eve-1 by small interfering RNA in HT1080 cells reduced the shedding of proHB-EGF induced by angiotensin II and 12-O-tetradecanoylphorbol-13-acetate, as well as the shedding of pro-transforming growth factor-alpha, promphiregulin, and proepiregulin by 12-O-tetradecanoylphorbol-13-acetate, suggesting that Eve-1 plays a role in positively regulating the activity of ADAMs in the signaling of EGFR-ligand shedding. |
| GO:0005515 protein binding | IPI PMID:15280379 ADAM binding protein Eve-1 is required for ectodomain sheddi... | REMOVE | Summary: Interaction with the SH3-domain adaptor Eve-1/SH3D19, whose knockdown reduces ADAM-dependent shedding of EGFR ligand precursors. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The functional readout in this paper is reduced EGFR-ligand shedding, which is already annotated for ADAM17 (GO:0006509, GO:0045742); the interaction itself supports no more specific ADAM17 molecular function here. Supporting Evidence: PMID:15280379 Knockdown of Eve-1 by small interfering RNA in HT1080 cells reduced the shedding of proHB-EGF induced by angiotensin II and 12-O-tetradecanoylphorbol-13-acetate, as well as the shedding of pro-transforming growth factor-alpha, promphiregulin, and proepiregulin by 12-O-tetradecanoylphorbol-13-acetate, suggesting that Eve-1 plays a role in positively regulating the activity of ADAMs in the signaling of EGFR-ligand shedding. |
| GO:0005515 protein binding | IPI PMID:18355445 Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... | REMOVE | Summary: Interaction with nardilysin (NRDC), which enhances TACE-mediated TNF-alpha cleavage in cells and in vitro. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The informative content of this reference - that ADAM17 cleaves pro-TNF and that this is stimulated by nardilysin - is already captured by the GO:0004222 and GO:0006509 annotations from the same paper. Supporting Evidence: PMID:18355445 A peptide cleavage assay in vitro showed that recombinant NRDc enhances the cleavage of TNF-alpha induced by TACE. |
| GO:0005515 protein binding | IPI PMID:18625725 Transforming growth factor beta engages TACE and ErbB3 to ac... | REMOVE | Summary: Interaction with ErbB3 in the TGF-beta/TACE/ErbB3 axis of HER2-overexpressing breast cancer cells. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The reference's functional claims concern phosphorylation and surface translocation of ADAM17 and increased shedding of ErbB ligands, which are covered by the shedding and EGFR-pathway annotations rather than by a generic binding term. Supporting Evidence: PMID:18625725 Treatment with TGF-beta or expression of an activated TGF-beta type I receptor (Alk5 with the mutation T204D [Alk5(T204D)]) induced phosphorylation of TACE/ADAM17 and its translocation to the cell surface, resulting in increased secretion of TGF-alpha, amphiregulin, and heregulin. |
| GO:0005515 protein binding | IPI PMID:18638486 Structural determinants of the ADAM inhibition by TIMP-3: cr... | REMOVE | Summary: Crystal structure of the TACE catalytic domain in complex with N-TIMP-3, the physiological tissue-inhibitor of ADAM17. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. Here the generic term is particularly uninformative because the interaction is an inhibitor binding the ADAM17 active-site cleft - a property of the enzyme's catalytic site that is already expressed by its metalloendopeptidase annotation. GO offers no molecular-function term for being inhibited, so no replacement is proposed. Supporting Evidence: PMID:18638486 TIMP-3 (tissue inhibitor of metalloproteinases 3) is unique among the TIMP inhibitors, in that it effectively inhibits the TNF-alpha converting enzyme PMID:18638486 The structure reveals that TIMP-3 exhibits a fold similar to those of TIMP-1 and TIMP-2, and interacts through its functional binding edge, which consists of the N-terminal segment and other loops, with the active-site cleft of TACE in a manner similar to that of matrix metalloproteinases (MMPs). |
| GO:0005515 protein binding | IPI PMID:22246777 Tumor necrosis factor signaling requires iRhom2 to promote t... | REMOVE | Summary: Interaction with iRhom2 (RHBDF2), required for TACE trafficking to the cell surface and for its activity in macrophages. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The biologically important statement - that ADAM17 functions as the catalytic subunit of an iRhom-dependent sheddase complex - cannot be expressed by GO:0005515 and is recorded in the gene notes and in the plasma-membrane/shedding annotations instead. Supporting Evidence: PMID:22246777 loss of iRhom2 led to a complete abolition of activity of immunoprecipitated TACE |
| GO:0005515 protein binding | IPI PMID:22413019 A disintegrin and metalloenzyme (ADAM) 17 activation is regu... | MODIFY | Summary: Interaction with integrin beta-1 (ITGB1) in kidney mesangial cells, where alpha5beta1 binds and inhibits recombinant ADAM17. Reason: The partner is an integrin and the interaction is domain-mapped, so the uninformative parent should be replaced by GO:0005178 integrin binding, which the gene already carries from the alpha5beta1 adhesion study. Proposed replacements: integrin binding Supporting Evidence: PMID:22413019 ADAM17 also has an important role in cell-fate decisions by shedding the ectodomain of Notch [7]. PMID:30455686 the interaction between integrin Ξ±5Ξ²1 and the disintegrin domain of ADAM17 has been shown to cause the inhibition of both the adhesive capacity of the integrin |
| GO:0005515 protein binding | IPI PMID:29897333 iTAP, a novel iRhom interactor, controls TNF secretion by po... | REMOVE | Summary: Interaction with iRhom2 (RHBDF2) within the iRhom/TACE sheddase complex, which controls TACE stability and TNF secretion. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The functional consequence reported is stabilisation and activation of the sheddase complex - a property of ADAM17's regulators - and is better recorded in the gene notes than as a generic binding annotation. Supporting Evidence: PMID:29897333 Within the sheddase complex, iRhom proteins serve as a platform that senses and transduces TACE-activating stimuli. |
| GO:0005515 protein binding | IPI PMID:29897333 iTAP, a novel iRhom interactor, controls TNF secretion by po... | REMOVE | Summary: Interaction with iTAP/FRMD8 within the iRhom/TACE sheddase complex, which controls TACE stability and TNF secretion. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The functional consequence reported is stabilisation and activation of the sheddase complex - a property of ADAM17's regulators - and is better recorded in the gene notes than as a generic binding annotation. Supporting Evidence: PMID:29897333 Within the sheddase complex, iRhom proteins serve as a platform that senses and transduces TACE-activating stimuli. |
| GO:0005515 protein binding | IPI PMID:29897336 FRMD8 promotes inflammatory and growth factor signalling by ... | REMOVE | Summary: Interaction with FRMD8, which stabilises the iRhom/ADAM17 sheddase complex at the cell surface. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The paper's substantive claim about ADAM17 is that it is the principal sheddase of EGFR ligands and that FRMD8 loss reduces that shedding; both are expressed by existing process annotations. Supporting Evidence: PMID:29897336 In addition, ADAM17 is the principal sheddase of the epidermal growth factor (EGF) receptor ligands amphiregulin (AREG), transforming growth factor alpha (TGFΞ±), heparin-binding EGF (HB-EGF), epigen, and epiregulin |
| GO:0005515 protein binding | IPI PMID:30455686 CD9 Controls Integrin Ξ±5Ξ²1-Mediated Cell Adhesion by Modulat... | MODIFY | Summary: CD9-modulated association between integrin alpha5beta1 and ADAM17 on the cell surface. Reason: The interaction partner characterised for ADAM17 in this study is integrin alpha5beta1 binding the disintegrin domain, so GO:0005178 integrin binding is the informative replacement for the generic parent. Proposed replacements: integrin binding Supporting Evidence: PMID:30455686 the interaction between integrin Ξ±5Ξ²1 and the disintegrin domain of ADAM17 has been shown to cause the inhibition of both the adhesive capacity of the integrin |
| GO:0005515 protein binding | IPI PMID:32405532 GPR50 Promotes Hepatocellular Carcinoma Progression via the ... | REMOVE | Summary: Direct interaction between the orphan receptor GPR50 and ADAM17 in hepatocellular carcinoma cells, reported to activate Notch signalling ligand-independently. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The reference assigns the functional consequence to GPR50 (which also raises ADAM17 transcription); it supports no more specific ADAM17 molecular function, and the ligand-independent Notch activation it describes is explicitly non-canonical. Supporting Evidence: PMID:32405532 Notably, GPR50 was found to directly interact with ADAM17. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: One row of a proteome-wide quantitative-fragmentomics affinity map of the human PDZ-PBM interactome, in which the ADAM17 C-terminal PDZ-binding motif is paired with a PDZ-domain protein (DLG/MAGI/GRIP/PATJ/SCRIB/WHRN family members). Reason: Every partner in this set is a PDZ-domain protein engaging the ADAM17 C-terminal group-I PDZ-binding motif, so the informative molecular function is GO:0030165 PDZ domain binding rather than the generic parent; that motif was mapped biochemically in the PTPH1 and SAP97 studies. Note the cached text of the fragmentomics paper reports the interactome method and not the individual ADAM17 pairs, which are in its supplementary tables, so the replacement term is justified from the primary motif-mapping references. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0005515 protein binding | IPI PMID:9774383 Evidence that tumor necrosis factor alpha converting enzyme ... | REMOVE | Summary: Interaction with amyloid precursor protein (APP) from the TACE-knockout alpha-secretase study. Reason: GO:0005515 protein binding carries no functional information about ADAM17 and is removed per the project curation guideline. Removal does not dispute the reported interaction, which remains recorded in IntAct and in the gene notes. The functional content - that ADAM17 performs regulated alpha-cleavage of APP - is already annotated from this same reference as GO:0004222 and GO:0042987, and GO has no APP-binding molecular-function term that could serve as a specific replacement. Supporting Evidence: PMID:9774383 we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. |
| GO:0005737 cytoplasm | IDA PMID:25468996 E-cadherin interactome complexity and robustness resolved by... | MARK AS OVER ANNOTATED | Summary: ADAM17 detected among 561 proteins by proximity biotinylation of the E-cadherin cytoplasmic tail. Reason: ADAM17 is a single-pass type I membrane protein with a short cytosolic tail; proximity labelling of a cytoplasmic bait detects that tail and does not establish a cytoplasmic pool of the protein. The informative locations are the plasma membrane and membrane rafts, both already annotated. Supporting Evidence: PMID:25468996 We used proximity biotinylation and quantitative proteomics to identify 561 proteins in the vicinity of the cytoplasmic tail of E-cadherin. |
| GO:0005737 cytoplasm | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cytoplasm localisation transferred electronically from the mouse ortholog. Reason: ADAM17 is an integral membrane protein whose only cytosolic element is its C-terminal tail; a bare cytoplasm annotation misdescribes its topology, and UniProt records the protein as a single-pass type I cell-membrane protein. Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-9662747 | MODIFY | Summary: Reactome TAS annotation placing ADAM17 in the endoplasmic reticulum lumen during iRhom2-dependent ER-to-Golgi transport. Reason: ADAM17 is a single-pass type I membrane protein: its ectodomain faces the ER lumen but the protein is not a soluble lumenal resident. GO:0005789 endoplasmic reticulum membrane states the same biology correctly, and ER residence before iRhom-dependent export is well documented. Proposed replacements: endoplasmic reticulum membrane Supporting Evidence: PMID:22246777 loss of iRhom2 led to a complete abolition of activity of immunoprecipitated TACE |
| GO:0005886 plasma membrane | EXP PMID:36078095 Tetraspanin 8 Subfamily Members Regulate Substrate-Specifici... | ACCEPT | Summary: Plasma-membrane localisation of ADAM17 shown together with its tetraspanin partners CD81 and TSPAN8. Reason: The plasma membrane is where ADAM17 acts on its substrates, and this is the best-supported location annotation for the gene. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically inferred (IBA) assertion that ADAM17 is active in the plasma membrane. Reason: Correct and appropriately specific: surface delivery is a prerequisite for sheddase activity, and loss of iRhom2 removes TACE from the surface and abolishes its activity. Supporting Evidence: PMID:22246777 loss of iRhom2 led to a complete abolition of activity of immunoprecipitated TACE |
| GO:0005886 plasma membrane | IDA PMID:17786981 HDLs activate ADAM17-dependent shedding. | ACCEPT | Summary: Surface and raft localisation of ADAM17 in the HDL-stimulated shedding study. Reason: Supported by direct cell-fractionation and shedding experiments at the plasma membrane, including on cell-free isolated plasma membranes. Supporting Evidence: PMID:17786981 HDLs reduced the cholesterol and proteins (including ADAM17) content of lipid rafts and triggered the ADAM17-dependent cleavage of TNF in the non-raft region of the membrane. |
| GO:0005886 plasma membrane | IDA PMID:24337742 ADAM17-mediated shedding of FcΞ³RIIIA on human NK cells: iden... | ACCEPT | Summary: ADAM17 detected on human NK cells, where stimulation triggers shedding of FcgammaRIIIA/CD16A and CD62L. Reason: Direct evidence of ADAM17 at the surface of primary human NK cells, consistent with its role as a cis-acting surface sheddase. Supporting Evidence: PMID:24337742 ADAM17 was found to be expressed on NK cells, and stimulation with PMA or N-ethyl-maleimide resulted in the shedding of FcΞ³RIIIA/CD16A and CD62L, a specific substrate of ADAM17. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma-membrane localisation from combined automated annotation methods. Reason: Agrees with the direct experimental and phylogenetic evidence and with the UniProt subcellular location (cell membrane, single-pass type I). Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-193679 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of alpha-secretase cleavage of the p75NTR extracellular domain. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3371385 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of cleavage of TNF-alpha by ADAM17. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9662818 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of iRHOM2-dependent transport of ADAM17:Zn2+ to the plasma membrane. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9662823 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of PLK2/MAPK14 phosphorylation of ADAM17. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-9662837 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of cleavage of CD163 by phosphorylated ADAM17. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-2063915 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of cleavage of Notch1 at site S2. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005886 plasma membrane | TAS Reactome:R-NUL-5362792 | ACCEPT | Summary: Reactome TAS annotation placing ADAM17 in the plasma membrane in the context of ADAM17-mediated release of Shh from the plasma membrane. Reason: The location is correct and independently supported by direct experiments; the plasma membrane is the compartment in which ADAM17 engages its transmembrane substrates. Supporting Evidence: PMID:36078095 Here, we show that ADAM17 associates with Tspans CD81 and Tspan8 at the plasma membrane. |
| GO:0005911 cell-cell junction | IDA PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | UNDECIDED | Summary: Colocalisation annotation for cell-cell junctions from the ADAM17/alpha5beta1 imaging study. Reason: The cached record for this reference is abstract-only and reports colocalisation in membrane ruffles, focal adhesions and at the leading edge of wounded monolayers; it does not state a cell-cell junction observation. The full text may contain it, so the annotation is left undecided rather than challenged. Supporting Evidence: PMID:14970227 Intriguingly, ADAM-17 and alpha(5)beta(1) were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. PMID:14970227 When confluent HeLa cell monolayers were wounded, ADAM-17 and alpha(5)beta(1) redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. |
| GO:0005925 focal adhesion | IDA PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | ACCEPT | Summary: Colocalisation of ADAM17 with integrin alpha5beta1 in focal adhesions of HeLa cells. Reason: Directly stated by the cited imaging experiments, and consistent with the ADAM17-alpha5beta1 ligand-receptor relationship mapped in the same study. Supporting Evidence: PMID:14970227 Intriguingly, ADAM-17 and alpha(5)beta(1) were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. |
| GO:0006508 proteolysis | IDA PMID:24227843 TMPRSS2 and ADAM17 cleave ACE2 differentially and only prote... | MODIFY | Summary: ADAM17-mediated proteolysis of ACE2, examined alongside TMPRSS2 cleavage of the same receptor. Reason: The proteolysis is specifically juxtamembrane cleavage of a transmembrane receptor's ectodomain, so GO:0006509 membrane protein ectodomain proteolysis states the biology at the informative level; GO:0006508 is the uninformative parent. Proposed replacements: membrane protein ectodomain proteolysis Supporting Evidence: PMID:24227843 TMPRSS2 was found to compete with the metalloprotease ADAM17 for ACE2 processing, but only cleavage by TMPRSS2 resulted in augmented SARS-S-driven entry |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: Proteolysis inferred from InterPro domain membership (reprolysin/adamalysin metalloprotease domain). Reason: The InterPro domain-based inference is correct in kind but uninformative: every documented ADAM17 proteolysis event is juxtamembrane cleavage of a transmembrane protein's ectodomain, which GO:0006509 states precisely and which the gene carries from many direct experiments. Proposed replacements: membrane protein ectodomain proteolysis Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0006509 membrane protein ectodomain proteolysis | IBA GO_REF:0000033 | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: phylogenetic (IBA) inference of ectodomain shedding. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:14625290 Tumor necrosis factor-alpha-converting enzyme controls surfa... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: c-Kit shedding, absent in TACE-inactive cells. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:14625290 we report that tumor necrosis factor alpha-converting enzyme (TACE; ADAM-17) mediates shedding of c-Kit PMID:14625290 PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (DeltaZn/DeltaZn), confirming the role of TACE in PMA-induced c-Kit shedding. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:15691827 Evidence for a role of ADAM17 (TACE) in the regulation of pl... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: shedding of platelet glycoprotein V. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:15691827 we show that recombinant ADAM17 ectodomain efficiently releases GPV from the platelet surface PMID:15691827 This shedding was inhibited by the broad range metalloproteinase inhibitor GM6001, the two potent ADAM17 inhibitors GW280264X and TAPI-2, and was absent in mice lacking functional ADAM17 |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:17010968 The shedding activity of ADAM17 is sequestered in lipid raft... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: raft-controlled shedding of TNF, TNFR1 and TNFR2. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:17010968 Membrane cholesterol depletion increases the ADAM17-dependent shedding of these substrates demonstrating the importance of lipid rafts in the control of this process. PMID:17010968 Consequently, ADAM17 shedding activity is sequestered in lipid rafts |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:17786981 HDLs activate ADAM17-dependent shedding. | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: HDL-stimulated shedding of TNF and its receptors. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:17786981 HDLs added to different cell types, increased the ectodomain shedding of TNFR2, TNFR1, and TNF, an effect reduced by inhibitors active on ADAM17. PMID:17786981 HDLs reduced the cholesterol and proteins (including ADAM17) content of lipid rafts and triggered the ADAM17-dependent cleavage of TNF in the non-raft region of the membrane. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:18355445 Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: nardilysin-enhanced ectodomain shedding of TNF-alpha. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:18355445 In a cell-based shedding assay, expression of NRDc synergistically enhanced TACE-induced TNF-alpha shedding. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:18676862 Tumor-associated MICA is shed by ADAM proteases. | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: release of soluble MICA from tumour cells. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:18676862 MICA shedding by tumor cells was inhibited by silencing of the related ADAM10 and ADAM17 proteases |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:24337742 ADAM17-mediated shedding of FcΞ³RIIIA on human NK cells: iden... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: shedding of FcgammaRIIIA/CD16A and CD62L from NK cells. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:24337742 We found that recombinant a disintegrin and metalloprotease (ADAM) 17 cleaved the ectodomain of FcΞ³RIIIA/CD16A and a peptide for which the sequence encompasses aa 191-201 of the FcΞ³RIIIA/CD16A stalk region but not ADAM10. PMID:24337742 ADAM17 was found to be expressed on NK cells, and stimulation with PMA or N-ethyl-maleimide resulted in the shedding of FcΞ³RIIIA/CD16A and CD62L, a specific substrate of ADAM17. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:36476876 Tace/ADAM17 is a bi-directional regulator of axon guidance t... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: cleavage of the Frazzled/DCC ectodomain. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:36476876 Here we establish a conserved and essential role for Tace and ADAM17 in cleaving Fra and Dcc and demonstrate that this proteolysis bi-directionally regulates axon guidance at the midline. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:9034190 A metalloproteinase disintegrin that releases tumour-necrosi... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: release of soluble TNF-alpha from cells. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:9034190 Inactivation of the gene in mouse cells caused a marked decrease in soluble TNF-alpha production. PMID:9034190 Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. |
| GO:0006509 membrane protein ectodomain proteolysis | IDA PMID:9574564 TNF-alpha convertase enzyme from human arthritis-affected ca... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: conversion of pro-TNF-alpha to mature TNF-alpha by recombinant TACE. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:9574564 This recombinant protein also cleaved the natural substrate GST-ProTNF-alpha to TNF-alpha (17 kDa) in vitro. |
| GO:0006509 membrane protein ectodomain proteolysis | IEA GO_REF:0000117 | ACCEPT | Summary: Ectodomain proteolysis assigned by an ARBA machine-learning model. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. The automated assignment coincides with the gene's best-supported process annotation and is at the correct level of specificity. Supporting Evidence: PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0006509 membrane protein ectodomain proteolysis | IMP PMID:12743035 TACE cleavage of proamphiregulin regulates GPCR-induced prol... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: GPCR-stimulated and basal shedding of pro-amphiregulin. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:12743035 The results of this study indicate that treatment of squamous cell carcinoma cells with GPCR ligands such as LPA and carbachol leads to the rapid and specific cleavage of proAR at the cell surface by TACE. PMID:12743035 siRNA-directed inhibition of TACE resulted in the accumulation of proAR at the cell surface of SCC-9 cells (Figure 7 C), supporting the view that TACE is involved in basal proAR ecto domain processing. |
| GO:0006509 membrane protein ectodomain proteolysis | IMP PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: shedding of IL-6 receptor alpha from airway epithelium. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:16034137 By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. |
| GO:0006509 membrane protein ectodomain proteolysis | IMP PMID:18373975 The role of CXCL16 and its processing metalloproteinases ADA... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: cytokine-induced shedding of CXCL16 from mesangial cells. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:18373975 We identified ADAM10 and ADAM17 as being responsible for the cytokine-induced shedding of CXCL16. |
| GO:0006509 membrane protein ectodomain proteolysis | IMP PMID:21170088 ADAM17 (TACE) regulates TGFΞ² signaling through the cleavage ... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: shedding of the vasorin ectodomain. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:21170088 we show that only the soluble form of VASN inhibits TGFΞ² and that the secretion of VASN is tightly controlled by ADAM17 |
| GO:0006509 membrane protein ectodomain proteolysis | IMP PMID:24990881 TREM2 mutations implicated in neurodegeneration impair cell ... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: shedding of the TREM2 ectodomain, abolished by disease variants. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the term is accepted. This paper, however, names only "ADAM proteases", and its authors later attribute the TREM2 shedding it reports to ADAM10 (see source_defects), so the row's reference does not show it for ADAM17. Supporting Evidence: PMID:24990881 missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells PMID:28855300 MALDIβTOF MS determination of the ectodomain cleavage site upon ADAM17 stimulation using PMA |
| GO:0006509 membrane protein ectodomain proteolysis | IMP PMID:9034191 Cloning of a disintegrin metalloproteinase that processes pr... | ACCEPT | Summary: Evidence for ADAM17-mediated ectodomain shedding: processing of the membrane TNF precursor by recombinant TACE. Reason: Membrane protein ectodomain proteolysis is ADAM17's core biological process: the gene product itself catalyses the juxtamembrane cleavage, so the participation requirement is met directly. This row adds an independently assayed substrate and should be retained. Supporting Evidence: PMID:9034191 The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-alpha to the mature form. |
| GO:0007155 cell adhesion | IDA PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | KEEP AS NON CORE | Summary: Cell adhesion mediated by the ADAM17 disintegrin/cysteine-rich region acting as a ligand for integrin alpha5beta1 in trans. Reason: This is a genuine non-proteolytic activity of ADAM17 - it serves as an integrin ligand, and the interaction reciprocally restrains its catalytic activity - but adhesion is peripheral to the gene's core sheddase function. Supporting Evidence: PMID:14970227 we now demonstrate a functional interaction between ADAM-17 and alpha(5)beta(1) integrin in a trans orientation PMID:14970227 Because ADAM-17-mediated adhesion was sensitive to RGD peptides and EDTA, and the integrin-binding site within ADAM-17 was narrowed down to the disintegrin/cysteine-rich region, the two molecules appear to have a ligand-receptor relationship mediated by the alpha(5)beta(1) ligand binding pocket. |
| GO:0007173 epidermal growth factor receptor signaling pathway | IDA PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg... | ACCEPT | Summary: ADAM17 knockdown attenuates UVA-induced EGFR activation and downstream AKT/cyclin D1 signalling in keratinocytes. Reason: ADAM17 executes a step of the EGFR pathway rather than merely being required upstream of it: it catalyses the release of the mature EGFR ligands (amphiregulin, TGF-alpha, HB-EGF, epiregulin, epigen) that activate the receptor, which satisfies the participation test. Supporting Evidence: PMID:18483258 Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of ADAM17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. PMID:29897336 In addition, ADAM17 is the principal sheddase of the epidermal growth factor (EGF) receptor ligands amphiregulin (AREG), transforming growth factor alpha (TGFΞ±), heparin-binding EGF (HB-EGF), epigen, and epiregulin |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred (IBA) involvement in the Notch signalling pathway. Reason: ADAM17 can perform the S2 cleavage of NOTCH1 in vitro, so the term is not wrong, but ADAM10 is the protease for physiological ligand-induced Notch activation and ADAM17 contributes mainly under ligand-independent or non-physiological conditions. The row is retained as non-core rather than accepted as a core ADAM17 process. Supporting Evidence: PMID:38771644 Conversely, ADAM17 can only activate Notch signaling under nonphysiological conditions in vitro (62β66). PMID:24226769 We thus propose a model where site-specific GALNT11 glycosylation of NOTCH1 adjacent to the ADAM cleavage site facilitates shedding and activates the pathway by increasing the amount of NICD. |
| GO:0007220 Notch receptor processing | IDA PMID:24226769 The heterotaxy gene GALNT11 glycosylates Notch to orchestrat... | ACCEPT | Summary: Recombinant ADAM17 cleaves the NOTCH1 juxtamembrane peptide, and GALNT11 O-glycosylation adjacent to the ADAM site enhances that cleavage and NICD production. Reason: Notch receptor processing is the proteolytic step itself, which ADAM17 performs in this assay; the participation requirement is therefore met directly. Physiological primacy of ADAM10 at this site does not invalidate the demonstrated ADAM17 activity. Supporting Evidence: PMID:24226769 GALNT11 O-glycosylation enhanced cleavage of the juxtamembrane peptide by ADAM 17 PMID:24226769 We thus propose a model where site-specific GALNT11 glycosylation of NOTCH1 adjacent to the ADAM cleavage site facilitates shedding and activates the pathway by increasing the amount of NICD. |
| GO:0008233 peptidase activity | TAS PMID:24966471 Tumor necrosis factor alpha: a link between neuroinflammatio... | MODIFY | Summary: Author-stated (TAS) peptidase activity in a review of TNF-alpha in neuroinflammation and excitotoxicity. Reason: The statement is correct but uses the generic peptidase parent in a review context. The informative term for this gene product is GO:0004222 metalloendopeptidase activity: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc-binding site, and the metal dependence is what the inhibitor and DeltaZn-mutant experiments actually report. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:24966471 In pathological conditions, microglia release large amounts of TNF-Ξ±; this de novo production of TNF-Ξ± is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders. |
| GO:0008237 metallopeptidase activity | IDA PMID:12777399 Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on s... | MODIFY | Summary: ADAM17 used as the reference enzyme in a comparison of synthetic peptide-substrate specificity across ADAM8, ADAM15 and ADAM28. Reason: The assay measures zinc-metalloprotease cleavage of peptide substrates, so the specific child term is appropriate. The informative term for this gene product is GO:0004222 metalloendopeptidase activity: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc-binding site, and the metal dependence is what the inhibitor and DeltaZn-mutant experiments actually report. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:12777399 By screening a library of synthetic peptides as potential substrates, we show that soluble recombinant forms of these enzymes have similar proteolytic substrate specificity, clearly distinct from that of ADAM17 (TNFalpha-converting enzyme). |
| GO:0008237 metallopeptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Metallopeptidase activity from combined automated annotation methods. Reason: Correct but one level too general: the enzyme is an endopeptidase, not a generic metallopeptidase, with a mapped internal cleavage site in pro-TNF (EC 3.4.24.86). GO:0004222 is the informative term and keeps the treatment of this term consistent across rows. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0008237 metallopeptidase activity | IMP PMID:12535668 Putative function of ADAM9, ADAM10, and ADAM17 as APP alpha-... | MODIFY | Summary: Knockdown and overexpression comparison concluding that ADAM9, ADAM10 and ADAM17 all contribute alpha-secretase cleavage of APP in A172 glioblastoma cells. Reason: The measured activity is zinc-metalloendopeptidase cleavage of APP, so the specific child term is warranted. The informative term for this gene product is GO:0004222 metalloendopeptidase activity: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc-binding site, and the metal dependence is what the inhibitor and DeltaZn-mutant experiments actually report. Note that later neuron-based knockdown work assigns constitutive alpha-secretase activity to ADAM10 and restricts the ADAM17 contribution largely to the stimulated (phorbol-ester) arm, so this reference should not be read as making ADAM17 the principal alpha-secretase. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:12535668 The results indicate that ADAM9, ADAM10, and ADAM17 catalyze alpha-secretory cleavage and therefore act as alpha-secretases in A172 cells. PMID:20676056 Knockdown of ADAM17 mildly reduced total APPs and APPsΞ± in HEK293 cells ( Figure 2A and B ), but had no significant effect in SH-SY5Y cells ( Figure 2C and D ). |
| GO:0008237 metallopeptidase activity | IMP PMID:38771644 ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-... | MODIFY | Summary: A human ADAM17 CANDIS-domain variant that lowers ADAM17 protein levels and causes hypotrichosis with woolly hair, used as loss-of-function evidence for its metallopeptidase activity. Reason: The gene product under study is a zinc metalloendopeptidase and the paper describes it as such, so the specific child term states the function better than the generic parent. The informative term for this gene product is GO:0004222 metalloendopeptidase activity: ADAM17 is a zinc-dependent adamalysin whose catalytic domain carries the HExxHxxGxxH zinc-binding site, and the metal dependence is what the inhibitor and DeltaZn-mutant experiments actually report. Proposed replacements: metalloendopeptidase activity Supporting Evidence: PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:18373975 The role of CXCL16 and its processing metalloproteinases ADA... | MARK AS OVER ANNOTATED | Summary: Reduced proliferation of human mesangial cells after inhibition of CXCL16, ADAM10 and ADAM17. Reason: The proliferative response is driven by the shed ligands downstream of ADAM17; ADAM17 performs no step of the cell-cycle machinery, and necessity shown by inhibition is not participation. The sheddase step is already annotated (GO:0006509 from the same reference). Supporting Evidence: PMID:18373975 Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. PMID:18373975 We identified ADAM10 and ADAM17 as being responsible for the cytokine-induced shedding of CXCL16. |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Response to xenobiotic stimulus, propagated electronically from the mouse ortholog. Reason: Phorbol esters and related xenobiotic agents are the classical activators of ADAM17-dependent shedding, so a response-to-xenobiotic annotation has a real mechanistic basis; the response is nevertheless a regulatory input to the sheddase rather than a core ADAM17 function. Supporting Evidence: PMID:14625290 PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (DeltaZn/DeltaZn), confirming the role of TACE in PMA-induced c-Kit shedding. |
| GO:0009410 response to xenobiotic stimulus | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | KEEP AS NON CORE | Summary: Response to xenobiotic stimulus transferred by sequence similarity from mouse Adam17. Reason: Phorbol esters and related xenobiotic agents are the classical activators of ADAM17-dependent shedding, so a response-to-xenobiotic annotation has a real mechanistic basis; the response is nevertheless a regulatory input to the sheddase rather than a core ADAM17 function. The ISS source (PMID:10433800) is a mouse cDNA/gene-structure and chromosomal-mapping paper; it establishes 92% identity between mouse and human ADAM17 and TNF-precursor cleavage, but contains none of the immunological or developmental phenotype data the term describes. The underlying mouse knockout biology is real, so the annotation is retained rather than removed, but it cannot be treated as a core human ADAM17 function. Supporting Evidence: PMID:10433800 Mouse TACE/ADAM17 has a 92% amino-acid identity with the human protein and was ubiquitously expressed. |
| GO:0009986 cell surface | IDA PMID:18383040 Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/A... | ACCEPT | Summary: Surface TACE measured on monocytes by ex vivo fluorogenic assay and antibody detection, including accumulation of catalytically inactive surface TACE after LPS and IL-10. Reason: Direct detection of ADAM17 at the cell surface, the compartment where it engages substrates. Supporting Evidence: PMID:18383040 Paradoxically, both LPS with or without IL-10 led to accumulation of surface TACE (albeit catalytically inactive) over a 24 h period. PMID:18383040 Using an ex vivo fluorogenic assay we observed that LPS rapidly induced TACE activity in monocytes coinciding with release of soluble TNF-alpha. |
| GO:0009986 cell surface | IDA PMID:18625725 Transforming growth factor beta engages TACE and ErbB3 to ac... | ACCEPT | Summary: TGF-beta-induced phosphorylation of TACE/ADAM17 and its translocation to the cell surface in HER2-overexpressing breast cancer cells. Reason: Surface localisation is directly reported and is the functionally relevant location for shedding. Supporting Evidence: PMID:18625725 Treatment with TGF-beta or expression of an activated TGF-beta type I receptor (Alk5 with the mutation T204D [Alk5(T204D)]) induced phosphorylation of TACE/ADAM17 and its translocation to the cell surface, resulting in increased secretion of TGF-alpha, amphiregulin, and heregulin. |
| GO:0009986 cell surface | IDA PMID:9034190 A metalloproteinase disintegrin that releases tumour-necrosi... | ACCEPT | Summary: Cell-surface localisation of TACE in the study that first purified and cloned the TNF-converting enzyme. Reason: ADAM17 is a cell-surface, membrane-anchored protease, as established in this paper's framing of ectodomain shedding and confirmed by direct surface detection in later work. Supporting Evidence: PMID:9034190 Mammalian cells proteolytically release (shed) the extracellular domains of many cell-surface proteins. PMID:18383040 Paradoxically, both LPS with or without IL-10 led to accumulation of surface TACE (albeit catalytically inactive) over a 24 h period. |
| GO:0010820 positive regulation of T cell chemotaxis | IMP PMID:18373975 The role of CXCL16 and its processing metalloproteinases ADA... | KEEP AS NON CORE | Summary: Blocking ADAM10 and ADAM17 in human mesangial cells reduces chemotaxis of Jurkat T cells. Reason: ADAM17 catalyses release of the chemoattractant (CXCL16 and, per the authors, additional substrates), so the regulatory claim has a mechanism; it is nevertheless a consequence of the shedding step and is best kept as non-core. Note the authors explicitly found that CXCL16 blockade alone did not reproduce the effect, so the responsible substrate is not fully identified. Supporting Evidence: PMID:18373975 Notably, targeting ADAM10 and ADAM17 in hMCs decreased the chemotaxis of T-Jurkat cells, whereas the inhibition of CXCL16 had no significant influence. |
| GO:0015629 actin cytoskeleton | IDA PMID:17010968 The shedding activity of ADAM17 is sequestered in lipid raft... | UNDECIDED | Summary: Actin-cytoskeleton localisation annotated from the lipid-raft sequestration study. Reason: The cached record is abstract-only and describes raft partitioning and furin maturation, not an actin-cytoskeleton observation. The full text may support it, so the annotation is left undecided; ADAM17's well-supported locations are the plasma membrane and membrane rafts. Supporting Evidence: PMID:17010968 Consequently, ADAM17 shedding activity is sequestered in lipid rafts |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: ADAM17 identified in a high-throughput membrane-proteome analysis of the NK-like YTS cell line. Reason: A broad but correct component annotation for a single-pass type I membrane protein, independently supported by targeted detection of ADAM17 on primary NK cells. Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores. PMID:24337742 ADAM17 was found to be expressed on NK cells, and stimulation with PMA or N-ethyl-maleimide resulted in the shedding of FcΞ³RIIIA/CD16A and CD62L, a specific substrate of ADAM17. |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Membrane localisation propagated electronically from the mouse ortholog. Reason: Correct though general; the specific plasma-membrane annotations carry the informative content. Supporting Evidence: PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0016324 apical plasma membrane | IDA PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | ACCEPT | Summary: TACE colocalises with IL-6 receptor alpha on the apical surface of airway epithelial cells after bacterial exposure. Reason: A specific, directly observed location in a polarised epithelium, and functionally meaningful because soluble IL-6R alpha accumulates apically as a result. Supporting Evidence: PMID:16034137 By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. |
| GO:0016485 protein processing | IDA PMID:9774383 Evidence that tumor necrosis factor alpha converting enzyme ... | MODIFY | Summary: Protein processing annotated from the TACE-knockout study of regulated APP alpha-cleavage. Reason: The processing event is juxtamembrane cleavage of a transmembrane protein's ectodomain, which GO:0006509 states precisely; GO:0016485 is an uninformative parent for this gene. Proposed replacements: membrane protein ectodomain proteolysis Supporting Evidence: PMID:9774383 we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. PMID:9774383 Furthermore, we show that inhibiting this enzyme affects both APP secretion and Abeta formation in cultured cells. |
| GO:0019955 cytokine binding | IPI PMID:12777399 Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on s... | MODIFY | Summary: Interaction with TNF (UniProtKB:P01375) recorded as cytokine binding, from the ADAM8/15/28 substrate-specificity study in which ADAM17 served as the comparator enzyme. Reason: The partner is specifically TNF, ADAM17's founding substrate, so GO:0043120 tumor necrosis factor binding - already annotated for this gene - is the informative term in place of the generic cytokine parent. Proposed replacements: tumor necrosis factor binding Supporting Evidence: PMID:12777399 By screening a library of synthetic peptides as potential substrates, we show that soluble recombinant forms of these enzymes have similar proteolytic substrate specificity, clearly distinct from that of ADAM17 (TNFalpha-converting enzyme). PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. |
| GO:0023061 signal release | IDA PMID:12777399 Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on s... | MODIFY | Summary: Signal release annotated from the same comparative ADAM substrate-specificity study. Reason: GO:0023061 is a vague parent; what ADAM17 does is cleave a cytokine precursor to release the soluble mediator, which GO:0140447 cytokine precursor processing states at the right level and which the gene already carries. Note this reference's own experimental conclusion about CD23 was negative for ADAM17, so the TNF-based evidence carries the claim. Proposed replacements: cytokine precursor processing Supporting Evidence: PMID:12777399 We found that ADAM8, ADAM15, and MDC-L, but not ADAM17, catalyzed ectodomain shedding of CD23, the low affinity IgE receptor. PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. |
| GO:0030165 PDZ domain binding | IPI PMID:12207026 Evidence for regulation of the tumor necrosis factor alpha-c... | ACCEPT | Summary: The PDZ domain of PTPH1/PTPN3 binds the COOH terminus of TACE, a group-I PDZ-binding sequence ending in cysteine. Reason: An informative, domain-mapped molecular function: ADAM17 carries a C-terminal group-I PDZ-binding motif that recruits PDZ-domain proteins, with functional consequences for ADAM17 levels and shedding. Retained as a non-core regulatory function alongside the core catalytic activity. Supporting Evidence: PMID:12207026 The interaction is mediated via binding of the PDZ domain of PTPH1 to the COOH terminus of TACE. PMID:12207026 The latter represents a novel group I PDZ binding sequence characterized by a terminal cysteine residue. |
| GO:0030183 B cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: B cell differentiation, propagated electronically from the mouse ortholog. Reason: A mouse organismal phenotype consequent on loss of ADAM17 shedding activity (TNF, TNF receptors, Notch ligands, L-selectin). ADAM17 performs no step of lymphocyte differentiation itself, so the row is retained as non-core. Supporting Evidence: PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0030183 B cell differentiation | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | KEEP AS NON CORE | Summary: B cell differentiation, transferred by sequence similarity from mouse Adam17. Reason: A mouse organismal phenotype consequent on loss of ADAM17 shedding activity (TNF, TNF receptors, Notch ligands, L-selectin). ADAM17 performs no step of lymphocyte differentiation itself, so the row is retained as non-core. The ISS source (PMID:10433800) is a mouse cDNA/gene-structure and chromosomal-mapping paper; it establishes 92% identity between mouse and human ADAM17 and TNF-precursor cleavage, but contains none of the immunological or developmental phenotype data the term describes. The underlying mouse knockout biology is real, so the annotation is retained rather than removed, but it cannot be treated as a core human ADAM17 function. Supporting Evidence: PMID:10433800 Mouse TACE/ADAM17 has a 92% amino-acid identity with the human protein and was ubiquitously expressed. |
| GO:0030307 positive regulation of cell growth | IMP PMID:18373975 The role of CXCL16 and its processing metalloproteinases ADA... | MARK AS OVER ANNOTATED | Summary: Reduced growth of human mesangial cells on inhibition of CXCL16, ADAM10 and ADAM17. Reason: As for the proliferation row from the same paper: growth is a downstream consequence of releasing mitogenic ligands, and inhibitor-based necessity does not establish that ADAM17 executes a step of cell growth. Supporting Evidence: PMID:18373975 Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. |
| GO:0030335 positive regulation of cell migration | IDA PMID:26617808 MiR-338-3p inhibits the proliferation and migration of gastr... | KEEP AS NON CORE | Summary: ADAM17 re-expression rescues migration and invasion of gastric cancer cells suppressed by miR-338-3p. Reason: Migration here is driven by ADAM17-dependent ligand release rather than by ADAM17 acting within the motility machinery; the rescue experiment is good evidence that the sheddase is required, which is weaker than participation. Kept as non-core rather than removed. Supporting Evidence: PMID:26617808 Importantly, ADAM17 rescued the miR-338-3p mediated inhibition of cell proliferation, migration and invasion. |
| GO:0030335 positive regulation of cell migration | IMP PMID:18373975 The role of CXCL16 and its processing metalloproteinases ADA... | KEEP AS NON CORE | Summary: Reduced migration of human mesangial cells after ADAM10/ADAM17 inhibition. Reason: Same reasoning: the shed substrates, not ADAM17, act in the migratory response. Retained as non-core because the requirement for ADAM17 activity is experimentally solid. Supporting Evidence: PMID:18373975 Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. PMID:18373975 We identified ADAM10 and ADAM17 as being responsible for the cytokine-induced shedding of CXCL16. |
| GO:0030512 negative regulation of transforming growth factor beta receptor signaling pathway | IMP PMID:21170088 ADAM17 (TACE) regulates TGFΞ² signaling through the cleavage ... | ACCEPT | Summary: ADAM17 cleaves vasorin (VASN); only the soluble VASN ectodomain inhibits TGF-beta, so ADAM17 inhibition up-regulates TGF-beta signalling and TGF-beta-mediated EMT. Reason: ADAM17 performs the proteolytic step that generates the soluble TGF-beta inhibitor, so it executes part of the regulatory event rather than merely being required upstream of it. Supporting Evidence: PMID:21170088 we show that only the soluble form of VASN inhibits TGFΞ² and that the secretion of VASN is tightly controlled by ADAM17 PMID:21170088 Hence, inhibition of ADAM17 leads to the upregulation of TGFΞ² signaling. |
| GO:0032496 response to lipopolysaccharide | IDA PMID:18383040 Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/A... | KEEP AS NON CORE | Summary: LPS rapidly induces TACE activity in monocytes, coinciding with soluble TNF-alpha release; IL-10 suppresses that activation. Reason: A genuine, directly measured response of ADAM17 activity to an exogenous stimulus, but the response is a regulatory input rather than a core function of the protein. Supporting Evidence: PMID:18383040 Using an ex vivo fluorogenic assay we observed that LPS rapidly induced TACE activity in monocytes coinciding with release of soluble TNF-alpha. PMID:18383040 Paradoxically, both LPS with or without IL-10 led to accumulation of surface TACE (albeit catalytically inactive) over a 24 h period. |
| GO:0032587 ruffle membrane | IDA PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | ACCEPT | Summary: Colocalisation of ADAM17 with integrin alpha5beta1 in membrane ruffles of HeLa cells. Reason: Directly observed by the cited imaging, and consistent with ADAM17 redistributing to the leading edge of wounded monolayers. Supporting Evidence: PMID:14970227 Intriguingly, ADAM-17 and alpha(5)beta(1) were found to co-localize in both membrane ruffles and focal adhesions in HeLa cells. PMID:14970227 When confluent HeLa cell monolayers were wounded, ADAM-17 and alpha(5)beta(1) redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. |
| GO:0032722 positive regulation of chemokine production | IMP PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | KEEP AS NON CORE | Summary: Bacteria induce TACE and IL-6R alpha shedding; the resulting IL-6 trans-signalling activates CCL-2 expression and limits further CXCL8 production. Reason: ADAM17 catalyses the step that produces the soluble receptor driving chemokine induction, so the regulation is mechanistically grounded, but chemokine production itself is executed by the responding epithelial transcriptional programme. Supporting Evidence: PMID:16034137 By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. PMID:16034137 Epithelial IL-6 and soluble IL-6Ralpha were shown to participate in trans-signaling, interacting with membrane-associated gp130 to activate CCL-2 expression and inhibit additional CXCL8 production. |
| GO:0032760 positive regulation of tumor necrosis factor production | IDA PMID:12777399 Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on s... | UNDECIDED | Summary: Positive regulation of TNF production annotated from the comparative ADAM substrate-specificity study. Reason: This reference characterises ADAM8, ADAM15 and ADAM28 and uses ADAM17 as a specificity comparator; its one explicit ADAM17 result (CD23 shedding) is negative. The claim itself is correct for ADAM17 on other evidence, but I cannot verify from the cached abstract what in this paper supports it, so the row is left undecided rather than endorsed or challenged. Supporting Evidence: PMID:12777399 By screening a library of synthetic peptides as potential substrates, we show that soluble recombinant forms of these enzymes have similar proteolytic substrate specificity, clearly distinct from that of ADAM17 (TNFalpha-converting enzyme). PMID:12777399 We found that ADAM8, ADAM15, and MDC-L, but not ADAM17, catalyzed ectodomain shedding of CD23, the low affinity IgE receptor. |
| GO:0032760 positive regulation of tumor necrosis factor production | IDA PMID:18355445 Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... | ACCEPT | Summary: Nardilysin synergistically enhances TACE-dependent TNF-alpha shedding, and NRDC expression in TACE-deficient fibroblasts increases released TNF-alpha. Reason: ADAM17 performs the cleavage that converts membrane pro-TNF into the released cytokine, so it executes the step that determines how much soluble TNF is produced. Supporting Evidence: PMID:18355445 In a cell-based shedding assay, expression of NRDc synergistically enhanced TACE-induced TNF-alpha shedding. PMID:18355445 The TNF-alpha-converting enzyme (TACE/ADAM17) is the major sheddase for ectodomain shedding of TNF-alpha. |
| GO:0033025 regulation of mast cell apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Regulation of mast cell apoptotic process, propagated electronically from the mouse ortholog. Reason: ADAM17 sheds c-Kit, the receptor required for mast-cell survival, and TACE-inactive mast cells show increased basal surface c-Kit with altered survival - so the annotation has a concrete mechanism. Regulation of mast-cell apoptosis is nonetheless a cellular outcome downstream of the shedding step. Supporting Evidence: PMID:14625290 PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (DeltaZn/DeltaZn), confirming the role of TACE in PMA-induced c-Kit shedding. PMID:14625290 we report that tumor necrosis factor alpha-converting enzyme (TACE; ADAM-17) mediates shedding of c-Kit |
| GO:0033025 regulation of mast cell apoptotic process | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | KEEP AS NON CORE | Summary: Regulation of mast cell apoptotic process, transferred by sequence similarity from mouse Adam17. Reason: ADAM17 sheds c-Kit, the receptor required for mast-cell survival, and TACE-inactive mast cells show increased basal surface c-Kit with altered survival - so the annotation has a concrete mechanism. Regulation of mast-cell apoptosis is nonetheless a cellular outcome downstream of the shedding step. The ISS source (PMID:10433800) is a mouse cDNA/gene-structure and chromosomal-mapping paper; it establishes 92% identity between mouse and human ADAM17 and TNF-precursor cleavage, but contains none of the immunological or developmental phenotype data the term describes. The underlying mouse knockout biology is real, so the annotation is retained rather than removed, but it cannot be treated as a core human ADAM17 function. Supporting Evidence: PMID:14625290 PMA decreased surface c-Kit levels on mast cells expressing wild-type (+/+) TACE but not on those expressing an inactive mutant (DeltaZn/DeltaZn), confirming the role of TACE in PMA-induced c-Kit shedding. |
| GO:0033077 T cell differentiation in thymus | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: T cell differentiation in thymus, propagated electronically from the mouse ortholog. Reason: A mouse developmental phenotype of ADAM17 deficiency, mediated by substrates such as Notch ligands and TNF-family proteins rather than by ADAM17 acting inside the differentiation programme. Supporting Evidence: PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0033077 T cell differentiation in thymus | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | KEEP AS NON CORE | Summary: T cell differentiation in thymus, transferred by sequence similarity from mouse Adam17. Reason: A mouse developmental phenotype of ADAM17 deficiency, mediated by substrates such as Notch ligands and TNF-family proteins rather than by ADAM17 acting inside the differentiation programme. The ISS source (PMID:10433800) is a mouse cDNA/gene-structure and chromosomal-mapping paper; it establishes 92% identity between mouse and human ADAM17 and TNF-precursor cleavage, but contains none of the immunological or developmental phenotype data the term describes. The underlying mouse knockout biology is real, so the annotation is retained rather than removed, but it cannot be treated as a core human ADAM17 function. Supporting Evidence: PMID:10433800 Mouse TACE/ADAM17 has a 92% amino-acid identity with the human protein and was ubiquitously expressed. |
| GO:0033627 cell adhesion mediated by integrin | IDA PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | KEEP AS NON CORE | Summary: ADAM17 supports integrin-mediated adhesion as an alpha5beta1 ligand through its disintegrin/cysteine-rich region. Reason: ADAM17 is the ligand in this adhesion event, which is genuine participation, but it is a peripheral non-proteolytic activity relative to the gene's sheddase role; CD9 modulation of the same complex supports the interaction independently. Supporting Evidence: PMID:14970227 we now demonstrate a functional interaction between ADAM-17 and alpha(5)beta(1) integrin in a trans orientation PMID:30455686 the interaction between integrin Ξ±5Ξ²1 and the disintegrin domain of ADAM17 has been shown to cause the inhibition of both the adhesive capacity of the integrin |
| GO:0035313 wound healing, spreading of epidermal cells | IEP PMID:14970227 Integrin alpha5beta1 and ADAM-17 interact in vitro and co-lo... | MARK AS OVER ANNOTATED | Summary: Expression-pattern (IEP) annotation from redistribution of ADAM17 and alpha5beta1 to the leading edge of wounded HeLa monolayers. Reason: The observation is relocalisation in a scratch assay using HeLa cervical carcinoma cells, which are not epidermal; IEP evidence of this kind cannot support a specific epidermal wound-healing process term. The underlying observation is retained through the ruffle and focal-adhesion component annotations. Supporting Evidence: PMID:14970227 When confluent HeLa cell monolayers were wounded, ADAM-17 and alpha(5)beta(1) redistributed to the leading edge and co-localized, which is suggestive of a cis orientation. |
| GO:0042987 amyloid precursor protein catabolic process | IDA PMID:9774383 Evidence that tumor necrosis factor alpha converting enzyme ... | ACCEPT | Summary: TACE-knockout evidence that ADAM17 performs regulated alpha-cleavage of APP, with effects on APP secretion and amyloid-beta formation in cultured cells. Reason: ADAM17 catalyses the alpha-cleavage of APP itself, so it executes a step of APP catabolism. Scope note: the evidence supports ADAM17 as the protease for the regulated (phorbol-ester/PKC-stimulated) alpha-secretase arm, whereas constitutive neuronal alpha-secretase activity is attributable to ADAM10; the annotation should not be read as making ADAM17 the principal APP alpha-secretase. Supporting Evidence: PMID:9774383 we now demonstrate that TACE (tumor necrosis factor alpha converting enzyme), a member of the ADAM family (a disintegrin and metalloprotease-family) of proteases, plays a central role in regulated alpha-cleavage of APP. PMID:20676056 This shows that ADAM10 is not required for PMA induction of APP shedding and suggests that under these conditions ADAM17 can directly cleave APP. |
| GO:0043120 tumor necrosis factor binding | IDA PMID:25049354 Matrix metalloproteinase-8 plays a pivotal role in neuroinfl... | ACCEPT | Summary: TNF binding inferred from assays of TACE activity on the TNF prodomain, in a study showing MMP-8 also has TNF-converting activity. Reason: Substrate binding by a protease is an informative molecular function, and TNF is ADAM17's best-established substrate with a mapped cleavage site. Retained as a substrate-recognition function rather than as the core catalytic annotation. Supporting Evidence: PMID:25049354 Subsequent experiments showed that MMP-8 exhibits TNF-Ξ±-converting enzyme (TACE) activity by cleaving the prodomain of TNF-Ξ± (A(74)/Q(75), A(76)/V(77) residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. |
| GO:0043130 ubiquitin binding | IMP PMID:38771644 ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-... | REMOVE | Summary: Ubiquitin binding annotated from the hypotrichosis study, in which a CANDIS-domain variant increases ADAM17 ubiquitination and TRIM47-dependent degradation. Reason: The experiments show that ADAM17 is a ubiquitination substrate - the mutant protein is hyperubiquitinated by the E3 ligase TRIM47 and degraded by the proteasome - which is the opposite direction of the claim: being modified by ubiquitin is not binding ubiquitin, and no ubiquitin-binding assay or ubiquitin-binding domain is reported. The paper's valid molecular-function content (metallopeptidase activity) is annotated separately from the same reference. Supporting Evidence: PMID:38771644 Further mechanistic investigations revealed that the variant in CANDIS enhanced ADAM17 susceptibility to ubiquitin-mediated degradation by enhancing its association with E3 ubiquitin ligase TRIM47. PMID:38771644 In summary, our findings indicate that the mutant ADAM17 displays elevated auto-ubiquitination levels, ultimately leading to decreased protein stability and lower abundance. |
| GO:0043491 phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg... | MARK AS OVER ANNOTATED | Summary: ADAM17 knockdown attenuates UVA-induced AKT activation downstream of EGFR in keratinocytes. Reason: ADAM17 acts upstream by releasing the EGFR ligand; it performs no step within the PI3K/AKT cascade itself, and siRNA-based necessity does not make it a participant. The EGFR-pathway annotations from the same work already capture the mechanism, and the authors note the inhibition was incomplete. Supporting Evidence: PMID:18483258 Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of ADAM17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. PMID:18483258 The incomplete inhibition of EGFR activation and G1-S transition by siRNA against ADAM17 compared to the metalloprotease inhibitor GM suggests that other mechanisms may contribute to UVA-induced EGFR activation. |
| GO:0043536 positive regulation of blood vessel endothelial cell migration | IDA PMID:24813629 MiR-152 reduces human umbilical vein endothelial cell prolif... | KEEP AS NON CORE | Summary: miR-152 targeting of ADAM17 reduces TNF-precursor cleavage and endothelial-cell migration in HUVECs. Reason: The migratory response is driven by the released mediators rather than by ADAM17 acting in the migration machinery; the knockdown establishes requirement, which is retained as a non-core process association. Supporting Evidence: PMID:24813629 We found that miR-152 could reduce TNF precursor cleavage and inhibit cell proliferation and migration by targeting ADAM17 in human umbilical vein endothelial cells (HUVECs). |
| GO:0045121 membrane raft | IDA PMID:17010968 The shedding activity of ADAM17 is sequestered in lipid raft... | ACCEPT | Summary: ADAM17 partitions into cholesterol-rich membrane microdomains, where its pro-domain is removed and its shedding activity is sequestered; cholesterol depletion or HDL treatment mobilises it. Reason: A directly demonstrated and functionally important location: raft partitioning is one of the principal mechanisms controlling which substrates ADAM17 can reach. Supporting Evidence: PMID:17010968 Consequently, ADAM17 shedding activity is sequestered in lipid rafts PMID:17010968 Membrane cholesterol depletion increases the ADAM17-dependent shedding of these substrates demonstrating the importance of lipid rafts in the control of this process. |
| GO:0045121 membrane raft | IDA PMID:17786981 HDLs activate ADAM17-dependent shedding. | ACCEPT | Summary: ADAM17 partitions into cholesterol-rich membrane microdomains, where its pro-domain is removed and its shedding activity is sequestered; cholesterol depletion or HDL treatment mobilises it. Reason: A directly demonstrated and functionally important location: raft partitioning is one of the principal mechanisms controlling which substrates ADAM17 can reach. Supporting Evidence: PMID:17786981 HDLs reduced the cholesterol and proteins (including ADAM17) content of lipid rafts and triggered the ADAM17-dependent cleavage of TNF in the non-raft region of the membrane. |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IDA PMID:12743035 TACE cleavage of proamphiregulin regulates GPCR-induced prol... | ACCEPT | Summary: TACE blockade by TIMP-3, a dominant-negative mutant, or RNA interference suppresses GPCR-stimulated amphiregulin release and EGFR activation. Reason: ADAM17 catalyses the ligand-release step that activates EGFR, so it executes part of the positive regulation rather than sitting merely upstream of it. Supporting Evidence: PMID:12743035 The results of this study indicate that treatment of squamous cell carcinoma cells with GPCR ligands such as LPA and carbachol leads to the rapid and specific cleavage of proAR at the cell surface by TACE. PMID:12743035 Thus, TACE can function as an effector of GPCR-mediated signalling and represents a key element of the cellular receptor cross-talk network. |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: Positive regulation of EGFR signalling assigned by an ARBA machine-learning model. Reason: Consistent with the direct experimental evidence that ADAM17 is the principal sheddase of the EGFR ligand family. Supporting Evidence: PMID:29897336 In addition, ADAM17 is the principal sheddase of the epidermal growth factor (EGF) receptor ligands amphiregulin (AREG), transforming growth factor alpha (TGFΞ±), heparin-binding EGF (HB-EGF), epigen, and epiregulin |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | IMP PMID:17655843 EGF receptor transactivation and PI3-kinase mediate stimulat... | UNDECIDED | Summary: Positive regulation of EGFR signalling inferred from alpha2A-adrenoreceptor-driven EGFR transactivation and wound healing in intestinal epithelial cells. Reason: The cached abstract reports broad-spectrum metalloprotease blockade and HB-EGF neutralisation rather than an ADAM17-specific perturbation, so I cannot verify from the available text what identifies ADAM17 here. The claim is well supported for ADAM17 by other references, so the row is left undecided rather than challenged. Supporting Evidence: PMID:17655843 Both effects are strongly attenuated by inhibition or desensitization of epidermal growth factor (EGF) receptor, matrix metalloproteinase (MMP) blockade, heparin-binding-EGF neutralization or phosphatidylinositol 3-kinase (PI3-kinase) inhibitors. |
| GO:0045742 positive regulation of epidermal growth factor receptor signaling pathway | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | ACCEPT | Summary: Positive regulation of EGFR signalling transferred by sequence similarity from mouse Adam17 (acts_upstream_of). Reason: The conclusion is correct and strongly supported for human ADAM17 by direct evidence that it releases the EGFR ligands amphiregulin, TGF-alpha, HB-EGF, epigen and epiregulin, even though the cited similarity source is a mouse gene-structure paper. Supporting Evidence: PMID:29897336 In addition, ADAM17 is the principal sheddase of the epidermal growth factor (EGF) receptor ligands amphiregulin (AREG), transforming growth factor alpha (TGFΞ±), heparin-binding EGF (HB-EGF), epigen, and epiregulin PMID:12743035 The results of this study indicate that treatment of squamous cell carcinoma cells with GPCR ligands such as LPA and carbachol leads to the rapid and specific cleavage of proAR at the cell surface by TACE. |
| GO:0048536 spleen development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Spleen development, propagated electronically from the mouse ortholog. Reason: An organismal developmental phenotype of ADAM17 deficiency in mouse, mediated through substrates that ADAM17 releases; the protein performs no step of spleen morphogenesis itself. Supporting Evidence: PMID:38771644 ADAM17), a type I transmembrane metallopeptidase, is responsible for shedding the ectodomains of over 90 substrates, including cytokines (such as TNF-Ξ±), cytokine receptors (such as IL-6R and TNFR), and adhesion proteins |
| GO:0048536 spleen development | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | KEEP AS NON CORE | Summary: Spleen development, transferred by sequence similarity from mouse Adam17. Reason: An organismal developmental phenotype of ADAM17 deficiency in mouse, mediated through substrates that ADAM17 releases; the protein performs no step of spleen morphogenesis itself. The ISS source (PMID:10433800) is a mouse cDNA/gene-structure and chromosomal-mapping paper; it establishes 92% identity between mouse and human ADAM17 and TNF-precursor cleavage, but contains none of the immunological or developmental phenotype data the term describes. The underlying mouse knockout biology is real, so the annotation is retained rather than removed, but it cannot be treated as a core human ADAM17 function. Supporting Evidence: PMID:10433800 Mouse TACE/ADAM17 has a 92% amino-acid identity with the human protein and was ubiquitously expressed. |
| GO:0048870 cell motility | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cell motility, propagated electronically from the mouse ortholog. Reason: Bare cell motility is both too general to be informative and a downstream consequence of releasing motogenic ligands: ADAM17 does not act within the motility machinery. More specific migration-related rows already record the experimentally observed effects. Supporting Evidence: PMID:18373975 Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. |
| GO:0048870 cell motility | ISS PMID:10433800 Characterization of the cDNA and gene for mouse tumour necro... | MARK AS OVER ANNOTATED | Summary: Cell motility, transferred by sequence similarity from mouse Adam17. Reason: Bare cell motility is both too general to be informative and a downstream consequence of releasing motogenic ligands: ADAM17 does not act within the motility machinery. More specific migration-related rows already record the experimentally observed effects. Supporting Evidence: PMID:18373975 Finally, we could show that the inhibition of CXCL16, ADAM10, and ADAM17 led to a strong reduction of cell proliferation and migration of hMCs. |
| GO:0050830 defense response to Gram-positive bacterium | IMP PMID:16034137 Bacterial induction of TNF-alpha converting enzyme expressio... | KEEP AS NON CORE | Summary: Staphylococcus aureus and Pseudomonas aeruginosa induce TACE transcription and IL-6R alpha shedding in airway epithelial cells, modulating the inflammatory response. Reason: ADAM17 is induced by, and shapes signalling during, Gram-positive bacterial challenge, so the association is real; but the defence response is executed by the epithelial and leukocyte programmes that the shed mediators engage. Supporting Evidence: PMID:16034137 Both Staphylococcus aureus and Pseudomonas aeruginosa were found to potently activate IL-6 expression immediately upon contact with epithelial cells, and by 1 h induced TNF-alpha converting enzyme (TACE) transcription. PMID:16034137 By 4 h of bacterial exposure, TACE colocalized with IL-6Ralpha on the apical surface of airway cells, and by 24 h, soluble IL-6Ralpha accumulated in the cell culture supernatant. |
| GO:0070573 metallodipeptidase activity | IEA GO_REF:0000107 | REMOVE | Summary: Metallodipeptidase activity propagated electronically from the mouse ortholog. Reason: The term denotes hydrolysis of a dipeptide, which is not what ADAM17 does: it is an endopeptidase that cleaves internal juxtamembrane peptide bonds in transmembrane proteins, with a defined cleavage site in pro-TNF (EC 3.4.24.86). The correct annotations GO:0004222 and GO:0004175 are already present, so this electronic inference is wrong in substance rather than merely imprecise. Supporting Evidence: PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. PMID:9034191 TACE is a membrane-bound disintegrin metalloproteinase. |
| GO:0071403 cellular response to high density lipoprotein particle stimulus | IDA PMID:17786981 HDLs activate ADAM17-dependent shedding. | ACCEPT | Summary: HDL treatment increases ADAM17-dependent shedding of TNF, TNFR1 and TNFR2, acting through cholesterol efflux and lipid-raft remodelling; apoA1 reproduces the effect in an ABCA1-dependent way. Reason: A directly measured cellular response in which the ADAM17 activity is the readout and the mechanism (raft cholesterol depletion repositioning the protease) is established. Supporting Evidence: PMID:17786981 HDLs added to different cell types, increased the ectodomain shedding of TNFR2, TNFR1, and TNF, an effect reduced by inhibitors active on ADAM17. PMID:17786981 HDLs reduced the cholesterol and proteins (including ADAM17) content of lipid rafts and triggered the ADAM17-dependent cleavage of TNF in the non-raft region of the membrane. |
| GO:0071679 commissural neuron axon guidance | IMP PMID:36476876 Tace/ADAM17 is a bi-directional regulator of axon guidance t... | ACCEPT | Summary: Conditional Adam17 deletion thins Robo3-positive commissures at the mouse ventral midline, and Tace/ADAM17 cleaves the Frazzled/DCC receptor to partition netrin-dependent and -independent signalling outputs. Reason: ADAM17 performs the cleavage of the guidance receptor that sets its signalling output, so it executes a step of the guidance process rather than being only required for it. Supporting Evidence: PMID:36476876 the thickness of Robo3-positive commissures at the ventral midline is significantly reduced in Adam17 cKO embryos, demonstrating that ADAM17 is required in vivo for the midline crossing of commissural axons (Figure 6J). PMID:36476876 Here we establish a conserved and essential role for Tace and ADAM17 in cleaving Fra and Dcc and demonstrate that this proteolysis bi-directionally regulates axon guidance at the midline. |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Negative regulation of cold-induced thermogenesis, propagated electronically from the mouse ortholog. Reason: Tace DeltaZn/DeltaZn mice are hypermetabolic and lean with elevated brown-adipose UCP1, which is the evidence behind this term. It is an organismal energy-balance phenotype of losing sheddase activity, not a thermogenic step ADAM17 carries out, and the data are murine. Supporting Evidence: PMID:18687778 Because this effect is not matched by increased food intake, mice lacking TACE exhibit a lean phenotype. PMID:18687778 Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace Ξ Zn /Ξ Zn mice when compared with weight-matched controls suggest that deficient TACE activity is linked to increased sympathetic outflow. |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:18687778 Deficiency of TNFalpha converting enzyme (TACE/ADAM17) cause... | KEEP AS NON CORE | Summary: Negative regulation of cold-induced thermogenesis, transferred by sequence similarity from the mouse TACE-deficiency study. Reason: Tace DeltaZn/DeltaZn mice are hypermetabolic and lean with elevated brown-adipose UCP1, which is the evidence behind this term. It is an organismal energy-balance phenotype of losing sheddase activity, not a thermogenic step ADAM17 carries out, and the data are murine. Supporting Evidence: PMID:18687778 Elevated levels of uncoupling protein-1 in brown adipose tissue from Tace Ξ Zn /Ξ Zn mice when compared with weight-matched controls suggest that deficient TACE activity is linked to increased sympathetic outflow. PMID:18687778 Because this effect is not matched by increased food intake, mice lacking TACE exhibit a lean phenotype. |
| GO:0140447 cytokine precursor processing | IDA PMID:24813629 MiR-152 reduces human umbilical vein endothelial cell prolif... | ACCEPT | Summary: ADAM17 knockdown by miR-152 reduces cleavage of the TNF precursor in endothelial cells. Reason: Cytokine precursor processing is precisely the reaction ADAM17 catalyses; this is a core process annotation with direct support. Supporting Evidence: PMID:24813629 We found that miR-152 could reduce TNF precursor cleavage and inhibit cell proliferation and migration by targeting ADAM17 in human umbilical vein endothelial cells (HUVECs). PMID:9034190 We have now purified and cloned a metalloproteinase that specifically cleaves precursor TNF-alpha. |
| GO:0140448 signaling receptor ligand precursor processing | IEA GO_REF:0000107 | ACCEPT | Summary: Signalling receptor ligand precursor processing, propagated electronically from the mouse ortholog. Reason: Accurate and well matched to ADAM17's established substrates: it is the principal sheddase converting the membrane-anchored EGFR-ligand precursors (amphiregulin, TGF-alpha, HB-EGF, epigen, epiregulin) and pro-TNF into their soluble signalling forms. Supporting Evidence: PMID:29897336 In addition, ADAM17 is the principal sheddase of the epidermal growth factor (EGF) receptor ligands amphiregulin (AREG), transforming growth factor alpha (TGFΞ±), heparin-binding EGF (HB-EGF), epigen, and epiregulin |
| GO:1900087 positive regulation of G1/S transition of mitotic cell cycle | IMP PMID:18483258 UVA-induced cell cycle progression is mediated by a disinteg... | MARK AS OVER ANNOTATED | Summary: ADAM17 knockdown blocks UVA-induced G1/S progression via the EGFR/AKT/cyclin D1 axis in keratinocytes. Reason: The cell-cycle transition is executed by the cyclin/CDK machinery; ADAM17 contributes only the upstream ligand-release step, which is already annotated as EGFR-pathway involvement. Requirement demonstrated by knockdown is not participation in the transition itself. Supporting Evidence: PMID:18483258 Furthermore, metalloprotease inhibitor GM6001 blocked UVA-induced cell cycle progression, and siRNA knockdown of ADAM17 had a similar inhibitory effect, demonstrating that ADAM17 mediates the EGFR/AKT/cyclin D1 pathway and cell cycle progression to the S phase induced by UVA radiation. PMID:18483258 The incomplete inhibition of EGFR activation and G1-S transition by siRNA against ADAM17 compared to the metalloprotease inhibitor GM suggests that other mechanisms may contribute to UVA-induced EGFR activation. |
| GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway | IDA PMID:18355445 Ectodomain shedding of TNF-alpha is enhanced by nardilysin v... | ACCEPT | Summary: Nardilysin-enhanced ADAM17 shedding of TNF-alpha increases soluble TNF available for receptor signalling. Reason: ADAM17 catalyses the step that generates the active soluble ligand of the TNF pathway, which is participation in positive regulation of that pathway rather than mere upstream necessity. Supporting Evidence: PMID:18355445 In a cell-based shedding assay, expression of NRDc synergistically enhanced TACE-induced TNF-alpha shedding. PMID:18355445 The TNF-alpha-converting enzyme (TACE/ADAM17) is the major sheddase for ectodomain shedding of TNF-alpha. |
| GO:1903265 positive regulation of tumor necrosis factor-mediated signaling pathway | IMP PMID:24813629 MiR-152 reduces human umbilical vein endothelial cell prolif... | ACCEPT | Summary: miR-152-mediated ADAM17 knockdown reduces TNF-precursor cleavage in endothelial cells, lowering TNF-mediated signalling. Reason: Same reasoning: the measured ADAM17 activity is production of the pathway's soluble ligand. Supporting Evidence: PMID:24813629 We found that miR-152 could reduce TNF precursor cleavage and inhibit cell proliferation and migration by targeting ADAM17 in human umbilical vein endothelial cells (HUVECs). |
| GO:1905564 positive regulation of vascular endothelial cell proliferation | IDA PMID:24813629 MiR-152 reduces human umbilical vein endothelial cell prolif... | MARK AS OVER ANNOTATED | Summary: Reduced proliferation of HUVECs when ADAM17 is knocked down by miR-152. Reason: Endothelial proliferation is downstream of the mediators ADAM17 releases; the gene product performs no step of the proliferative programme, and the experiment is a microRNA knockdown that also affects other targets. Supporting Evidence: PMID:24813629 We found that miR-152 could reduce TNF precursor cleavage and inhibit cell proliferation and migration by targeting ADAM17 in human umbilical vein endothelial cells (HUVECs). |
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Download this section (compressed HTML)Q: Should ADAM17's regulated (stimulus-induced) alpha-secretase cleavage of APP be annotated differently from ADAM10's constitutive activity, given that neuronal knockdown assigns the constitutive arm to ADAM10 and leaves the physiological relevance of ADAM17-mediated APP cleavage explicitly open?
Suggested experts: Alzheimer disease curators, membrane proteolysis curators
Q: Is there a GO representation for a protease that functions only as the catalytic subunit of an obligate complex with a non-catalytic partner? ADAM17 requires an iRhom (RHBDF1/RHBDF2) plus FRMD8 for surface delivery and activation, but no sheddase-complex cellular-component term exists.
Suggested experts: GO cellular component curators, sheddase biology experts
Q: How should downstream signalling and proliferation terms be handled for sheddases generally? ADAM17 carries several such annotations (PI3K/AKT signal transduction, G1/S transition, cell growth and proliferation) that record requirement rather than participation.
Suggested experts: GO biological process curators
Q: Which of ADAM17's ~90 reported in vitro substrates are physiologically relevant in vivo, and should GO annotate substrate-specific shedding events only where in vivo evidence exists?
Suggested experts: ADAM/protease biologists, GO annotation consortium
Experiment: Compare APP alpha-secretase product (sAPPalpha) generation in human iPSC-derived neurons carrying catalytically inactive ADAM17, inactive ADAM10, or both, under basal conditions and after muscarinic M1 or PKC stimulation.
Hypothesis: ADAM10 accounts for constitutive neuronal alpha-cleavage while ADAM17 is required specifically for the receptor- or PKC-stimulated arm.
Type: isogenic knock-in neuronal culture with stimulus-resolved sAPPalpha measurement
Experiment: Perform surface-proteome shedding profiling (secretome and surface proteomics) in cells expressing ADAM17 with selective disruption of iRhom binding, raft targeting, or tetraspanin association, to separate substrate repertoires attributable to each control layer.
Hypothesis: Substrate selectivity is set by the sheddase complex and membrane microenvironment rather than by the catalytic domain's intrinsic specificity.
Type: quantitative secretome/surfaceome proteomics with separation-of-function mutants
Experiment: Test whether ADAM17-dependent TREM2 shedding is rate-limiting for microglial TREM2 signalling by comparing soluble and membrane TREM2, phagocytosis and ligand-induced signalling in ADAM17-null versus ADAM10-null human microglia.
Hypothesis: ADAM17 is the principal TREM2 sheddase in microglia and sets the balance between membrane TREM2 signalling and the soluble TREM2 pool measured in CSF.
Type: isogenic human microglial knockout with shedding and functional readouts
Experiment: Determine whether ADAM17 cleavage of a given substrate occurs in cis or in trans in primary cells, using separated co-cultures of protease-null and substrate-null cells for TNF, IL-6R, CD16A and TREM2.
Hypothesis: ADAM17 acts predominantly in cis, so substrate shedding reports on the activation state of the same cell rather than of neighbouring cells.
Type: mixed-genotype co-culture shedding assay
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