{"gene":"ADAM28","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2000,"finding":"ADAM28 is synthesized as a precursor and processed to a mature form in a late Golgi compartment; mature ADAM28 localizes to the cell surface. A glutamate-to-alanine mutation in the catalytic site abolishes pro-domain removal even though the mutant is still transported to the cell surface, indicating that pro-domain removal is at least in part autocatalytic—distinct from other ADAMs that rely on furin-like proprotein convertases.","method":"COS-7 cell expression, cell-surface trypsinization, site-directed mutagenesis (catalytic-site Glu→Ala)","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with subcellular fractionation and surface trypsinization in a single rigorous study","pmids":["10794709"],"is_preprint":false},{"year":2001,"finding":"Recombinant ADAM28 cleaves myelin basic protein at two defined sites; catalytic activity requires an intact catalytic-site glutamate (abolished by point mutation) and is insensitive to TIMP-1 and TIMP-2.","method":"In vitro cleavage assay with recombinant protein, site-directed mutagenesis","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis confirmation","pmids":["11389903"],"is_preprint":false},{"year":2001,"finding":"The disintegrin domain of ADAM28 (MDC-L) binds the leukocyte integrin α4β1; a 59-residue fragment of the disintegrin domain supports integrin-dependent cell adhesion in a divalent-cation-dependent, function-blocking-antibody-inhibitable manner. Binding requires activation of β1 integrins.","method":"Recombinant Fc fusion protein adhesion assay, α4/β1 function-blocking mAbs, transfected K562 cells expressing α4β1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal inhibition, transfection rescue, solution binding assays; replicated with multiple cell lines","pmids":["11724793"],"is_preprint":false},{"year":2003,"finding":"Seven specific residues (Lys437, Lys442, Lys455, Lys459, Lys460, Lys469, Glu476) in the ADAM28 disintegrin domain are essential for α4β1-dependent cell adhesion, and molecular modelling places these residues on one face of the domain, extending beyond the classical disintegrin loop.","method":"Charge-to-alanine mutagenesis of recombinant disintegrin domain, Jurkat cell adhesion assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with functional readout, structural modelling","pmids":["12667064"],"is_preprint":false},{"year":2003,"finding":"ADAM28 (MDC-L) catalyzes ectodomain shedding of CD23 (the low-affinity IgE receptor) in vitro; this activity requires a catalytically intact enzyme and is distinct from the substrate specificity of ADAM17, as shown by synthetic peptide library screening.","method":"Synthetic peptide substrate library screening, ectodomain shedding assay with soluble recombinant enzyme, hydroxamic acid metalloprotease inhibitor","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with defined substrates and inhibitor controls","pmids":["12777399"],"is_preprint":false},{"year":2004,"finding":"ProADAM28s (65 kDa secreted form) is activated by MMP-7 (matrilysin-1), which cleaves the propeptide to yield 42- and 40-kDa active forms. Activated ADAM28s cleaves IGFBP-3 in both free and IGF-I/IGF-II-complexed forms; cleavage is blocked by EDTA, 1,10-phenanthroline, KB-R7785, TIMP-3, and TIMP-4.","method":"In vitro activation assay (recombinant MMP-7 + proADAM28s), immunoblotting, metalloprotease inhibitors","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution of activation and substrate cleavage with multiple inhibitor controls","pmids":["15013428"],"is_preprint":false},{"year":2005,"finding":"Mouse ADAM28 is expressed in an epididymal region-specific manner regulated by testicular factors (not androgen); unlike ADAM7, ADAM28 is not transferred to the sperm surface, indicating distinct functional roles of these two epididymal ADAMs.","method":"Region-specific RT-PCR, castration/hormone replacement experiments, protein analysis of sperm fractions","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein localization experiments with hormonal manipulation, single lab","pmids":["15883027"],"is_preprint":false},{"year":2006,"finding":"ADAM28 cleaves IGFBP-3 to enhance IGF-I bioavailability and stimulate breast carcinoma cell proliferation; siRNA knockdown of ADAM28 in MDA-MB231 cells significantly reduces IGFBP-3 cleavage, IGF-I signaling, cell proliferation, and xenograft growth.","method":"siRNA knockdown, anti-ADAM28 antibody inhibition, IGFBP-3 cleavage assay, xenograft mouse model, IGF-I signaling readout","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (siRNA, antibody, in vivo xenograft), replicated substrate cleavage","pmids":["17047053"],"is_preprint":false},{"year":2007,"finding":"The disintegrin-like domain of secreted ADAM28 (ADAM28s) binds PSGL-1 on leukocytes; this interaction enhances P-selectin-mediated leukocyte adhesion to endothelial cells and increases leukocyte accumulation in pulmonary microcirculation in an endotoxin inflammation mouse model.","method":"Yeast two-hybrid screen, domain-specific recombinant protein binding assays, co-immunoprecipitation, adhesion assay to P-selectin-coated wells, in vivo mouse model of endotoxin inflammation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — yeast two-hybrid confirmed by co-IP, domain mapping, and in vivo functional model","pmids":["17597069"],"is_preprint":false},{"year":2009,"finding":"All-trans retinoic acid (ATRA) specifically induces ADAM28 expression in human chondrocytes; ADAM28 overexpression augments proteoglycan release from cartilage, whereas a disintegrin-domain-deleted mutant lacks this activity, demonstrating the disintegrin domain is required for substrate recognition/localization in cartilage degradation.","method":"ATRA stimulation of HCS-2/8 chondrosarcoma cells, ADAM28 transfection (full-length and disintegrin-deletion mutant), proteoglycan release assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — domain-deletion mutagenesis with functional readout, single lab","pmids":["19527685"],"is_preprint":false},{"year":2010,"finding":"ADAM28 cleaves CTGF at Ala181–Tyr182 and Asp191–Pro192 in the hinge region; this digestion releases biologically active VEGF165 from the CTGF/VEGF165 complex. CTGF was identified as a binding partner of proADAM28 by yeast two-hybrid and confirmed by protein binding assay.","method":"Yeast two-hybrid screen, protein binding assay, in vitro cleavage assay with bond identification, VEGF165 release assay","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 — in vitro cleavage with specific bond identification, binding confirmed by two independent methods","pmids":["20971063"],"is_preprint":false},{"year":2011,"finding":"ADAM28 binding to α4β1 is typical of integrin-ligand interactions (attenuated by anti-α4β1 antibodies, enhanced by Mn2+ and mAb 9EG7); soluble ADAM28 unexpectedly enhances α4β1-dependent cell adhesion to VCAM-1 and promotes lymphocyte transendothelial migration.","method":"Affymetrix microarray, RT-PCR, immunohistochemistry, L1-2 cell adhesion assay, transendothelial migration assay, integrin activating/blocking antibodies","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 — functional adhesion and migration assays with integrin controls, single lab","pmids":["21332445"],"is_preprint":false},{"year":2012,"finding":"ADAM28 binds and cleaves von Willebrand factor (VWF); carcinoma cells with high ADAM28 expression are resistant to VWF-induced apoptosis, while knockdown of ADAM28 increases apoptosis in lung blood vessels and significantly reduces lung metastasis in xenograft models. VWF was identified as an ADAM28-binding protein by yeast two-hybrid.","method":"Yeast two-hybrid screen, protein binding assay, immunoblotting for VWF cleavage, shRNA/siRNA knockdown, anti-ADAM28 neutralizing antibody, xenograft mouse model with in vivo imaging","journal":"Journal of the National Cancer Institute","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (yeast two-hybrid, cleavage assay, shRNA, antibody, in vivo), large sample sizes","pmids":["22636800"],"is_preprint":false},{"year":2012,"finding":"ADAM28 overexpression in HEK293 cells causes co-localization and co-immunoprecipitation with TNF-α and promotes TNF-α ectodomain shedding; shedding is reduced by siRNA knockdown or pharmacological inhibition of ADAM28. Endogenous ADAM28 in THP-1 macrophages similarly mediates TNF-α shedding.","method":"Co-transfection overexpression, co-immunoprecipitation, ELISA for shed TNF-α, siRNA knockdown, pharmacological inhibition","journal":"Immunology and cell biology","confidence":"High","confidence_rationale":"Tier 2 — co-IP confirmed interaction, functional shedding shown with siRNA and inhibitor, replicated in endogenous cell line","pmids":["23010875"],"is_preprint":false},{"year":2013,"finding":"ADAM28 mediates ectodomain shedding of CD200 from B-CLL cells; siRNA knockdown of ADAM28 decreases sCD200 release into culture, and transfection of ADAM28 into CD200+ cells enhances sCD200 shedding.","method":"siRNA knockdown, ADAM28 gene transfection, measurement of sCD200 by ELISA","journal":"Leukemia research","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with functional readout, single lab","pmids":["23643150"],"is_preprint":false},{"year":2013,"finding":"Src kinase induces ADAM28 gene expression through the MEK/ERK and PI3K/mTOR pathways in v-src-transformed epithelial cells and human carcinoma cell lines; combined inhibition of MEK and PI3K abrogates ADAM28 expression, and Src phosphorylation correlates with ADAM28 co-expression in human tumor tissues.","method":"Oncogene-transformed MDCK cells, kinase inhibitors (Src, MEK, PI3K, mTOR), RT-PCR, immunoblotting, IHC of human tumor tissues, in vivo tumor suppression by anti-ADAM28 antibody","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — multiple inhibitor approaches, in vivo validation, pathway epistasis established","pmids":["24007880"],"is_preprint":false},{"year":2016,"finding":"ADAM28 is expressed in normal epithelial cells (epididymis, bronchus, stomach) where it binds and cleaves C1q; ADAM28 cleavage of C1q attenuates C1q-induced apoptosis (via p38/caspase-3) and cell death with autophagy (via LC3-II/autophagosome accumulation) in bronchial epithelial cells. C1q was identified as an ADAM28-binding protein by yeast two-hybrid and confirmed by binding assay, immunoprecipitation, and surface plasmon resonance.","method":"Yeast two-hybrid, protein binding assay, co-immunoprecipitation, surface plasmon resonance, siRNA knockdown, recombinant ADAM28 pre-treatment, apoptosis/autophagy assays","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple binding confirmation methods (SPR, IP, binding assay), functional siRNA and recombinant protein rescue","pmids":["26918856"],"is_preprint":false},{"year":2017,"finding":"CD19 controls differentiation of marginal zone precursor (MZP) cells to MZ B cells by suppressing Foxo1, which in turn upregulates ADAM28 expression; ADAM28 mediates cleavage of Notch2, enabling MZP-to-MZ B cell differentiation.","method":"CD19-deficient mice, CD19 rescue transfection, Notch2 cleavage assay, ADAM28 expression analysis in MZP cells","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — genetic (CD19 KO) with mechanistic rescue and Notch2 cleavage readout, single lab","pmids":["28707394"],"is_preprint":false},{"year":2017,"finding":"ADAM28 localizes to HLA-G+ distal column trophoblasts in first-trimester placenta; siRNA-mediated loss of ADAM28 impairs trophoblast column outgrowth and increases apoptosis in matrix-invading trophoblasts in placental explant cultures.","method":"qPCR, immunofluorescence microscopy, siRNA knockdown in Matrigel-embedded placental explant cultures, apoptosis assay","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization with functional loss-of-function, single lab","pmids":["28623976"],"is_preprint":false},{"year":2018,"finding":"ADAM28 promotes AML leukemic cell proliferation, migration, and invasion through IGFBP-3 degradation and enhanced IGF-I-induced proliferation; ADAM28 knockout in HL-60 cells reduces growth and dissemination in xenotransplantation mouse models.","method":"ADAM28 overexpression/knockdown/knockout, IGFBP-3 cleavage assay, IGF-I stimulation, xenotransplantation mouse model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — KO in vivo model plus mechanistic substrate cleavage, single lab","pmids":["30429106"],"is_preprint":false},{"year":2018,"finding":"Anti-ADAM28 neutralizing antibody 211-14 (KD = 94.7 pmol/L) binds the junctional region between the cysteine-rich domain and the secreted-specific domain of ADAM28s; it inhibits IGF-1-stimulated proliferation and promotes VWF-induced cell death in lung adenocarcinoma cells, and reduces tumor growth and metastasis in lung metastasis mouse models.","method":"Antibody epitope mapping, IC50 determination, KD measurement, cell proliferation assay, VWF-induced cell death assay, mouse lung metastasis model","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 — epitope mapping, multiple functional readouts, in vivo efficacy, rigorous controls","pmids":["30190423"],"is_preprint":false},{"year":2018,"finding":"EBNA3C (Epstein-Barr virus) represses the ADAM28-ADAMDEC1 locus in transformed B cells by interacting with the histone lysine demethylase KDM2B, which removes the activating H3K4me3 mark; EBNA3C also recruits Polycomb proteins to deposit repressive H3K27me3, demonstrating two distinct epigenetic mechanisms of ADAM28 locus silencing.","method":"Recombinant EBV with EBNA3C RBPJ-interaction motif mutations, gene expression analysis, chromatin immunoprecipitation (ChIP) for H3K27me3, H3K4me3, BMI1, SUZ12, KDM2B","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 — ChIP with multiple histone marks, genetic rescue with mutant viruses; mechanistic dissection of two distinct repression pathways","pmids":["30135119"],"is_preprint":false},{"year":2019,"finding":"miR-198 directly targets the ADAM28 3'-UTR to suppress ADAM28 expression, and overexpression of ADAM28 blocks JAK/STAT pathway activation, linking ADAM28 to JAK-STAT signaling in colorectal cancer cells.","method":"Luciferase reporter assay (miR-198 binding to ADAM28 3'-UTR), Western blot for JAK/STAT proteins, ADAM28 rescue overexpression","journal":"European review for medical and pharmacological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — luciferase validation of target plus pathway protein readout, single lab","pmids":["30840270"],"is_preprint":false},{"year":2021,"finding":"ADAM28 from both gastric cancer cells and vascular endothelial cells (HUVECs) cleaves VWF, preventing VWF-induced apoptosis of gastric cancer cells; knockdown of ADAM28 in HUVECs increases VWF in conditioned medium and raises integrin β3, p-TP53 and cleaved caspase-3 in co-cultured gastric cancer cells.","method":"ADAM28 overexpression/knockdown, co-culture system, ELISA for VWF, Western blot for apoptosis markers, MTT/wound healing/flow cytometry assays","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — co-culture mechanistic model with gain/loss of function, single lab","pmids":["33675784"],"is_preprint":false},{"year":2022,"finding":"NEAT1 lncRNA sponges miR-128-3p to upregulate ADAM28 expression; ADAM28 activates JAK2/STAT3 signaling (as shown by increased phospho-JAK2/STAT3), promoting autophagy and suppressing apoptosis in NSCLC cells; miR-128-3p overexpression-induced apoptosis is rescued by ADAM28 re-expression.","method":"Dual-luciferase reporter assay (NEAT1-miR-128-3p and miR-128-3p-ADAM28 3'-UTR), Western blot for p-JAK2/p-STAT3/autophagy proteins, siRNA/overexpression, in vivo xenograft","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 3 — luciferase validation plus pathway protein readout; pathway placement is indirect, single lab","pmids":["36054559"],"is_preprint":false},{"year":2023,"finding":"ADAM28 promotes M1 macrophage polarization in non-eosinophilic chronic rhinosinusitis with nasal polyps; ADAM28 knockdown in THP-1 macrophages reduces M1 marker expression and, via conditioned medium experiments, decreases EMT (restores E-cadherin, reduces α-SMA) and improves tight junction protein expression in nasal epithelial cells.","method":"siRNA knockdown in THP-1 macrophages, M1 polarization markers (Western blot), conditioned medium transfer to HNEPC/pHNECs, EMT and tight junction protein assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with mechanistic cell-to-cell signaling readout, single lab","pmids":["39954661"],"is_preprint":false},{"year":1999,"finding":"ADAM28 (eMDC II) in human and macaque epididymis contains the extended catalytic-centre consensus sequence of a reprolysin-like metalloproteinase, placing it among the catalytically active ADAMs expressed in the male reproductive tract.","method":"cDNA cloning, sequence determination, Northern blot analysis","journal":"Molecular human reproduction","confidence":"Low","confidence_rationale":"Tier 4 — sequence-based prediction only, no enzymatic assay","pmids":["10587367"],"is_preprint":false}],"current_model":"ADAM28 is a catalytically active disintegrin metalloproteinase (zinc-dependent, TIMP-3/4-sensitive but TIMP-1/2-insensitive) that undergoes at least partially autocatalytic pro-domain removal in a late Golgi compartment and can be further activated by MMP-7; it cleaves multiple substrates—IGFBP-3, VWF, CTGF, CD23, CD200, Notch2, TNF-α, and myelin basic protein—to regulate IGF-I bioavailability, cancer cell survival in the vasculature, VEGF165 release, leukocyte adhesion (via PSGL-1/P-selectin), and complement-mediated cell death (via C1q cleavage), while its disintegrin domain mediates integrin α4β1/α4β7 binding to modulate lymphocyte adhesion and transendothelial migration; Src kinase drives ADAM28 transcription through MEK/ERK and PI3K/mTOR pathways in carcinoma cells, and EBV EBNA3C silences the ADAM28 locus via KDM2B-mediated H3K4me3 removal coupled with Polycomb-dependent H3K27me3 deposition."},"narrative":{"teleology":[{"year":1999,"claim":"Cloning of ADAM28 from epididymis revealed a reprolysin-like catalytic consensus, predicting it to be a catalytically active ADAM—setting the stage for functional enzymology.","evidence":"cDNA cloning and sequence analysis from human and macaque epididymis","pmids":["10587367"],"confidence":"Low","gaps":["Sequence prediction only; no enzymatic activity demonstrated","Expression restricted to one tissue at this stage"]},{"year":2000,"claim":"Demonstration that ADAM28 pro-domain removal is autocatalytic (not furin-dependent) in a late Golgi compartment established a unique activation mechanism among ADAMs.","evidence":"Catalytic-site Glu→Ala mutagenesis in COS-7 cells with surface trypsinization and subcellular fractionation","pmids":["10794709"],"confidence":"High","gaps":["Whether additional proteases contribute to activation in vivo","Exact Golgi sub-compartment not determined"]},{"year":2001,"claim":"Two key properties were established: ADAM28 is a zinc metalloproteinase capable of cleaving myelin basic protein and is insensitive to TIMP-1/TIMP-2, while its disintegrin domain binds integrin α4β1 in a divalent-cation-dependent manner—distinguishing its catalytic and adhesive functions.","evidence":"In vitro cleavage assays with mutagenesis (catalytic activity) and Fc-fusion adhesion assays with function-blocking antibodies on transfected K562 cells (integrin binding)","pmids":["11389903","11724793"],"confidence":"High","gaps":["Physiological relevance of MBP cleavage unclear","Other integrin partners not yet surveyed"]},{"year":2003,"claim":"Mapping of the α4β1-binding interface on the disintegrin domain to seven specific residues extending beyond the classical RGD loop, and identification of CD23 as a catalytic substrate, separated the structural determinants of adhesion from those of proteolysis.","evidence":"Charge-to-alanine mutagenesis with Jurkat adhesion assay (binding); synthetic peptide library screening and ectodomain shedding assay (CD23 cleavage)","pmids":["12667064","12777399"],"confidence":"High","gaps":["No crystal structure of the disintegrin domain","Relative contribution of ADAM28 vs. ADAM10/ADAM17 to CD23 shedding in vivo"]},{"year":2004,"claim":"Discovery that MMP-7 activates secreted proADAM28s and that the active enzyme cleaves IGFBP-3 (inhibitable by TIMP-3/TIMP-4) established a proteolytic cascade linking extracellular matrix remodeling to IGF-I signaling.","evidence":"In vitro reconstitution of MMP-7-mediated activation, IGFBP-3 cleavage assay with metalloprotease inhibitor panel","pmids":["15013428"],"confidence":"High","gaps":["In vivo MMP-7-dependent activation not yet shown","Whether other MMPs also activate proADAM28"]},{"year":2006,"claim":"ADAM28-mediated IGFBP-3 cleavage was shown to have direct cancer relevance: siRNA knockdown in breast carcinoma cells reduced IGF-I signaling, proliferation, and xenograft tumor growth, placing ADAM28 as a pro-tumorigenic protease.","evidence":"siRNA knockdown and anti-ADAM28 antibody in MDA-MB231 cells with IGFBP-3 cleavage, IGF-I signaling readout, and xenograft model","pmids":["17047053"],"confidence":"High","gaps":["Contribution of other IGFBP-3-degrading proteases in tumors","Human clinical validation absent"]},{"year":2007,"claim":"Identification of PSGL-1 as a disintegrin domain binding partner that enhances P-selectin-mediated leukocyte adhesion and pulmonary accumulation demonstrated ADAM28's non-catalytic role in inflammation.","evidence":"Yeast two-hybrid confirmed by co-IP, domain binding assays, and in vivo endotoxin inflammation model","pmids":["17597069"],"confidence":"High","gaps":["Whether ADAM28 also cleaves PSGL-1","Relative importance in neutrophil vs. lymphocyte recruitment"]},{"year":2010,"claim":"Discovery that ADAM28 cleaves CTGF at defined bonds to liberate VEGF165 from the CTGF/VEGF complex connected ADAM28 to angiogenic signaling.","evidence":"Yeast two-hybrid, protein binding assay, in vitro cleavage with bond identification, VEGF165 release measurement","pmids":["20971063"],"confidence":"High","gaps":["In vivo angiogenesis readout not performed","Whether ADAM28-released VEGF165 is sufficient to drive neovascularization"]},{"year":2012,"claim":"Two new substrates—VWF and TNF-α—were identified: ADAM28-mediated VWF cleavage protects carcinoma cells from VWF-induced apoptosis during hematogenous metastasis, and ADAM28 contributes to TNF-α ectodomain shedding in macrophages.","evidence":"VWF: yeast two-hybrid, cleavage assay, shRNA/siRNA, neutralizing antibody, xenograft metastasis model; TNF-α: co-IP, ELISA, siRNA in THP-1 cells","pmids":["22636800","23010875"],"confidence":"High","gaps":["Relative contribution of ADAM28 vs. ADAM17 (TACE) to TNF-α shedding","VWF cleavage site not identified"]},{"year":2013,"claim":"Src kinase was identified as a transcriptional inducer of ADAM28 through MEK/ERK and PI3K/mTOR, explaining ADAM28 upregulation in carcinomas and providing a signaling link to oncogenic transformation.","evidence":"Kinase inhibitors in v-src-transformed MDCK cells and human carcinoma lines, RT-PCR, IHC tissue correlation, in vivo anti-ADAM28 antibody tumor suppression","pmids":["24007880"],"confidence":"High","gaps":["Direct transcription factor(s) binding the ADAM28 promoter not identified","Whether Src-independent mechanisms maintain ADAM28 in non-transformed cells"]},{"year":2016,"claim":"Identification of C1q as a physiological ADAM28 substrate in normal epithelia revealed a cytoprotective function: ADAM28 cleavage of C1q attenuates complement-driven apoptosis and autophagy, defining a homeostatic role beyond cancer.","evidence":"Yeast two-hybrid, co-IP, SPR, siRNA knockdown, recombinant ADAM28 pre-treatment with apoptosis/autophagy assays in bronchial epithelial cells","pmids":["26918856"],"confidence":"High","gaps":["Whether C1q cleavage modulates classical complement activation in vivo","Cleavage site in C1q not mapped"]},{"year":2017,"claim":"ADAM28 was linked to Notch2 signaling in B-cell differentiation (MZP→MZ B cells via CD19/Foxo1) and to trophoblast invasion in early placenta, broadening its physiological roles beyond immunity and cancer.","evidence":"CD19-KO mice with Notch2 cleavage assay (B cells); siRNA in placental explant cultures with apoptosis readout (trophoblast)","pmids":["28707394","28623976"],"confidence":"Medium","gaps":["Whether ADAM28 directly cleaves Notch2 or acts indirectly","Redundancy with other Notch-processing ADAMs (ADAM10/17) in MZ B-cell fate"]},{"year":2018,"claim":"Epigenetic silencing of the ADAM28 locus by EBV EBNA3C was mechanistically dissected into two pathways—KDM2B-mediated H3K4me3 removal and Polycomb-dependent H3K27me3 deposition—explaining ADAM28 downregulation in EBV-transformed B cells.","evidence":"Recombinant EBV with EBNA3C mutations, ChIP for H3K4me3, H3K27me3, KDM2B, BMI1, SUZ12","pmids":["30135119"],"confidence":"High","gaps":["Functional consequence of ADAM28 silencing for EBV latency","Whether EBNA3C-dependent silencing is reversible in vivo"]},{"year":2022,"claim":"Multiple studies placed ADAM28 downstream of miRNA/lncRNA regulatory circuits (miR-198, miR-128-3p/NEAT1) and upstream of JAK2/STAT3 signaling, linking ADAM28 to autophagy and apoptosis regulation in solid tumors.","evidence":"Dual-luciferase reporter assays for miRNA–3′-UTR binding, Western blot for p-JAK2/p-STAT3/autophagy markers, siRNA/overexpression with in vivo xenograft","pmids":["30840270","36054559"],"confidence":"Medium","gaps":["Mechanism by which ADAM28 activates JAK2/STAT3 is unknown","Whether the effect is substrate-cleavage-dependent or disintegrin-mediated"]},{"year":null,"claim":"Key unresolved questions include the identity of the transcription factor(s) directly driving ADAM28 promoter activity downstream of Src/MEK/ERK, the structural basis of substrate recognition (no crystal structure exists), the mechanism linking ADAM28 to JAK/STAT activation, and the relative physiological contribution of ADAM28 vs. ADAM10/ADAM17 in Notch2 and TNF-α processing in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of any ADAM28 domain","Direct ADAM28-Notch2 cleavage assay lacking","In vivo ADAM28 knockout phenotype in mammals not reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,5,7,10,12,13,14,16]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[2,3,8,11]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,5,10,12,16]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[5,8,10,12]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[4,8,13,16,25]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,15,22,24]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[17,18]}],"complexes":[],"partners":["ITGA4","ITGB1","SELPLG","IGFBP3","VWF","CTGF","C1QA","TNF"],"other_free_text":[]},"mechanistic_narrative":"ADAM28 is a catalytically active disintegrin metalloproteinase that processes multiple extracellular substrates—including IGFBP-3, VWF, CTGF, CD23, CD200, Notch2, TNF-α, C1q, and myelin basic protein—to regulate IGF-I bioavailability, cancer cell survival, VEGF165 release, complement-mediated cell death, and leukocyte adhesion [PMID:11389903, PMID:15013428, PMID:20971063, PMID:22636800, PMID:26918856, PMID:12777399, PMID:23010875, PMID:28707394]. ADAM28 undergoes autocatalytic pro-domain removal in a late Golgi compartment and can be further activated by MMP-7; its metalloproteinase activity is inhibited by TIMP-3 and TIMP-4 but not TIMP-1 or TIMP-2 [PMID:10794709, PMID:15013428, PMID:11389903]. Its disintegrin domain independently mediates binding to integrin α4β1 on leukocytes and to PSGL-1, promoting lymphocyte adhesion to VCAM-1, transendothelial migration, and P-selectin-dependent leukocyte recruitment during inflammation [PMID:11724793, PMID:12667064, PMID:17597069, PMID:21332445]. Src kinase drives ADAM28 transcription through MEK/ERK and PI3K/mTOR signaling in carcinoma cells, and the ADAM28 locus is epigenetically silenced by EBV EBNA3C via KDM2B-mediated H3K4me3 removal and Polycomb-dependent H3K27me3 deposition [PMID:24007880, PMID:30135119]."},"prefetch_data":{"uniprot":{"accession":"Q9UKQ2","full_name":"Disintegrin and metalloproteinase domain-containing protein 28","aliases":["Epididymal metalloproteinase-like, disintegrin-like, and cysteine-rich protein II","eMDC II","Metalloproteinase-like, disintegrin-like, and cysteine-rich protein L","MDC-L"],"length_aa":775,"mass_kda":87.1,"function":"May play a role in the adhesive and proteolytic events that occur during lymphocyte emigration or may function in ectodomain shedding of lymphocyte surface target proteins, such as FASL and CD40L. May be involved in sperm maturation","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q9UKQ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM28","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADAM28","total_profiled":1310},"omim":[{"mim_id":"607310","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 7; ADAM7","url":"https://www.omim.org/entry/607310"},{"mim_id":"606393","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN-LIKE PROTEIN DECYSIN 1; ADAMDEC1","url":"https://www.omim.org/entry/606393"},{"mim_id":"606188","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 28; ADAM28","url":"https://www.omim.org/entry/606188"},{"mim_id":"144755","title":"HYPEROSTOSIS CRANIALIS INTERNA; HCIN","url":"https://www.omim.org/entry/144755"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"epididymis","ntpm":336.5},{"tissue":"stomach 1","ntpm":103.8}],"url":"https://www.proteinatlas.org/search/ADAM28"},"hgnc":{"alias_symbol":["eMDCII","MDC-Lm","MDC-Ls","ADAM23"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKQ2","domains":[{"cath_id":"-","chopping":"19-38_53-75_106-160","consensus_level":"medium","plddt":81.8553,"start":19,"end":160},{"cath_id":"3.40.390.10","chopping":"169-176_202-396","consensus_level":"high","plddt":85.7848,"start":169,"end":396},{"cath_id":"3.40.1620.60","chopping":"496-629","consensus_level":"high","plddt":88.069,"start":496,"end":629}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKQ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKQ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKQ2-F1-predicted_aligned_error_v6.png","plddt_mean":75.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM28","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM28"},"sequence":{"accession":"Q9UKQ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKQ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKQ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKQ2"}},"corpus_meta":[{"pmid":"12777399","id":"PMC_12777399","title":"Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12777399","citation_count":147,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17047053","id":"PMC_17047053","title":"ADAM28 is overexpressed in human breast carcinomas: implications for carcinoma cell proliferation through cleavage of insulin-like growth factor binding protein-3.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17047053","citation_count":106,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10794709","id":"PMC_10794709","title":"Cloning and characterization of ADAM28: evidence for autocatalytic pro-domain removal and for cell surface localization of mature ADAM28.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10794709","citation_count":99,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15013428","id":"PMC_15013428","title":"ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15013428","citation_count":95,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18974846","id":"PMC_18974846","title":"LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11.","date":"2008","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18974846","citation_count":94,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22636800","id":"PMC_22636800","title":"Effect of ADAM28 on carcinoma cell metastasis by cleavage of von Willebrand factor.","date":"2012","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/22636800","citation_count":79,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19796686","id":"PMC_19796686","title":"LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology.","date":"2009","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/19796686","citation_count":77,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16052521","id":"PMC_16052521","title":"ADAM28 is overexpressed in human non-small cell lung carcinomas and correlates with cell proliferation and lymph node metastasis.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16052521","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17284367","id":"PMC_17284367","title":"Methylation profile of genes CDKN2A (p14 and p16), DAPK1, CDH1, and ADAM23 in head and neck cancer.","date":"2007","source":"Cancer genetics and cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/17284367","citation_count":70,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16103878","id":"PMC_16103878","title":"ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation.","date":"2005","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/16103878","citation_count":59,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11389903","id":"PMC_11389903","title":"Catalytic activity of ADAM28.","date":"2001","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/11389903","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10433968","id":"PMC_10433968","title":"Cloning and chromosomal mapping of mouse ADAM11, ADAM22 and ADAM23.","date":"1999","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10433968","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33682697","id":"PMC_33682697","title":"CircRNA_100565 contributes to cisplatin resistance of NSCLC cells by regulating proliferation, apoptosis and autophagy via miR-337-3p/ADAM28 axis.","date":"2021","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/33682697","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35634306","id":"PMC_35634306","title":"CD20+CD22+ADAM28+ B Cells in Tertiary Lymphoid Structures Promote Immunotherapy Response.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35634306","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14661055","id":"PMC_14661055","title":"Epigenetic silencing of the adhesion molecule ADAM23 is highly frequent in breast tumors.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14661055","citation_count":51,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19549921","id":"PMC_19549921","title":"ADAM23 negatively modulates alpha(v)beta(3) integrin activation during metastasis.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19549921","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15883027","id":"PMC_15883027","title":"Molecular, biochemical, and cellular characterization of epididymal ADAMs, ADAM7 and ADAM28.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15883027","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30598502","id":"PMC_30598502","title":"ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment.","date":"2019","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30598502","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17597069","id":"PMC_17597069","title":"Binding of ADAM28 to P-selectin glycoprotein ligand-1 enhances P-selectin-mediated leukocyte adhesion to endothelial cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17597069","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15505805","id":"PMC_15505805","title":"ADAM23 is a cell-surface glycoprotein expressed by central nervous system neurons.","date":"2004","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/15505805","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20971063","id":"PMC_20971063","title":"Connective tissue growth factor is a substrate of ADAM28.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20971063","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23643150","id":"PMC_23643150","title":"Ectodomain shedding of CD200 from the B-CLL cell surface is regulated by ADAM28 expression.","date":"2013","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/23643150","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25620615","id":"PMC_25620615","title":"CXCL12 and ADAM23 hypermethylation are associated with advanced breast cancers.","date":"2015","source":"Translational research : the journal of laboratory and clinical medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25620615","citation_count":30,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22405860","id":"PMC_22405860","title":"Leucine-rich glioma inactivated 3 regulates adipogenesis through ADAM23.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22405860","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20112342","id":"PMC_20112342","title":"ADAM28 is a serological and histochemical marker for non-small-cell lung cancers.","date":"2010","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20112342","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21782798","id":"PMC_21782798","title":"Characterization of ADAM28 as a biomarker of bladder transitional cell carcinomas by urinary proteome analysis.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21782798","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19089928","id":"PMC_19089928","title":"Promoter hypermethylation of the ADAM23 gene in colorectal cancer cell lines and cancer tissues.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19089928","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26800504","id":"PMC_26800504","title":"ADAM23 is downregulated in side population and suppresses lung metastasis of lung carcinoma cells.","date":"2016","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/26800504","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30840270","id":"PMC_30840270","title":"MiR-198 affects the proliferation and apoptosis of colorectal cancer through regulation of ADAM28/JAK-STAT signaling pathway.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30840270","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21332445","id":"PMC_21332445","title":"Modulation of integrin α4β1 by ADAM28 promotes lymphocyte adhesion and transendothelial migration.","date":"2011","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/21332445","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35003396","id":"PMC_35003396","title":"Mechanism and Role of the Neuropeptide LGI1 Receptor ADAM23 in Regulating Biomarkers of Ferroptosis and Progression of Esophageal Cancer.","date":"2021","source":"Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/35003396","citation_count":25,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36054559","id":"PMC_36054559","title":"LncRNA NEAT1 induces autophagy through the miR-128-3p/ADAM28 axis to suppress apoptosis of nonsmall-cell lung cancer.","date":"2022","source":"The Kaohsiung journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36054559","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27317750","id":"PMC_27317750","title":"Dendritic cell expression of ADAM23 governs T cell proliferation and cytokine production through the α(v)β(3) integrin receptor.","date":"2016","source":"Journal of leukocyte biology","url":"https://pubmed.ncbi.nlm.nih.gov/27317750","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23010875","id":"PMC_23010875","title":"ADAM28 is elevated in humans with the metabolic syndrome and is a novel sheddase of human tumour necrosis factor-α.","date":"2012","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23010875","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19601836","id":"PMC_19601836","title":"ADAM28 as a target for human cancers.","date":"2009","source":"Current pharmaceutical design","url":"https://pubmed.ncbi.nlm.nih.gov/19601836","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26084559","id":"PMC_26084559","title":"Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene.","date":"2015","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/26084559","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30371220","id":"PMC_30371220","title":"ADAM23 in Cardiomyocyte Inhibits Cardiac Hypertrophy by Targeting FAK - AKT Signaling.","date":"2018","source":"Journal of the American Heart Association","url":"https://pubmed.ncbi.nlm.nih.gov/30371220","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28143391","id":"PMC_28143391","title":"ADAM23 is a common risk gene for canine idiopathic epilepsy.","date":"2017","source":"BMC genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28143391","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24662834","id":"PMC_24662834","title":"Intratumoral heterogeneity of ADAM23 promotes tumor growth and metastasis through LGI4 and nitric oxide signals.","date":"2014","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/24662834","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27760137","id":"PMC_27760137","title":"Secretion-Positive LGI1 Mutations Linked to Lateral Temporal Epilepsy Impair Binding to ADAM22 and ADAM23 Receptors.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27760137","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21913264","id":"PMC_21913264","title":"Urinary protein profiling by liquid chromatography/tandem mass spectrometry: ADAM28 is overexpressed in bladder transitional cell carcinoma.","date":"2011","source":"Rapid communications in mass spectrometry : RCM","url":"https://pubmed.ncbi.nlm.nih.gov/21913264","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20544843","id":"PMC_20544843","title":"ADAM28: a potential oncogene involved in asbestos-related lung adenocarcinomas.","date":"2010","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20544843","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26340916","id":"PMC_26340916","title":"ADAM28 overexpression regulated via the PI3K/Akt pathway is associated with relapse in de novo adult B-cell acute lymphoblastic leukemia.","date":"2015","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/26340916","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26918856","id":"PMC_26918856","title":"ADAM28 is expressed by epithelial cells in human normal tissues and protects from C1q-induced cell death.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/26918856","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30429106","id":"PMC_30429106","title":"ADAM28 promotes tumor growth and dissemination of acute myeloid leukemia through IGFBP-3 degradation and IGF-I-induced cell proliferation.","date":"2018","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/30429106","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15862898","id":"PMC_15862898","title":"ADAM23 methylation and expression analysis in brain tumors.","date":"2005","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15862898","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21329817","id":"PMC_21329817","title":"ADAM28 manipulates proliferation, differentiation, and apoptosis of human dental pulp stem cells.","date":"2011","source":"Journal of endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/21329817","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28828010","id":"PMC_28828010","title":"ADAM23 promotes neuronal differentiation of human neural progenitor cells.","date":"2017","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/28828010","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33675784","id":"PMC_33675784","title":"ADAM28 from both endothelium and gastric cancer cleaves von Willebrand Factor to eliminate von Willebrand Factor-induced apoptosis of gastric cancer cells.","date":"2021","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33675784","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32861707","id":"PMC_32861707","title":"ADAM28: Another ambivalent protease in cancer.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/32861707","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36828548","id":"PMC_36828548","title":"LGI3/2-ADAM23 interactions cluster Kv1 channels in myelinated axons to regulate refractory period.","date":"2023","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/36828548","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17333391","id":"PMC_17333391","title":"ADAM23 plays multiple roles in neuronal differentiation of P19 embryonal carcinoma cells.","date":"2007","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/17333391","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30189837","id":"PMC_30189837","title":"Decreased methylation in the SNAI2 and ADAM23 genes associated with de-differentiation and haematogenous dissemination in breast cancers.","date":"2018","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30189837","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29254295","id":"PMC_29254295","title":"Serum levels of ADAM10, ADAM12, ADAM17 AND ADAM28 in colorectal cancer patients.","date":"2017","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/29254295","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30965109","id":"PMC_30965109","title":"ADAM23 is a negative regulator of Kv1.1/Kv1.4 potassium currents.","date":"2019","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/30965109","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16836973","id":"PMC_16836973","title":"ADAM28 participates in the regulation of tooth development.","date":"2006","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/16836973","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21429053","id":"PMC_21429053","title":"The expression of ADAM23 and its correlation with promoter methylation in non-small-cell lung carcinoma.","date":"2011","source":"International journal of experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21429053","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28707394","id":"PMC_28707394","title":"CD19 regulates ADAM28-mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28707394","citation_count":12,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30190423","id":"PMC_30190423","title":"Selective Inhibition of ADAM28 Suppresses Lung Carcinoma Cell Growth and Metastasis.","date":"2018","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/30190423","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19477226","id":"PMC_19477226","title":"Characterization of a specific interaction between ADAM23 and cellular prion protein.","date":"2009","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/19477226","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28430139","id":"PMC_28430139","title":"The Metalloproteinase ADAM28 Promotes Metabolic Dysfunction in Mice.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28430139","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18690470","id":"PMC_18690470","title":"Essential role of ADAM28 in regulating the proliferation and differentiation of human dental papilla mesenchymal cells (hDPMCs).","date":"2008","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18690470","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38194969","id":"PMC_38194969","title":"Oligodendrocyte-derived LGI3 and its receptor ADAM23 organize juxtaparanodal Kv1 channel clustering for short-term synaptic plasticity.","date":"2024","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/38194969","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30647853","id":"PMC_30647853","title":"Microenvironment-derived ADAM28 prevents cancer dissemination.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30647853","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23527725","id":"PMC_23527725","title":"Expression of ADAM28 and IGFBP-3 genes in patients with colorectal cancer - a preliminary report.","date":"2013","source":"International journal of immunopathology and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23527725","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19527685","id":"PMC_19527685","title":"All-trans retinoic acid-induced ADAM28 degrades proteoglycans in human chondrocytes.","date":"2009","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/19527685","citation_count":10,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24007880","id":"PMC_24007880","title":"Src plays a key role in ADAM28 expression in v-src-transformed epithelial cells and human carcinoma cells.","date":"2013","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24007880","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30135119","id":"PMC_30135119","title":"Epstein-Barr Virus Nuclear Antigen 3C Inhibits Expression of COBLL1 and the ADAM28-ADAMDEC1 Locus via Interaction with the Histone Lysine Demethylase KDM2B.","date":"2018","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/30135119","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"14697522","id":"PMC_14697522","title":"Two novel isoforms of Adam23 expressed in the developmental process of mouse and human brains.","date":"2004","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/14697522","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38148887","id":"PMC_38148887","title":"Identification of ADAM23 as a Potential Signature for Psoriasis Using Integrative Machine-Learning and Experimental Verification.","date":"2023","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38148887","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32782619","id":"PMC_32782619","title":"MicroRNA-574-3p inhibits the malignant behavior of liver cancer cells by targeting ADAM28.","date":"2020","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/32782619","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26078788","id":"PMC_26078788","title":"Differential Expression of ADAM23, CDKN2A (P16), MMP14 and VIM Associated with Giant Cell Tumor of Bone.","date":"2015","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26078788","citation_count":7,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22973984","id":"PMC_22973984","title":"ADAM23 knockdown promotes neuronal differentiation of P19 embryonal carcinoma cells by up-regulating P27KIP1 expression.","date":"2012","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/22973984","citation_count":6,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28623976","id":"PMC_28623976","title":"ADAM28 localizes to HLA-G+ trophoblasts and promotes column cell outgrowth.","date":"2017","source":"Placenta","url":"https://pubmed.ncbi.nlm.nih.gov/28623976","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36685493","id":"PMC_36685493","title":"Role for the metalloproteinase ADAM28 in the control of airway inflammation, remodelling and responsiveness in asthma.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/36685493","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19580958","id":"PMC_19580958","title":"Influence of ADAM28 on biological characteristics of human dental follicle cells.","date":"2009","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/19580958","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20851106","id":"PMC_20851106","title":"SP1 acts as a key factor, contributes to upregulation of ADAM23 expression under serum deprivation.","date":"2010","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/20851106","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33296662","id":"PMC_33296662","title":"Endocytosis of the non-catalytic ADAM23: Recycling and long half-life properties.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33296662","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22937229","id":"PMC_22937229","title":"ADAM23, a Gene Related to LGI1, Is Not Linked to Autosomal Dominant Lateral Temporal Epilepsy.","date":"2010","source":"Epilepsy research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/22937229","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29792904","id":"PMC_29792904","title":"Monoclonal Antibody DL11C8 Identifies ADAM23 as a Component of Lipid Raft Microdomains.","date":"2018","source":"Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29792904","citation_count":2,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40455867","id":"PMC_40455867","title":"Biallelic LGI1 and ADAM23 variants cause hippocampal epileptic encephalopathy via the LGI1-ADAM22/23 pathway.","date":"2025","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/40455867","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40252142","id":"PMC_40252142","title":"Research progress on ADAM28 in malignant tumors.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40252142","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25130845","id":"PMC_25130845","title":"[Research advances on ADAM28 expression and ADAM28-mediated tumor metastasis].","date":"2014","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/25130845","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38024245","id":"PMC_38024245","title":"A novel program of infiltrative control in astrocytomas: ADAM23 depletion promotes cell invasion by activating γ-secretase complex.","date":"2023","source":"Neuro-oncology advances","url":"https://pubmed.ncbi.nlm.nih.gov/38024245","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19907862","id":"PMC_19907862","title":"[Effects of ADAM28 AS-ODN on proliferation, differentiation and apoptosis of HPDLSC].","date":"2009","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/19907862","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30552542","id":"PMC_30552542","title":"ADAM28 dramatically regulates the biological features of human gingival fibroblasts.","date":"2018","source":"Odontology","url":"https://pubmed.ncbi.nlm.nih.gov/30552542","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17268172","id":"PMC_17268172","title":"Genomic organization of the region spanning D14Mit262 and D14Mit86 on mouse chromosome 14 and exclusion of Adam28 and Adamdec1 as the cataract-causing gene, lr2.","date":"2007","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/17268172","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36927684","id":"PMC_36927684","title":"Differential Expressions of ADAM28 and ADAMTSL3 in Gingival Tissue of Patients with Periodontitis.","date":"2023","source":"The Tohoku journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36927684","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39954661","id":"PMC_39954661","title":"ADAM28 promotes epithelial mesenchymal transition and impairs tight junctions in non-eosinophilic chronic rhinosinusitis with nasal polyps by inducing M1 polarization of macrophages.","date":"2025","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39954661","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40519920","id":"PMC_40519920","title":"Case Report: Anti-ADAM23 antibody: an overlooked autoantibody against VGKC-complex in autoimmune encephalitis.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40519920","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33543212","id":"PMC_33543212","title":"[Construction of ADAM28 shRNA interference vector and its inhibitory effect on human periodontal ligament stem cells].","date":"2020","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/33543212","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41568889","id":"PMC_41568889","title":"Species-Specific Parent-Of-Origin Expression of Adam23 in the Mammalian Brain.","date":"2026","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/41568889","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16685358","id":"PMC_16685358","title":"[Effects of ADAM28 AS-ODN on proliferation and AKPase of HDFCs].","date":"2006","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/16685358","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20635038","id":"PMC_20635038","title":"[Effects of ADAM28 on biological functions of human dental pulp stem cells].","date":"2010","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/20635038","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41677656","id":"PMC_41677656","title":"Epitranscriptomic Regulation of Platinum Resistance via the METTL3-ADAM23 Axis in Ovarian Cancer.","date":"2026","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41677656","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25543593","id":"PMC_25543593","title":"[The effects of ADAM28 AS-ODN on biological function of human gingival fibroblasts].","date":"2014","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/25543593","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18661070","id":"PMC_18661070","title":"[The effects of ADAM28 on HDPC biological characteristics].","date":"2008","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/18661070","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17924028","id":"PMC_17924028","title":"[The construction of ADAM28 eukaryotic expression plasmid and expression after transfected into HDFC].","date":"2007","source":"Shanghai kou qiang yi xue = Shanghai journal of stomatology","url":"https://pubmed.ncbi.nlm.nih.gov/17924028","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40865352","id":"PMC_40865352","title":"ADAM23 haploinsufficiency as a putative oligogenic contributor in an individual with focal epilepsy.","date":"2025","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/40865352","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"41020821","id":"PMC_41020821","title":"Histone-, Receptor-, and Integrin-Related Gene Products and ADAM28 as Relevant to B-Cell Acute Lymphoblastic Leukemia (B-ALL).","date":"2025","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/41020821","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20881960","id":"PMC_20881960","title":"Hundreds of variants clustered in genomic loci and biological pathways affect human height.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20881960","citation_count":1451,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10737800","id":"PMC_10737800","title":"Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10737800","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11724793","id":"PMC_11724793","title":"The lymphocyte metalloprotease MDC-L (ADAM 28) is a ligand for the integrin alpha4beta1.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11724793","citation_count":70,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29987050","id":"PMC_29987050","title":"Estrogen-regulated feedback loop limits the efficacy of estrogen receptor-targeted breast cancer therapy.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29987050","citation_count":59,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10506182","id":"PMC_10506182","title":"MDC-L, a novel metalloprotease disintegrin cysteine-rich protein family member expressed by human lymphocytes.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10506182","citation_count":58,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19054571","id":"PMC_19054571","title":"Polymorphisms in genes involved in neurodevelopment may be associated with altered brain morphology in schizophrenia: preliminary evidence.","date":"2008","source":"Psychiatry research","url":"https://pubmed.ncbi.nlm.nih.gov/19054571","citation_count":52,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27661126","id":"PMC_27661126","title":"MicroRNA-552 enhances metastatic capacity of colorectal cancer cells by targeting a disintegrin and metalloprotease 28.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27661126","citation_count":36,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31602160","id":"PMC_31602160","title":"Oncogenic ADAM28 induces gemcitabine resistance and predicts a poor prognosis in pancreatic cancer.","date":"2019","source":"World journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31602160","citation_count":30,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23284306","id":"PMC_23284306","title":"A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells.","date":"2012","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23284306","citation_count":29,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12667064","id":"PMC_12667064","title":"Integrin alpha4beta1-dependent adhesion to ADAM 28 (MDC-L) requires an extended surface of the disintegrin domain.","date":"2003","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12667064","citation_count":28,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37827155","id":"PMC_37827155","title":"Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability.","date":"2023","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/37827155","citation_count":23,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36724073","id":"PMC_36724073","title":"Sequential genome-wide CRISPR-Cas9 screens identify genes regulating cell-surface expression of tetraspanins.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/36724073","citation_count":20,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25453333","id":"PMC_25453333","title":"The roles of ADAM33, ADAM28, IL-13 and IL-4 in the development of lung injuries in children with lethal non-pandemic acute infectious pneumonia.","date":"2014","source":"Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology","url":"https://pubmed.ncbi.nlm.nih.gov/25453333","citation_count":18,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10587367","id":"PMC_10587367","title":"Identification, sequence analysis and expression of transcripts encoding a putative metalloproteinase, eMDC II, in human and macaque epididymis.","date":"1999","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/10587367","citation_count":16,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29969578","id":"PMC_29969578","title":"SUMO-specific protease 2 (SENP2) suppresses keratinocyte migration by targeting NDR1 for de-SUMOylation.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29969578","citation_count":14,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21698479","id":"PMC_21698479","title":"A proteomic approach for identification and localization of the pericellular components of chondrocytes.","date":"2011","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/21698479","citation_count":13,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27749584","id":"PMC_27749584","title":"Overexpression and knock-down studies highlight that a disintegrin and metalloproteinase 28 controls proliferation and migration in human prostate cancer.","date":"2016","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27749584","citation_count":12,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19896699","id":"PMC_19896699","title":"Overexpression of A disintegrin and metalloproteinase 28 is correlated with high histologic grade in conventional chondrosarcoma.","date":"2009","source":"Human pathology","url":"https://pubmed.ncbi.nlm.nih.gov/19896699","citation_count":11,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23640157","id":"PMC_23640157","title":"Localization of the gene for hyperostosis cranialis interna to chromosome 8p21 with analysis of three candidate genes.","date":"2013","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/23640157","citation_count":9,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20450360","id":"PMC_20450360","title":"The regulatory role of a disintegrin and metalloproteinase 28 on the biologic property of human periodontal ligament stem cells.","date":"2010","source":"Journal of periodontology","url":"https://pubmed.ncbi.nlm.nih.gov/20450360","citation_count":5,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21077327","id":"PMC_21077327","title":"[ADAM28: involvement in cancer cell proliferation, invasion and metastasis].","date":"2010","source":"Seikagaku. The Journal of Japanese Biochemical Society","url":"https://pubmed.ncbi.nlm.nih.gov/21077327","citation_count":2,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48366,"output_tokens":4503,"usd":0.106321},"stage2":{"model":"claude-opus-4-6","input_tokens":8033,"output_tokens":3951,"usd":0.20841},"total_usd":0.67942,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60736,"output_tokens":6806,"usd":0.142149},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":10532,"output_tokens":3828,"usd":0.22254}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"ADAM28 undergoes autocatalytic pro-domain removal: a catalytic-site glutamate-to-alanine mutation abolishes pro-domain removal even though the mutant is transported to the cell surface normally, indicating maturation is at least partly autocatalytic (distinct from furin-dependent ADAMs). Mature ADAM28 localizes predominantly to the cell surface.\",\n      \"method\": \"Site-directed mutagenesis of catalytic glutamate; cell-surface trypsinization; immunoblotting of COS-7 transfectants\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis + functional readout in a rigorous single-paper study\",\n      \"pmids\": [\"10794709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Recombinant ADAM28 cleaves myelin basic protein at two sites; catalytic activity is abolished by a catalytic-site mutation and is insensitive to TIMP-1 and TIMP-2.\",\n      \"method\": \"In vitro proteolytic assay with recombinant ADAM28; catalytic-site mutagenesis; TIMP inhibition assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro enzymatic assay with mutagenesis confirmation\",\n      \"pmids\": [\"11389903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAM28 (MDC-L) catalyzes ectodomain shedding of CD23 (low-affinity IgE receptor) from the cell surface; this activity requires a functional metalloprotease active site and has a substrate specificity distinct from ADAM17.\",\n      \"method\": \"Synthetic peptide substrate library screening; ectodomain shedding assay with recombinant enzyme; hydroxamic acid metalloprotease inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted shedding assay with inhibitor controls, replicated across multiple ADAMs\",\n      \"pmids\": [\"12777399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ProADAM28s (secreted isoform) is activated by MMP-7 (matrilysin-1) cleavage, removing the propeptide to yield 42/40 kDa active forms. Active ADAM28s cleaves IGFBP-3 in both free and IGF-I/IGF-II-complexed forms; cleavage is blocked by EDTA, 1,10-phenanthroline, KB-R7785, TIMP-3, and TIMP-4.\",\n      \"method\": \"In vitro protease activation assay; immunoblotting; metalloprotease inhibitor panel\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro activation and substrate cleavage with multiple inhibitor controls\",\n      \"pmids\": [\"15013428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM28 is overexpressed in breast carcinoma cells and promotes cell proliferation by cleaving IGFBP-3, thereby increasing bioavailable IGF-I. siRNA knockdown of ADAM28 reduces IGFBP-3 cleavage, IGF-I signaling, cell proliferation, and xenograft tumor growth.\",\n      \"method\": \"siRNA knockdown; anti-ADAM28 antibody inhibition; ADAM inhibitor treatment; xenograft mouse model; immunoblotting for IGFBP-3 cleavage\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal KD/inhibition approaches with defined molecular readout (IGFBP-3 cleavage) and in vivo validation\",\n      \"pmids\": [\"17047053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The disintegrin-like domain of secreted ADAM28s binds P-selectin glycoprotein ligand-1 (PSGL-1); this interaction enhances P-selectin-mediated leukocyte rolling adhesion to endothelial cells and promotes leukocyte accumulation in the pulmonary microcirculation in an endotoxin inflammation model.\",\n      \"method\": \"Yeast two-hybrid screen; domain-specific recombinant protein binding assays; co-immunoprecipitation; co-immunolocalization; in vivo mouse model of inflammation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding confirmed by multiple methods including co-IP, domain mapping, and functional in vivo assay\",\n      \"pmids\": [\"17597069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM28 cleaves connective tissue growth factor (CTGF) at Ala181-Tyr182 and Asp191-Pro192 bonds in the hinge region, selectively releasing biologically active VEGF165 from the CTGF/VEGF165 complex.\",\n      \"method\": \"Yeast two-hybrid screen; protein binding assay; in vitro cleavage assay with site mapping by N-terminal sequencing; immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage with precise site identification, confirmed by binding assays\",\n      \"pmids\": [\"20971063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM28 binds and cleaves von Willebrand factor (VWF), inactivating its pro-apoptotic activity in carcinoma cells; ADAM28 knockdown (shRNA/siRNA) or antibody inhibition increases carcinoma cell apoptosis in blood vessels and significantly reduces lung metastasis in mouse xenograft models.\",\n      \"method\": \"Yeast two-hybrid screen; protein binding assays; immunoblotting for VWF cleavage; shRNA/siRNA knockdown; in vivo xenograft lung metastasis model with bioluminescence imaging\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — substrate identification plus mechanistic in vivo validation with multiple inhibition strategies\",\n      \"pmids\": [\"22636800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM28 co-localizes and co-immunoprecipitates with TNF-α in HEK293 cells; overexpression of ADAM28 promotes TNF-α shedding, which is significantly reduced by siRNA knockdown or pharmacological inhibition of ADAM28. Endogenous ADAM28 in THP-1 macrophages similarly mediates TNF-α shedding.\",\n      \"method\": \"Co-immunoprecipitation; co-localization; siRNA knockdown; pharmacological inhibition; ELISA for soluble TNF-α\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional shedding assay, single lab\",\n      \"pmids\": [\"23010875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM28 mediates ectodomain shedding of CD200 from B-CLL cell surfaces; siRNA knockdown of ADAM28 decreases soluble CD200 release, while ADAM28 overexpression in CD200+ cells increases sCD200 release.\",\n      \"method\": \"siRNA knockdown; ADAM28 overexpression by transfection; measurement of soluble CD200 in culture supernatants\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional gain/loss-of-function with defined molecular readout, single lab\",\n      \"pmids\": [\"23643150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Src kinase induces ADAM28 gene expression in carcinoma cells through the MEK/ERK and PI3K/mTOR signaling pathways; combined inhibition of MEK and PI3K abrogates ADAM28 expression in v-src-transformed cells and human carcinoma lines.\",\n      \"method\": \"Oncogene transformation of MDCK cells; kinase inhibitor panel; immunoblotting; immunohistochemistry for phospho-Src/ADAM28 co-expression in human tumors\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistatic pharmacological dissection with multiple inhibitors and cellular models\",\n      \"pmids\": [\"24007880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM28 disintegrin domain is necessary for proteoglycan-releasing activity in cartilage degradation; all-trans retinoic acid (ATRA) specifically induces ADAM28 expression in chondrocytes, and a disintegrin-domain deletion mutant loses proteoglycan-releasing activity.\",\n      \"method\": \"ATRA stimulation of HCS-2/8 chondrocytes and primary chondrocytes; ADAM28 transfection; disintegrin-domain deletion mutagenesis; proteoglycan release assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion mutagenesis with functional readout, moderate evidence\",\n      \"pmids\": [\"19527685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAM28 binding to integrin α4β1 (via disintegrin domain) unexpectedly enhances α4β1-dependent cell adhesion to VCAM-1 and promotes lymphocyte transendothelial migration.\",\n      \"method\": \"Affymetrix microarray expression profiling; recombinant soluble ADAM28 binding assays; anti-integrin antibody blocking; Mn2+-activation; transendothelial migration assay\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — integrin-ligand interaction validated with multiple antibody/activation approaches plus functional migration assay\",\n      \"pmids\": [\"21332445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM28 mediates Notch2 cleavage in marginal zone precursor (MZP) B cells, and this is regulated by CD19 signaling: CD19 upregulates ADAM28 expression by suppressing Foxo1, and ADAM28-mediated Notch2 cleavage is required for MZP-to-MZ B cell differentiation.\",\n      \"method\": \"CD19-deficient mouse model; CD19 reconstitution rescue experiment; ADAM28 siRNA knockdown; Notch2 cleavage immunoblotting; Foxo1 overexpression/knockdown\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in mouse model with defined molecular cleavage event, single lab\",\n      \"pmids\": [\"28707394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM28 expressed in HLA-G+ trophoblasts promotes column cell outgrowth and survival; siRNA-directed ADAM28 knockdown in placental explant cultures impairs trophoblast column outgrowth and increases apoptosis in matrix-invading trophoblasts.\",\n      \"method\": \"qPCR and immunofluorescence localization; siRNA knockdown in Matrigel-embedded placental explant cultures; apoptosis assay\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — localization tied to functional knockdown phenotype in primary tissue model\",\n      \"pmids\": [\"28623976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Human neutralizing antibody 211-14 targeting the junctison of ADAM28s cysteine-rich/secreted-specific domain inhibits IGF-1-stimulated proliferation and promotes VWF-induced cell death in NSCLC lines; in vivo, the antibody significantly reduces PC-9 tumor growth and metastasis and prolongs survival.\",\n      \"method\": \"Antibody development and epitope mapping; IC50 determination; surface plasmon resonance (KD measurement); cell proliferation assay; lung metastasis mouse model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic inhibition of defined substrates (IGFBP-3, VWF pathways) confirmed in vitro and in vivo with epitope-characterized neutralizing antibody\",\n      \"pmids\": [\"30190423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM28 is expressed in epithelial cells of normal tissues (epididymis, bronchus, stomach); ADAM28 binds and cleaves complement C1q (identified by yeast two-hybrid, confirmed by co-IP and surface plasmon resonance), and this cleavage attenuates C1q-induced apoptosis and autophagic cell death in bronchial epithelial cells.\",\n      \"method\": \"Yeast two-hybrid; protein binding assays; immunoprecipitation; surface plasmon resonance; siRNA knockdown; apoptosis/autophagy assays; recombinant ADAM28 pre-treatment\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel substrate identified and validated by orthogonal binding methods plus functional cell-death assay with KD\",\n      \"pmids\": [\"26918856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM28 from both endothelial cells and gastric cancer cells cleaves VWF, thereby eliminating VWF-induced apoptosis of gastric cancer cells; knockdown of ADAM28 in endothelial cells increases VWF levels in supernatant and raises integrin β3, p-TP53, and c-Casp3 in co-cultured cancer cells.\",\n      \"method\": \"Co-culture system; ADAM28 overexpression/knockdown; ELISA for VWF; Western blot for apoptosis markers; vWF knockdown rescue experiment\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic rescue experiment confirms VWF as the downstream effector, single lab\",\n      \"pmids\": [\"33675784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EBV nuclear antigen 3C (EBNA3C) represses the ADAM28-ADAMDEC1 locus through interaction with histone lysine demethylase KDM2B, which removes the activating H3K4me3 mark, cooperating with Polycomb-mediated H3K27me3 deposition.\",\n      \"method\": \"Recombinant EBV with RBPJ-interaction motif mutations; gene expression analysis; chromatin immunoprecipitation (ChIP) for H3K27me3, H3K4me3, BMI1, SUZ12; co-immunoprecipitation for EBNA3C-KDM2B interaction\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and co-IP establish epigenetic mechanism of ADAM28 repression, single lab\",\n      \"pmids\": [\"30135119\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM28 is a zinc-dependent ADAM metalloprotease that undergoes autocatalytic pro-domain removal and localizes to the cell surface, where its metalloprotease domain cleaves substrates including IGFBP-3 (activated by MMP-7), VWF, CTGF/VEGF complexes, CD23, TNF-α, Notch2, and C1q, while its disintegrin-like domain engages PSGL-1 and integrins α4β1/α4β7/α9β1; collectively these activities promote tumor cell proliferation, survival in the vasculature, and lung metastasis, and modulate leukocyte adhesion and B-cell differentiation. ADAM28 expression in carcinoma cells is driven transcriptionally by the Src–MEK/ERK and Src–PI3K/mTOR pathways, and is epigenetically repressed in normal B cells by EBV EBNA3C via KDM2B-mediated H3K4me3 removal.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper, then extract discoveries only from KEEP papers.\n\n**Classification notes:**\n- Papers about ADAM23, ADAM22, ADAM11, LGI1/LGI3/LGI4 interactions with ADAM22/23 → EXCLUDE (different genes)\n- Papers about ADAM28 (canonical protein) → KEEP\n- circRNA/lncRNA papers that use ADAM28 as a downstream target but describe no ADAM28 mechanism → EXCLUDE or limited KEEP\n- Papers about ADAM23 methylation in cancer → EXCLUDE\n\nKey KEEP papers: [1],[2],[3],[4],[6],[8],[11],[17],[19],[21],[22],[29],[30],[32],[34],[35],[44],[45],[47],[49],[50],[56],[58],[59],[62],[64],[66],[67],[68],[74],[75],[82],[86],[88],[89] and curated papers [8],[10],[12],[13],[15],[18],[19],[21],[22],[23],[24],[25].\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"ADAM28 is synthesized as a precursor and processed to a mature form in a late Golgi compartment; mature ADAM28 localizes to the cell surface. A glutamate-to-alanine mutation in the catalytic site abolishes pro-domain removal even though the mutant is still transported to the cell surface, indicating that pro-domain removal is at least in part autocatalytic—distinct from other ADAMs that rely on furin-like proprotein convertases.\",\n      \"method\": \"COS-7 cell expression, cell-surface trypsinization, site-directed mutagenesis (catalytic-site Glu→Ala)\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with subcellular fractionation and surface trypsinization in a single rigorous study\",\n      \"pmids\": [\"10794709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Recombinant ADAM28 cleaves myelin basic protein at two defined sites; catalytic activity requires an intact catalytic-site glutamate (abolished by point mutation) and is insensitive to TIMP-1 and TIMP-2.\",\n      \"method\": \"In vitro cleavage assay with recombinant protein, site-directed mutagenesis\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis confirmation\",\n      \"pmids\": [\"11389903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The disintegrin domain of ADAM28 (MDC-L) binds the leukocyte integrin α4β1; a 59-residue fragment of the disintegrin domain supports integrin-dependent cell adhesion in a divalent-cation-dependent, function-blocking-antibody-inhibitable manner. Binding requires activation of β1 integrins.\",\n      \"method\": \"Recombinant Fc fusion protein adhesion assay, α4/β1 function-blocking mAbs, transfected K562 cells expressing α4β1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal inhibition, transfection rescue, solution binding assays; replicated with multiple cell lines\",\n      \"pmids\": [\"11724793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Seven specific residues (Lys437, Lys442, Lys455, Lys459, Lys460, Lys469, Glu476) in the ADAM28 disintegrin domain are essential for α4β1-dependent cell adhesion, and molecular modelling places these residues on one face of the domain, extending beyond the classical disintegrin loop.\",\n      \"method\": \"Charge-to-alanine mutagenesis of recombinant disintegrin domain, Jurkat cell adhesion assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with functional readout, structural modelling\",\n      \"pmids\": [\"12667064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAM28 (MDC-L) catalyzes ectodomain shedding of CD23 (the low-affinity IgE receptor) in vitro; this activity requires a catalytically intact enzyme and is distinct from the substrate specificity of ADAM17, as shown by synthetic peptide library screening.\",\n      \"method\": \"Synthetic peptide substrate library screening, ectodomain shedding assay with soluble recombinant enzyme, hydroxamic acid metalloprotease inhibitor\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with defined substrates and inhibitor controls\",\n      \"pmids\": [\"12777399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ProADAM28s (65 kDa secreted form) is activated by MMP-7 (matrilysin-1), which cleaves the propeptide to yield 42- and 40-kDa active forms. Activated ADAM28s cleaves IGFBP-3 in both free and IGF-I/IGF-II-complexed forms; cleavage is blocked by EDTA, 1,10-phenanthroline, KB-R7785, TIMP-3, and TIMP-4.\",\n      \"method\": \"In vitro activation assay (recombinant MMP-7 + proADAM28s), immunoblotting, metalloprotease inhibitors\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution of activation and substrate cleavage with multiple inhibitor controls\",\n      \"pmids\": [\"15013428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Mouse ADAM28 is expressed in an epididymal region-specific manner regulated by testicular factors (not androgen); unlike ADAM7, ADAM28 is not transferred to the sperm surface, indicating distinct functional roles of these two epididymal ADAMs.\",\n      \"method\": \"Region-specific RT-PCR, castration/hormone replacement experiments, protein analysis of sperm fractions\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein localization experiments with hormonal manipulation, single lab\",\n      \"pmids\": [\"15883027\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ADAM28 cleaves IGFBP-3 to enhance IGF-I bioavailability and stimulate breast carcinoma cell proliferation; siRNA knockdown of ADAM28 in MDA-MB231 cells significantly reduces IGFBP-3 cleavage, IGF-I signaling, cell proliferation, and xenograft growth.\",\n      \"method\": \"siRNA knockdown, anti-ADAM28 antibody inhibition, IGFBP-3 cleavage assay, xenograft mouse model, IGF-I signaling readout\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (siRNA, antibody, in vivo xenograft), replicated substrate cleavage\",\n      \"pmids\": [\"17047053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The disintegrin-like domain of secreted ADAM28 (ADAM28s) binds PSGL-1 on leukocytes; this interaction enhances P-selectin-mediated leukocyte adhesion to endothelial cells and increases leukocyte accumulation in pulmonary microcirculation in an endotoxin inflammation mouse model.\",\n      \"method\": \"Yeast two-hybrid screen, domain-specific recombinant protein binding assays, co-immunoprecipitation, adhesion assay to P-selectin-coated wells, in vivo mouse model of endotoxin inflammation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — yeast two-hybrid confirmed by co-IP, domain mapping, and in vivo functional model\",\n      \"pmids\": [\"17597069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"All-trans retinoic acid (ATRA) specifically induces ADAM28 expression in human chondrocytes; ADAM28 overexpression augments proteoglycan release from cartilage, whereas a disintegrin-domain-deleted mutant lacks this activity, demonstrating the disintegrin domain is required for substrate recognition/localization in cartilage degradation.\",\n      \"method\": \"ATRA stimulation of HCS-2/8 chondrosarcoma cells, ADAM28 transfection (full-length and disintegrin-deletion mutant), proteoglycan release assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-deletion mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"19527685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM28 cleaves CTGF at Ala181–Tyr182 and Asp191–Pro192 in the hinge region; this digestion releases biologically active VEGF165 from the CTGF/VEGF165 complex. CTGF was identified as a binding partner of proADAM28 by yeast two-hybrid and confirmed by protein binding assay.\",\n      \"method\": \"Yeast two-hybrid screen, protein binding assay, in vitro cleavage assay with bond identification, VEGF165 release assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro cleavage with specific bond identification, binding confirmed by two independent methods\",\n      \"pmids\": [\"20971063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ADAM28 binding to α4β1 is typical of integrin-ligand interactions (attenuated by anti-α4β1 antibodies, enhanced by Mn2+ and mAb 9EG7); soluble ADAM28 unexpectedly enhances α4β1-dependent cell adhesion to VCAM-1 and promotes lymphocyte transendothelial migration.\",\n      \"method\": \"Affymetrix microarray, RT-PCR, immunohistochemistry, L1-2 cell adhesion assay, transendothelial migration assay, integrin activating/blocking antibodies\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional adhesion and migration assays with integrin controls, single lab\",\n      \"pmids\": [\"21332445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM28 binds and cleaves von Willebrand factor (VWF); carcinoma cells with high ADAM28 expression are resistant to VWF-induced apoptosis, while knockdown of ADAM28 increases apoptosis in lung blood vessels and significantly reduces lung metastasis in xenograft models. VWF was identified as an ADAM28-binding protein by yeast two-hybrid.\",\n      \"method\": \"Yeast two-hybrid screen, protein binding assay, immunoblotting for VWF cleavage, shRNA/siRNA knockdown, anti-ADAM28 neutralizing antibody, xenograft mouse model with in vivo imaging\",\n      \"journal\": \"Journal of the National Cancer Institute\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (yeast two-hybrid, cleavage assay, shRNA, antibody, in vivo), large sample sizes\",\n      \"pmids\": [\"22636800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM28 overexpression in HEK293 cells causes co-localization and co-immunoprecipitation with TNF-α and promotes TNF-α ectodomain shedding; shedding is reduced by siRNA knockdown or pharmacological inhibition of ADAM28. Endogenous ADAM28 in THP-1 macrophages similarly mediates TNF-α shedding.\",\n      \"method\": \"Co-transfection overexpression, co-immunoprecipitation, ELISA for shed TNF-α, siRNA knockdown, pharmacological inhibition\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP confirmed interaction, functional shedding shown with siRNA and inhibitor, replicated in endogenous cell line\",\n      \"pmids\": [\"23010875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM28 mediates ectodomain shedding of CD200 from B-CLL cells; siRNA knockdown of ADAM28 decreases sCD200 release into culture, and transfection of ADAM28 into CD200+ cells enhances sCD200 shedding.\",\n      \"method\": \"siRNA knockdown, ADAM28 gene transfection, measurement of sCD200 by ELISA\",\n      \"journal\": \"Leukemia research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with functional readout, single lab\",\n      \"pmids\": [\"23643150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Src kinase induces ADAM28 gene expression through the MEK/ERK and PI3K/mTOR pathways in v-src-transformed epithelial cells and human carcinoma cell lines; combined inhibition of MEK and PI3K abrogates ADAM28 expression, and Src phosphorylation correlates with ADAM28 co-expression in human tumor tissues.\",\n      \"method\": \"Oncogene-transformed MDCK cells, kinase inhibitors (Src, MEK, PI3K, mTOR), RT-PCR, immunoblotting, IHC of human tumor tissues, in vivo tumor suppression by anti-ADAM28 antibody\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple inhibitor approaches, in vivo validation, pathway epistasis established\",\n      \"pmids\": [\"24007880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM28 is expressed in normal epithelial cells (epididymis, bronchus, stomach) where it binds and cleaves C1q; ADAM28 cleavage of C1q attenuates C1q-induced apoptosis (via p38/caspase-3) and cell death with autophagy (via LC3-II/autophagosome accumulation) in bronchial epithelial cells. C1q was identified as an ADAM28-binding protein by yeast two-hybrid and confirmed by binding assay, immunoprecipitation, and surface plasmon resonance.\",\n      \"method\": \"Yeast two-hybrid, protein binding assay, co-immunoprecipitation, surface plasmon resonance, siRNA knockdown, recombinant ADAM28 pre-treatment, apoptosis/autophagy assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple binding confirmation methods (SPR, IP, binding assay), functional siRNA and recombinant protein rescue\",\n      \"pmids\": [\"26918856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD19 controls differentiation of marginal zone precursor (MZP) cells to MZ B cells by suppressing Foxo1, which in turn upregulates ADAM28 expression; ADAM28 mediates cleavage of Notch2, enabling MZP-to-MZ B cell differentiation.\",\n      \"method\": \"CD19-deficient mice, CD19 rescue transfection, Notch2 cleavage assay, ADAM28 expression analysis in MZP cells\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic (CD19 KO) with mechanistic rescue and Notch2 cleavage readout, single lab\",\n      \"pmids\": [\"28707394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM28 localizes to HLA-G+ distal column trophoblasts in first-trimester placenta; siRNA-mediated loss of ADAM28 impairs trophoblast column outgrowth and increases apoptosis in matrix-invading trophoblasts in placental explant cultures.\",\n      \"method\": \"qPCR, immunofluorescence microscopy, siRNA knockdown in Matrigel-embedded placental explant cultures, apoptosis assay\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional loss-of-function, single lab\",\n      \"pmids\": [\"28623976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM28 promotes AML leukemic cell proliferation, migration, and invasion through IGFBP-3 degradation and enhanced IGF-I-induced proliferation; ADAM28 knockout in HL-60 cells reduces growth and dissemination in xenotransplantation mouse models.\",\n      \"method\": \"ADAM28 overexpression/knockdown/knockout, IGFBP-3 cleavage assay, IGF-I stimulation, xenotransplantation mouse model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO in vivo model plus mechanistic substrate cleavage, single lab\",\n      \"pmids\": [\"30429106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Anti-ADAM28 neutralizing antibody 211-14 (KD = 94.7 pmol/L) binds the junctional region between the cysteine-rich domain and the secreted-specific domain of ADAM28s; it inhibits IGF-1-stimulated proliferation and promotes VWF-induced cell death in lung adenocarcinoma cells, and reduces tumor growth and metastasis in lung metastasis mouse models.\",\n      \"method\": \"Antibody epitope mapping, IC50 determination, KD measurement, cell proliferation assay, VWF-induced cell death assay, mouse lung metastasis model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epitope mapping, multiple functional readouts, in vivo efficacy, rigorous controls\",\n      \"pmids\": [\"30190423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EBNA3C (Epstein-Barr virus) represses the ADAM28-ADAMDEC1 locus in transformed B cells by interacting with the histone lysine demethylase KDM2B, which removes the activating H3K4me3 mark; EBNA3C also recruits Polycomb proteins to deposit repressive H3K27me3, demonstrating two distinct epigenetic mechanisms of ADAM28 locus silencing.\",\n      \"method\": \"Recombinant EBV with EBNA3C RBPJ-interaction motif mutations, gene expression analysis, chromatin immunoprecipitation (ChIP) for H3K27me3, H3K4me3, BMI1, SUZ12, KDM2B\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with multiple histone marks, genetic rescue with mutant viruses; mechanistic dissection of two distinct repression pathways\",\n      \"pmids\": [\"30135119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-198 directly targets the ADAM28 3'-UTR to suppress ADAM28 expression, and overexpression of ADAM28 blocks JAK/STAT pathway activation, linking ADAM28 to JAK-STAT signaling in colorectal cancer cells.\",\n      \"method\": \"Luciferase reporter assay (miR-198 binding to ADAM28 3'-UTR), Western blot for JAK/STAT proteins, ADAM28 rescue overexpression\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase validation of target plus pathway protein readout, single lab\",\n      \"pmids\": [\"30840270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM28 from both gastric cancer cells and vascular endothelial cells (HUVECs) cleaves VWF, preventing VWF-induced apoptosis of gastric cancer cells; knockdown of ADAM28 in HUVECs increases VWF in conditioned medium and raises integrin β3, p-TP53 and cleaved caspase-3 in co-cultured gastric cancer cells.\",\n      \"method\": \"ADAM28 overexpression/knockdown, co-culture system, ELISA for VWF, Western blot for apoptosis markers, MTT/wound healing/flow cytometry assays\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-culture mechanistic model with gain/loss of function, single lab\",\n      \"pmids\": [\"33675784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NEAT1 lncRNA sponges miR-128-3p to upregulate ADAM28 expression; ADAM28 activates JAK2/STAT3 signaling (as shown by increased phospho-JAK2/STAT3), promoting autophagy and suppressing apoptosis in NSCLC cells; miR-128-3p overexpression-induced apoptosis is rescued by ADAM28 re-expression.\",\n      \"method\": \"Dual-luciferase reporter assay (NEAT1-miR-128-3p and miR-128-3p-ADAM28 3'-UTR), Western blot for p-JAK2/p-STAT3/autophagy proteins, siRNA/overexpression, in vivo xenograft\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — luciferase validation plus pathway protein readout; pathway placement is indirect, single lab\",\n      \"pmids\": [\"36054559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAM28 promotes M1 macrophage polarization in non-eosinophilic chronic rhinosinusitis with nasal polyps; ADAM28 knockdown in THP-1 macrophages reduces M1 marker expression and, via conditioned medium experiments, decreases EMT (restores E-cadherin, reduces α-SMA) and improves tight junction protein expression in nasal epithelial cells.\",\n      \"method\": \"siRNA knockdown in THP-1 macrophages, M1 polarization markers (Western blot), conditioned medium transfer to HNEPC/pHNECs, EMT and tight junction protein assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with mechanistic cell-to-cell signaling readout, single lab\",\n      \"pmids\": [\"39954661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"ADAM28 (eMDC II) in human and macaque epididymis contains the extended catalytic-centre consensus sequence of a reprolysin-like metalloproteinase, placing it among the catalytically active ADAMs expressed in the male reproductive tract.\",\n      \"method\": \"cDNA cloning, sequence determination, Northern blot analysis\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 — sequence-based prediction only, no enzymatic assay\",\n      \"pmids\": [\"10587367\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM28 is a catalytically active disintegrin metalloproteinase (zinc-dependent, TIMP-3/4-sensitive but TIMP-1/2-insensitive) that undergoes at least partially autocatalytic pro-domain removal in a late Golgi compartment and can be further activated by MMP-7; it cleaves multiple substrates—IGFBP-3, VWF, CTGF, CD23, CD200, Notch2, TNF-α, and myelin basic protein—to regulate IGF-I bioavailability, cancer cell survival in the vasculature, VEGF165 release, leukocyte adhesion (via PSGL-1/P-selectin), and complement-mediated cell death (via C1q cleavage), while its disintegrin domain mediates integrin α4β1/α4β7 binding to modulate lymphocyte adhesion and transendothelial migration; Src kinase drives ADAM28 transcription through MEK/ERK and PI3K/mTOR pathways in carcinoma cells, and EBV EBNA3C silences the ADAM28 locus via KDM2B-mediated H3K4me3 removal coupled with Polycomb-dependent H3K27me3 deposition.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAM28 is a zinc-dependent metalloprotease of the ADAM family that functions as a cell-surface and secreted sheddase with broad substrate specificity, integrating proteolytic and adhesion-modulatory activities in immunity, tissue homeostasis, and cancer progression. The metalloprotease domain undergoes autocatalytic pro-domain removal and cleaves substrates including IGFBP-3, VWF, CTGF, CD23, TNF-α, Notch2, CD200, and complement C1q, with the secreted isoform additionally activated by MMP-7 [PMID:10794709, PMID:11389903, PMID:15013428, PMID:12777399, PMID:22636800, PMID:26918856]. The disintegrin-like domain engages P-selectin glycoprotein ligand-1 (PSGL-1) and integrin α4β1, enhancing leukocyte rolling adhesion, transendothelial migration, and cartilage proteoglycan release [PMID:17597069, PMID:21332445, PMID:19527685]. In carcinomas, ADAM28 promotes tumor cell proliferation through IGFBP-3 cleavage that liberates bioavailable IGF-I and protects circulating tumor cells from VWF-induced apoptosis to facilitate lung metastasis, with its expression driven by the Src–MEK/ERK and Src–PI3K/mTOR pathways [PMID:17047053, PMID:22636800, PMID:24007880, PMID:30190423].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that ADAM28 matures via autocatalytic pro-domain removal rather than furin-dependent processing resolved how this ADAM is activated and showed mature enzyme reaches the cell surface.\",\n      \"evidence\": \"Catalytic-site Glu→Ala mutagenesis in COS-7 transfectants; cell-surface trypsinization and immunoblotting\",\n      \"pmids\": [\"10794709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of autocatalysis versus other proteases in vivo not determined\", \"Crystal structure of pro-domain/catalytic domain interface unavailable\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrating that recombinant ADAM28 possesses metalloprotease activity insensitive to TIMP-1 and TIMP-2 defined its catalytic competence and unusual inhibitor profile among ADAMs.\",\n      \"evidence\": \"In vitro cleavage of myelin basic protein with catalytic-site mutagenesis and TIMP inhibition panel\",\n      \"pmids\": [\"11389903\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Myelin basic protein is a generic substrate; physiological substrates were not yet identified\", \"Sensitivity to TIMP-3/4 not tested in this study\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of CD23 as a shedding substrate established ADAM28 as a functional sheddase with immunological relevance distinct from ADAM17-mediated CD23 processing.\",\n      \"evidence\": \"Synthetic peptide substrate library screening; reconstituted ectodomain shedding assay with hydroxamic acid inhibitor\",\n      \"pmids\": [\"12777399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo contribution of ADAM28 versus ADAM10/ADAM17 to CD23 shedding not resolved\", \"Biological consequence of ADAM28-specific CD23 cleavage not demonstrated\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that MMP-7 activates proADAM28s, which then cleaves IGFBP-3 (inhibitable by TIMP-3/4), revealed a proteolytic cascade linking MMP-7 to IGF bioavailability.\",\n      \"evidence\": \"In vitro protease activation assay; immunoblotting with metalloprotease inhibitor panel\",\n      \"pmids\": [\"15013428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MMP-7 activates ADAM28s in vivo not confirmed\", \"IGFBP-3 cleavage sites not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Linking ADAM28 overexpression in breast carcinoma to IGFBP-3 cleavage and IGF-I-driven proliferation provided the first mechanistic explanation for ADAM28's pro-tumorigenic role, validated in vivo.\",\n      \"evidence\": \"siRNA knockdown, anti-ADAM28 antibody, ADAM inhibitor in breast cancer cells and xenograft mouse model\",\n      \"pmids\": [\"17047053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM28 acts on additional IGFBPs not tested\", \"Contribution relative to other IGFBP-3 proteases in tumors unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that the ADAM28 disintegrin domain binds PSGL-1 and augments P-selectin-mediated leukocyte rolling established a non-catalytic adhesion-modulatory function relevant to inflammation.\",\n      \"evidence\": \"Yeast two-hybrid; domain-specific binding assays; co-IP; in vivo mouse endotoxin model\",\n      \"pmids\": [\"17597069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PSGL-1 binding and metalloprotease activity are coordinated in the same cellular context remains unclear\", \"Structural basis of the disintegrin–PSGL-1 interaction not determined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that the disintegrin domain is required for cartilage proteoglycan release extended the non-catalytic role to extracellular matrix remodeling beyond leukocyte adhesion.\",\n      \"evidence\": \"Disintegrin-domain deletion mutagenesis in ATRA-stimulated chondrocytes; proteoglycan release assay\",\n      \"pmids\": [\"19527685\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The matrix substrate(s) engaged by the disintegrin domain were not identified\", \"Whether metalloprotease activity also contributes was not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Mapping ADAM28 cleavage of CTGF at specific hinge-region bonds showed it liberates VEGF165 from CTGF/VEGF complexes, linking ADAM28 to angiogenic factor availability.\",\n      \"evidence\": \"Yeast two-hybrid; in vitro cleavage with N-terminal sequencing for site mapping\",\n      \"pmids\": [\"20971063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence on endothelial cell angiogenesis not tested\", \"In vivo relevance of CTGF cleavage not assessed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Finding that soluble ADAM28 enhances integrin α4β1-dependent adhesion to VCAM-1 and promotes transendothelial migration revealed a second integrin partner through which ADAM28 modulates leukocyte trafficking.\",\n      \"evidence\": \"Recombinant ADAM28 binding assays; anti-integrin antibody blocking; transendothelial migration assay\",\n      \"pmids\": [\"21332445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAM28 binding activates α4β1 not elucidated\", \"Single study; awaits independent confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of VWF as an ADAM28 substrate that normally induces tumor-cell apoptosis in the vasculature established a mechanism by which ADAM28 promotes survival of circulating cancer cells and lung metastasis.\",\n      \"evidence\": \"Yeast two-hybrid; shRNA/siRNA knockdown and antibody inhibition; xenograft lung metastasis model with bioluminescence\",\n      \"pmids\": [\"22636800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage sites in VWF not mapped\", \"Relative importance of VWF cleavage versus IGFBP-3 cleavage for metastasis not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showing that ADAM28 mediates TNF-α shedding in macrophages broadened its sheddase repertoire to include a key pro-inflammatory cytokine beyond ADAM17.\",\n      \"evidence\": \"Co-IP and co-localization in HEK293; siRNA knockdown and pharmacological inhibition; ELISA for soluble TNF-α in THP-1 macrophages\",\n      \"pmids\": [\"23010875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo quantitative contribution relative to ADAM17-mediated TNF-α shedding not determined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that Src kinase induces ADAM28 transcription via MEK/ERK and PI3K/mTOR explained how oncogenic signaling drives ADAM28 overexpression in carcinomas.\",\n      \"evidence\": \"Kinase inhibitor panel in v-src-transformed MDCK and human carcinoma cells; immunohistochemistry for phospho-Src/ADAM28 co-expression\",\n      \"pmids\": [\"24007880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcription factor(s) downstream of MEK/ERK and PI3K/mTOR that bind the ADAM28 promoter not identified\", \"Whether this regulatory axis operates in non-epithelial contexts unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying C1q as a substrate whose cleavage attenuates apoptosis and autophagic cell death in normal epithelial cells revealed a cytoprotective function of ADAM28 independent of cancer.\",\n      \"evidence\": \"Yeast two-hybrid; co-IP; surface plasmon resonance; siRNA knockdown; apoptosis and autophagy assays in bronchial epithelial cells\",\n      \"pmids\": [\"26918856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo impact on complement-mediated tissue damage not tested\", \"Whether other complement components are ADAM28 substrates unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovering that CD19-dependent Foxo1 suppression upregulates ADAM28, which then cleaves Notch2 for MZ B-cell differentiation, placed ADAM28 in a defined developmental signaling cascade.\",\n      \"evidence\": \"CD19-deficient mouse model; rescue and epistasis experiments; ADAM28 siRNA; Notch2 cleavage immunoblotting\",\n      \"pmids\": [\"28707394\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ADAM28 is the sole S2 cleavage enzyme for Notch2 in MZP B cells not resolved\", \"Confirmation in ADAM28-knockout mice lacking\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that EBV EBNA3C represses ADAM28 transcription through KDM2B-mediated H3K4me3 removal and Polycomb H3K27me3 deposition provided the first epigenetic mechanism governing ADAM28 silencing.\",\n      \"evidence\": \"Recombinant EBV mutants; ChIP for H3K4me3, H3K27me3, BMI1, SUZ12; co-IP for EBNA3C–KDM2B\",\n      \"pmids\": [\"30135119\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this epigenetic silencing is reversible during B-cell reactivation not tested\", \"Whether non-EBV contexts use similar KDM2B-mediated repression unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Development of a neutralizing antibody targeting the cysteine-rich/secreted-specific domain of ADAM28s that blocks both IGFBP-3 cleavage and VWF cleavage validated ADAM28 as a druggable target for NSCLC.\",\n      \"evidence\": \"Epitope-mapped human antibody; SPR KD measurement; proliferation and apoptosis assays in NSCLC lines; tumor growth and metastasis in mouse model\",\n      \"pmids\": [\"30190423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Antibody activity in immunocompetent tumor models not assessed\", \"Whether the antibody also blocks non-catalytic disintegrin functions not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirming that both endothelial and gastric cancer cell ADAM28 cleave VWF to prevent apoptosis extended the VWF-cleavage mechanism to a second cancer type and to stromal cells.\",\n      \"evidence\": \"Co-culture system; ADAM28 overexpression/knockdown; ELISA for VWF; VWF knockdown rescue\",\n      \"pmids\": [\"33675784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether endothelial ADAM28 contributes to metastasis in vivo not tested\", \"Generalizability across additional cancer types remains unexamined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No ADAM28-null mouse phenotype has been characterized, the structural basis for substrate selectivity and TIMP-3/4 sensitivity is unknown, and the relative in vivo contributions of catalytic versus disintegrin-mediated activities remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ADAM28 knockout mouse characterization reported\", \"No crystal or cryo-EM structure available\", \"In vivo substrate hierarchy not determined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 6, 7, 8, 9, 13, 16, 17]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5, 12]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5, 6, 7, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 10, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 5, 8, 16]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"IGFBP3\",\n      \"VWF\",\n      \"PSGL1\",\n      \"ITGA4\",\n      \"CTGF\",\n      \"C1Q\",\n      \"NOTCH2\",\n      \"MMP7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ADAM28 is a catalytically active disintegrin metalloproteinase that processes multiple extracellular substrates—including IGFBP-3, VWF, CTGF, CD23, CD200, Notch2, TNF-α, C1q, and myelin basic protein—to regulate IGF-I bioavailability, cancer cell survival, VEGF165 release, complement-mediated cell death, and leukocyte adhesion [PMID:11389903, PMID:15013428, PMID:20971063, PMID:22636800, PMID:26918856, PMID:12777399, PMID:23010875, PMID:28707394]. ADAM28 undergoes autocatalytic pro-domain removal in a late Golgi compartment and can be further activated by MMP-7; its metalloproteinase activity is inhibited by TIMP-3 and TIMP-4 but not TIMP-1 or TIMP-2 [PMID:10794709, PMID:15013428, PMID:11389903]. Its disintegrin domain independently mediates binding to integrin α4β1 on leukocytes and to PSGL-1, promoting lymphocyte adhesion to VCAM-1, transendothelial migration, and P-selectin-dependent leukocyte recruitment during inflammation [PMID:11724793, PMID:12667064, PMID:17597069, PMID:21332445]. Src kinase drives ADAM28 transcription through MEK/ERK and PI3K/mTOR signaling in carcinoma cells, and the ADAM28 locus is epigenetically silenced by EBV EBNA3C via KDM2B-mediated H3K4me3 removal and Polycomb-dependent H3K27me3 deposition [PMID:24007880, PMID:30135119].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Cloning of ADAM28 from epididymis revealed a reprolysin-like catalytic consensus, predicting it to be a catalytically active ADAM—setting the stage for functional enzymology.\",\n      \"evidence\": \"cDNA cloning and sequence analysis from human and macaque epididymis\",\n      \"pmids\": [\"10587367\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Sequence prediction only; no enzymatic activity demonstrated\", \"Expression restricted to one tissue at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstration that ADAM28 pro-domain removal is autocatalytic (not furin-dependent) in a late Golgi compartment established a unique activation mechanism among ADAMs.\",\n      \"evidence\": \"Catalytic-site Glu→Ala mutagenesis in COS-7 cells with surface trypsinization and subcellular fractionation\",\n      \"pmids\": [\"10794709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional proteases contribute to activation in vivo\", \"Exact Golgi sub-compartment not determined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Two key properties were established: ADAM28 is a zinc metalloproteinase capable of cleaving myelin basic protein and is insensitive to TIMP-1/TIMP-2, while its disintegrin domain binds integrin α4β1 in a divalent-cation-dependent manner—distinguishing its catalytic and adhesive functions.\",\n      \"evidence\": \"In vitro cleavage assays with mutagenesis (catalytic activity) and Fc-fusion adhesion assays with function-blocking antibodies on transfected K562 cells (integrin binding)\",\n      \"pmids\": [\"11389903\", \"11724793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of MBP cleavage unclear\", \"Other integrin partners not yet surveyed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapping of the α4β1-binding interface on the disintegrin domain to seven specific residues extending beyond the classical RGD loop, and identification of CD23 as a catalytic substrate, separated the structural determinants of adhesion from those of proteolysis.\",\n      \"evidence\": \"Charge-to-alanine mutagenesis with Jurkat adhesion assay (binding); synthetic peptide library screening and ectodomain shedding assay (CD23 cleavage)\",\n      \"pmids\": [\"12667064\", \"12777399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of the disintegrin domain\", \"Relative contribution of ADAM28 vs. ADAM10/ADAM17 to CD23 shedding in vivo\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery that MMP-7 activates secreted proADAM28s and that the active enzyme cleaves IGFBP-3 (inhibitable by TIMP-3/TIMP-4) established a proteolytic cascade linking extracellular matrix remodeling to IGF-I signaling.\",\n      \"evidence\": \"In vitro reconstitution of MMP-7-mediated activation, IGFBP-3 cleavage assay with metalloprotease inhibitor panel\",\n      \"pmids\": [\"15013428\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo MMP-7-dependent activation not yet shown\", \"Whether other MMPs also activate proADAM28\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"ADAM28-mediated IGFBP-3 cleavage was shown to have direct cancer relevance: siRNA knockdown in breast carcinoma cells reduced IGF-I signaling, proliferation, and xenograft tumor growth, placing ADAM28 as a pro-tumorigenic protease.\",\n      \"evidence\": \"siRNA knockdown and anti-ADAM28 antibody in MDA-MB231 cells with IGFBP-3 cleavage, IGF-I signaling readout, and xenograft model\",\n      \"pmids\": [\"17047053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of other IGFBP-3-degrading proteases in tumors\", \"Human clinical validation absent\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of PSGL-1 as a disintegrin domain binding partner that enhances P-selectin-mediated leukocyte adhesion and pulmonary accumulation demonstrated ADAM28's non-catalytic role in inflammation.\",\n      \"evidence\": \"Yeast two-hybrid confirmed by co-IP, domain binding assays, and in vivo endotoxin inflammation model\",\n      \"pmids\": [\"17597069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM28 also cleaves PSGL-1\", \"Relative importance in neutrophil vs. lymphocyte recruitment\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Discovery that ADAM28 cleaves CTGF at defined bonds to liberate VEGF165 from the CTGF/VEGF complex connected ADAM28 to angiogenic signaling.\",\n      \"evidence\": \"Yeast two-hybrid, protein binding assay, in vitro cleavage with bond identification, VEGF165 release measurement\",\n      \"pmids\": [\"20971063\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo angiogenesis readout not performed\", \"Whether ADAM28-released VEGF165 is sufficient to drive neovascularization\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Two new substrates—VWF and TNF-α—were identified: ADAM28-mediated VWF cleavage protects carcinoma cells from VWF-induced apoptosis during hematogenous metastasis, and ADAM28 contributes to TNF-α ectodomain shedding in macrophages.\",\n      \"evidence\": \"VWF: yeast two-hybrid, cleavage assay, shRNA/siRNA, neutralizing antibody, xenograft metastasis model; TNF-α: co-IP, ELISA, siRNA in THP-1 cells\",\n      \"pmids\": [\"22636800\", \"23010875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of ADAM28 vs. ADAM17 (TACE) to TNF-α shedding\", \"VWF cleavage site not identified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Src kinase was identified as a transcriptional inducer of ADAM28 through MEK/ERK and PI3K/mTOR, explaining ADAM28 upregulation in carcinomas and providing a signaling link to oncogenic transformation.\",\n      \"evidence\": \"Kinase inhibitors in v-src-transformed MDCK cells and human carcinoma lines, RT-PCR, IHC tissue correlation, in vivo anti-ADAM28 antibody tumor suppression\",\n      \"pmids\": [\"24007880\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcription factor(s) binding the ADAM28 promoter not identified\", \"Whether Src-independent mechanisms maintain ADAM28 in non-transformed cells\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of C1q as a physiological ADAM28 substrate in normal epithelia revealed a cytoprotective function: ADAM28 cleavage of C1q attenuates complement-driven apoptosis and autophagy, defining a homeostatic role beyond cancer.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, SPR, siRNA knockdown, recombinant ADAM28 pre-treatment with apoptosis/autophagy assays in bronchial epithelial cells\",\n      \"pmids\": [\"26918856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C1q cleavage modulates classical complement activation in vivo\", \"Cleavage site in C1q not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"ADAM28 was linked to Notch2 signaling in B-cell differentiation (MZP→MZ B cells via CD19/Foxo1) and to trophoblast invasion in early placenta, broadening its physiological roles beyond immunity and cancer.\",\n      \"evidence\": \"CD19-KO mice with Notch2 cleavage assay (B cells); siRNA in placental explant cultures with apoptosis readout (trophoblast)\",\n      \"pmids\": [\"28707394\", \"28623976\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ADAM28 directly cleaves Notch2 or acts indirectly\", \"Redundancy with other Notch-processing ADAMs (ADAM10/17) in MZ B-cell fate\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Epigenetic silencing of the ADAM28 locus by EBV EBNA3C was mechanistically dissected into two pathways—KDM2B-mediated H3K4me3 removal and Polycomb-dependent H3K27me3 deposition—explaining ADAM28 downregulation in EBV-transformed B cells.\",\n      \"evidence\": \"Recombinant EBV with EBNA3C mutations, ChIP for H3K4me3, H3K27me3, KDM2B, BMI1, SUZ12\",\n      \"pmids\": [\"30135119\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ADAM28 silencing for EBV latency\", \"Whether EBNA3C-dependent silencing is reversible in vivo\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Multiple studies placed ADAM28 downstream of miRNA/lncRNA regulatory circuits (miR-198, miR-128-3p/NEAT1) and upstream of JAK2/STAT3 signaling, linking ADAM28 to autophagy and apoptosis regulation in solid tumors.\",\n      \"evidence\": \"Dual-luciferase reporter assays for miRNA–3′-UTR binding, Western blot for p-JAK2/p-STAT3/autophagy markers, siRNA/overexpression with in vivo xenograft\",\n      \"pmids\": [\"30840270\", \"36054559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAM28 activates JAK2/STAT3 is unknown\", \"Whether the effect is substrate-cleavage-dependent or disintegrin-mediated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the transcription factor(s) directly driving ADAM28 promoter activity downstream of Src/MEK/ERK, the structural basis of substrate recognition (no crystal structure exists), the mechanism linking ADAM28 to JAK/STAT activation, and the relative physiological contribution of ADAM28 vs. ADAM10/ADAM17 in Notch2 and TNF-α processing in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of any ADAM28 domain\", \"Direct ADAM28-Notch2 cleavage assay lacking\", \"In vivo ADAM28 knockout phenotype in mammals not reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 5, 7, 10, 12, 13, 14, 16]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [2, 3, 8, 11]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 5, 10, 12, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [5, 8, 10, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [4, 8, 13, 16, 25]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 15, 22, 24]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [17, 18]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ITGA4\",\n      \"ITGB1\",\n      \"SELPLG\",\n      \"IGFBP3\",\n      \"VWF\",\n      \"CTGF\",\n      \"C1QA\",\n      \"TNF\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}