{"gene":"ADAM9","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":1996,"finding":"MDC9 (ADAM9) cytoplasmic tail contains two proline-rich sequences that bind the SH3 domain of Src, demonstrating SH3 ligand function. MDC9 is present on the plasma membrane of NIH 3T3 fibroblasts as an ~84 kDa glycoprotein.","method":"Protein domain analysis, cell surface biotinylation, 125I-labeling, immunofluorescence of COS-7 cells expressing MDC9","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical cell-surface experiments and SH3 binding demonstrated in a single study with multiple orthogonal methods","pmids":["8647900"],"is_preprint":false},{"year":1998,"finding":"PKCδ binds in vivo and in vitro to the cytoplasmic domain of MDC9/ADAM9. Constitutively active PKCδ or MDC9 overexpression induces ectodomain shedding of proHB-EGF, while MDC9 lacking the metalloprotease domain and kinase-negative PKCδ suppress TPA-induced HB-EGF ectodomain shedding.","method":"Co-immunoprecipitation (in vivo and in vitro binding), dominant-negative/constitutively active mutant overexpression, ectodomain shedding assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vivo and in vitro Co-IP, domain deletion mutants and dominant-negative/active constructs, replicated with multiple approaches in a single rigorous study","pmids":["9857183"],"is_preprint":false},{"year":1999,"finding":"The prodomain of MDC9/ADAM9 is removed by a furin-type proprotein convertase in the secretory pathway before cell surface emergence. Soluble MDC9 metalloprotease domain is catalytically active, cleaving insulin B-chain. MDC9 activity is inhibited by hydroxamic acid metalloprotease inhibitors (low nM range). Cysteine-switch peptides inhibit MDC9 in low µM range, providing evidence for cysteine-switch regulation. MDC9 becomes phosphorylated upon phorbol ester (PMA) treatment.","method":"Biochemical cleavage assays (insulin B-chain), inhibitor profiling, cysteine-switch peptide inhibition, metabolic labeling/phosphorylation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic activity assay with mutagenesis-equivalent prodomain removal, inhibitor characterization, and phosphorylation assay; multiple orthogonal methods in single rigorous study","pmids":["9920899"],"is_preprint":false},{"year":1999,"finding":"The cytoplasmic domains of MDC9/ADAM9 interact with two SH3 domain-containing proteins: endophilin I (SH3GL2/SH3p4) and a novel protein SH3PX1 (containing SH3 and PX domains). Both proteins preferentially bind the precursor but not the processed form of MDC9 in COS-7 cells.","method":"Yeast two-hybrid screen, GST pulldown with bacterial fusion proteins, co-immunoprecipitation from eukaryotic cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by orthogonal pulldown and Co-IP; precursor vs. processed form selectivity demonstrated","pmids":["10531379"],"is_preprint":false},{"year":1999,"finding":"MDC9 co-expressed with APP695 in COS cells promotes exclusive alpha-secretory cleavage of APP upon phorbol ester treatment. Inhibition of MDC9 by the hydroxamate inhibitor SI-27 enhanced beta-secretase cleavage of APP.","method":"Co-expression in COS cells, APP cleavage assay (alpha-secretory site mutant), hydroxamate inhibitor treatment","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based overexpression and inhibitor assay, single lab, two orthogonal approaches (mutant substrate + inhibitor)","pmids":["10510302"],"is_preprint":false},{"year":1999,"finding":"The cytoplasmic domain of MDC9/ADAM9 interacts with a novel MAD2-related protein, MAD2β (23% identity to MAD2, a spindle assembly checkpoint component). Interaction confirmed biochemically.","method":"Yeast two-hybrid screen, biochemical confirmation of interaction","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid with biochemical confirmation, single lab; functional consequence not established","pmids":["10527948"],"is_preprint":false},{"year":2000,"finding":"MDC9/ADAM9 is localized to the basolateral surface of renal cortical tubule cells and glomerular visceral epithelial cells, co-localizing with β1 integrin. Expression of soluble disintegrin domain in glomerular epithelial cells causes cell rounding and detachment, indicating functional role in epithelial cell-matrix adhesion.","method":"Immunohistochemistry, GFP-chimera expression, Western blot of kidney fractions, cell morphology assay","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by multiple methods tied to functional consequence (cell detachment upon disintegrin domain expression)","pmids":["10752518"],"is_preprint":false},{"year":2001,"finding":"ADAM9 is involved in monocyte fusion (multinucleated giant cell formation). Anti-ADAM9 antibody blocks CD98-mediated and RANKL-mediated multinucleated giant cell formation. The metalloprotease inhibitor SI-27 (which suppresses ADAM9 activity) also suppresses this fusion.","method":"Antibody blocking assay, metalloprotease inhibitor treatment, RT-PCR for expression","journal":"Cellular immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — antibody blocking and inhibitor experiments in primary human monocytes, single lab, functional phenotype clearly defined","pmids":["11831872"],"is_preprint":false},{"year":2002,"finding":"Loss of MDC9/ADAM9 (mdc9−/− mice) does not impair constitutive or stimulated HB-EGF ectodomain shedding in embryonic fibroblasts, nor does it alter APP alpha-secretase (p3) or beta/gamma-secretase (Aβ) processing in hippocampal neurons, arguing against essential non-redundant roles in these processes in vivo.","method":"Genetic knockout (mdc9−/− mice), ectodomain shedding assay in primary fibroblasts, Aβ/p3 measurement in hippocampal neurons","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic KO model with multiple specific substrate assays; negative results for HB-EGF shedding and APP processing are mechanistically informative","pmids":["11839819"],"is_preprint":false},{"year":2002,"finding":"Soluble ADAM9 activity is not inhibited by TIMP-1, TIMP-2, TIMP-3, or TIMP-4 (tissue inhibitors of metalloproteinases), but can be inhibited by hydroxamate inhibitors, distinguishing it from ADAM10, ADAM12, ADAM17, and MT-MMPs.","method":"In vitro protease activity assay with TIMP inhibition profiling","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrates and inhibitor panel; single lab but rigorous biochemical method","pmids":["12135759"],"is_preprint":false},{"year":2002,"finding":"A secreted splice variant of human ADAM9 (hADAM9s), lacking the C-terminal transmembrane and cytoplasmic domains, is secreted from transfected COS cells and has alpha-secretase-like activity for APP upon phorbol ester treatment.","method":"Cloning of splice variant, COS cell transfection, APP cleavage assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based cleavage assay with defined splice variant; single lab, two orthogonal approaches (cloning + functional assay)","pmids":["12054541"],"is_preprint":false},{"year":2003,"finding":"ADAM9, ADAM10, and ADAM17 each catalyze alpha-secretory cleavage of APP in COS-7 cells. Lipofection of dsRNA to suppress endogenous ADAM9 in A172 glioblastoma cells reduces alpha-secretase cleavage, indicating that endogenous ADAM9 contributes to constitutive and regulated alpha-secretase activity.","method":"Overexpression in COS-7 cells, RNAi knockdown in A172 cells, APP cleavage measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (RNAi) combined with gain-of-function (overexpression), single lab","pmids":["12535668"],"is_preprint":false},{"year":2005,"finding":"A secreted form of ADAM9 (ADAM9-S) is secreted by hepatic stellate cells, binds directly to α6β4 and α2β1 integrins on colon carcinoma cells via its disintegrin domain, and promotes carcinoma invasion. ADAM9-S also cleaves laminin. Protease activity of ADAM9-S is required for invasion.","method":"Matrigel invasion assay, direct binding assay (disintegrin domain to integrins), laminin cleavage assay, protease-inactive mutant","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay, substrate cleavage (laminin), and protease-dead mutant all used in single study; multiple orthogonal methods","pmids":["15930291"],"is_preprint":false},{"year":2005,"finding":"The disintegrin domain of ADAM9 is a polyvalent ligand for multiple β1 renal integrins (α1, α3, α6, αv, β1). Expression of ADAM9 on HEK-293 cells decreases adhesion to collagen I/IV, vitronectin, and laminin via competitive inhibition of cell-matrix binding through the disintegrin domain. The cysteine-rich domain alone has no effect on adhesion.","method":"Recombinant GST-disintegrin domain pulldown, adhesion assay with integrin-blocking antibodies, GFP-chimera expression, Western blot","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple adhesion and binding assays with antibody blocking and domain deletion constructs; multiple orthogonal methods","pmids":["15361064"],"is_preprint":false},{"year":2005,"finding":"ADAM9 participates in constitutive secretion of PrPc N1 fragment in HEK293 cells, TSM1 neurons, and fibroblasts; ADAM9 antisense reduces N1 and sAPPα recoveries. However, ADAM9 requires ADAM10 for this activity: ADAM9 cannot cleave alpha-secretase substrates in ADAM10−/− fibroblasts, but co-expression of ADAM9 and ADAM10 enhances activity beyond ADAM10 alone. ADAM9 contributes to PrPc processing indirectly by promoting shedding of ADAM10.","method":"Transient and stable transfection, antisense knockdown, ADAM10−/− fibroblasts, fluorimetric substrate assay, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic ADAM10 KO cells combined with complementation, antisense knockdown, and quantitative enzyme assays; multiple orthogonal methods revealing epistatic relationship","pmids":["16236709"],"is_preprint":false},{"year":2005,"finding":"ADAM9 loss in the W10 prostate cancer mouse model results in mostly well-differentiated tumors, while ADAM9-expressing controls develop poorly differentiated tumors. ADAM9 overexpression in mouse prostate epithelium causes hyperplasia and prostatic intraepithelial neoplasia. In cell-based assays, ADAM9 cleaves and releases EGF and FGFR2iiib from cells.","method":"Genetic KO in tumor mouse model (W10 × mdc9−/−), prostate-specific overexpression transgenic mice, cell-based shedding assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function genetic mouse models combined with cell-based shedding assays; multiple orthogonal approaches","pmids":["16230393"],"is_preprint":false},{"year":2007,"finding":"The recombinant disintegrin-cysteine-rich domain of ADAM-9 specifically interacts with the β1 integrin subunit on keratinocytes (confirmed by solid-phase binding assay and co-immunoprecipitation). Engagement of integrin receptors by this domain induces ERK phosphorylation and increased MMP-9 synthesis. Keratinocytes adhering to immobilized ADAM-9 disintegrin-cysteine-rich domain show increased motility, partially dependent on MMP-9 induction.","method":"Solid-phase binding assay, antibody inhibition, Co-immunoprecipitation, ERK phosphorylation assay, MMP-9 Western blot, migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, binding assay, signaling readout (ERK), and functional migration assay; multiple orthogonal methods in single study","pmids":["17704059"],"is_preprint":false},{"year":2009,"finding":"ADAM9 deficiency (Adam9−/−) significantly reduces pathological neovascularization in OIR (oxygen-induced retinopathy) and laser-induced choroidal neovascularization models, and reduces tumor growth from heterotopically injected melanoma cells. ADAM9 overexpression enhances shedding of EphB4, Tie-2, Flk-1, CD40, VCAM, and VE-cadherin. ADAM9 expression and shedding are upregulated by reactive oxygen species (H2O2).","method":"Adam9−/− mouse models (OIR, CNV, tumor xenograft), cell-based overexpression shedding assay, ROS stimulation assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in multiple in vivo models plus cell-based substrate shedding and ROS stimulation; multiple orthogonal methods","pmids":["19273593"],"is_preprint":false},{"year":2009,"finding":"ADAMs 9 and 10 are the major collagen XVII sheddases in primary keratinocytes. Adam9−/− keratinocytes show a 55% decrease in constitutive collagen XVII ectodomain shedding. H2O2 enhances ADAM9 expression and stimulates collagen XVII shedding in wild-type but not Adam9−/− skin/keratinocytes.","method":"Adam9−/− and Adam10−/− primary keratinocyte cultures, ADAM10-selective inhibitor (GI254023X), phorbol ester treatment, H2O2 stimulation, collagen XVII shedding assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model with selective inhibitor, multiple substimuli, quantitative shedding assay; multiple orthogonal approaches","pmids":["19574220"],"is_preprint":false},{"year":2009,"finding":"LPS activates ADAM9-dependent shedding of ACE from endothelial cells. ADAM9 requires both membrane anchorage and its catalytic domain to shed ACE, as shown by transient transfection of ADAM9 and ACE cDNAs in HEK293 cells.","method":"siRNA knockdown, inhibitor profiling (TIMP-based), HEK293 co-transfection with ADAM9 and ACE, catalytic domain mutant","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown confirmed by transfection with catalytic mutant; single lab, two orthogonal approaches","pmids":["22480688"],"is_preprint":false},{"year":2010,"finding":"ADAM9 expression in melanoma cells is required for adhesion to fibroblasts. The disintegrin-like and cysteine-rich domains of ADAM-9 mediate Mn2+-dependent integrin-mediated adhesion of melanoma cells and fibroblasts (via multiple β1 integrins, independent of RGD and ECD motifs). Interaction with soluble DC-9 induces MMP-1 and MMP-2 expression in fibroblasts and melanoma cells. ADAM9 silencing in fibroblasts abolishes cellular interactions and melanoma invasion.","method":"Recombinant DC-9 domain adhesion assay, integrin-blocking antibodies, siRNA knockdown, MMP expression assay, invasion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — recombinant domain adhesion assay, antibody blocking, siRNA knockdown with multiple functional readouts; multiple orthogonal methods","pmids":["21135106"],"is_preprint":false},{"year":2010,"finding":"Adam9−/− mice show accelerated wound repair due to increased keratinocyte migration. Re-epithelialization is faster in Adam9−/− wounds, and increased migration (not proliferation) of keratinocytes is responsible. This is mechanistically linked to modulation of collagen XVII shedding by ADAM9.","method":"Adam9−/− genetic KO, excisional wound model, immunolocalization, keratinocyte migration assay, proliferation assay","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific in vivo and in vitro phenotypic readouts, mechanism linked to collagen XVII shedding","pmids":["20376065"],"is_preprint":false},{"year":2010,"finding":"Secreted ADAM9 (ADAM9-S) promotes breast cancer cell migration via its metalloproteinase activity. Membrane-bound ADAM9 (ADAM9-L) suppresses migration independent of metalloproteinase activity but requiring a functional disintegrin domain and integrin binding. The two isoforms thus have opposing effects on migration.","method":"Isoform-specific overexpression, metalloproteinase-dead mutant, disintegrin domain mutant, migration assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — isotype-specific constructs, catalytic and disintegrin domain mutants, functional migration assay; multiple orthogonal methods distinguishing two isoform mechanisms","pmids":["20736367"],"is_preprint":false},{"year":2010,"finding":"An ADAM9 deletion (removing exons 15 and 16, introducing a premature stop and removing critical domains) causes cone-rod dystrophy 3 (crd3) in Glen of Imaal Terriers, establishing homology to human CORD9. Light and electron microscopy show the primary lesion is failure of retinal pigment epithelium apical microvilli to invest photoreceptor outer segments.","method":"Genome-wide association, sequencing, light and electron microscopy, electroretinography","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutation identified with structural/histological characterization; ortholog (canine) study","pmids":["20806078"],"is_preprint":false},{"year":2011,"finding":"The ADAM9 prodomain (proA9) is a competitive inhibitor of ADAM9 catalytic/disintegrin domain (Ki = 280 ± 34 nM) with high specificity. Inhibition of ADAM9 by proA9 in SY5Y neuroblastoma cells reduces ADAM10 shedding into the medium while increasing membrane-bound ADAM10, resulting in higher sAPPα and lower sAPPβ levels. This demonstrates that ADAM9 controls ADAM10 membrane localization and alpha-secretase activity.","method":"Recombinant prodomain expression from E. coli, competitive inhibition assay, Western blot, fluorescent peptide substrate assay (proteolytic activity matrix analysis), proteomic quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical inhibition with Ki measurement, cell-based mechanistic assay linking ADAM9 inhibition to ADAM10 localization and APP processing; multiple orthogonal methods","pmids":["21956108"],"is_preprint":false},{"year":2012,"finding":"MT1-MMP (MMP14) forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, protecting FGFR2 from ADAM9-mediated ectodomain shedding. In Mmp14−/− osteoblasts, ADAM9 is upregulated and FGFR2 shedding increases, compromising FGF-induced proliferation and signaling. Adam9 depletion completely rescues defective FGFR2 signaling and largely restores calvarial bone growth in Mmp14−/− embryos.","method":"Co-immunoprecipitation (complex formation), Mmp14−/− and Adam9 depletion mouse models, FGFR2 shedding assay, downstream signaling assay, skeletal phenotype analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genetic KO, genetic rescue (double KO), in vivo phenotype rescue; multiple orthogonal methods with rigorous controls","pmids":["22632802"],"is_preprint":false},{"year":2014,"finding":"ADAM9 enhances tissue plasminogen activator (tPA)-mediated cleavage and activation of the promigratory protein CDCP1, promoting lung cancer metastasis to the brain. Blocking this mechanism prolongs survival in tumor-bearing mice, and cooperates with dexamethasone and dasatinib treatment.","method":"In vivo tumor metastasis model, survival analysis, inhibitor combination studies, protein cleavage assay","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo tumor model with mechanistic substrate cleavage assay; single lab with multiple functional readouts","pmids":["25060522"],"is_preprint":false},{"year":2014,"finding":"ADAM9 is stored in gelatinase and specific granules and secretory vesicles of human PMNs (not synthesized de novo). PMN activation with degranulating agonists rapidly increases surface ADAM9. ADAM9 degrades ECM proteins (fibronectin, entactin, laminin, insoluble elastin) as potently as MMP-9, but does not degrade type I, III, or IV collagens or denatured collagens in vitro. Adam9 increases mortality and promotes alveolar-capillary barrier injury during LPS- and bleomycin-induced acute lung injury in mice; Adam9 does not regulate PMN/macrophage recruitment.","method":"Subcellular fractionation, flow cytometry, in vitro ECM degradation assays, Adam9−/− mouse lung injury models","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — subcellular fractionation defining storage granules, in vitro substrate assays (positive and negative), and genetic KO in vivo model; multiple orthogonal methods","pmids":["25063875"],"is_preprint":false},{"year":2015,"finding":"Platelet integrin α6β1 directly binds to ADAM9 on tumor cell surfaces via the disintegrin-cysteine domain of ADAM9 (DC-9 recombinant protein). This platelet-tumor cell interaction promotes platelet activation, tumor cell extravasation, and efficient lung metastasis. Genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis.","method":"Knockdown approach (siRNA), static and flow-based adhesion assays with recombinant DC-9, α6β1 KO mouse model (experimental and spontaneous metastasis), pharmacological inhibition","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assay with recombinant domain, ADAM9 knockdown, and integrin KO mouse models with multiple metastasis readouts; multiple orthogonal methods","pmids":["27699237"],"is_preprint":false},{"year":2015,"finding":"TNC (tenascin-C) stimulates BTIC (brain tumor-initiating cell) invasiveness in a metalloproteinase-dependent manner involving ADAM-9. TNC increases ADAM-9 protein expression in 4 BTIC lines. RNAi-mediated ADAM-9 knockdown and inhibition of JNK attenuate TNC-stimulated ADAM-9 expression, proteolytic activity, and BTIC invasiveness.","method":"Microarray gene expression screen, lentiviral RNAi knockdown, ADAM-9 activity assay, JNK inhibitor treatment, orthotopic xenograft","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined phenotypic readout and pathway inhibitor; single lab with multiple methods","pmids":["25646025"],"is_preprint":false},{"year":2017,"finding":"ADAM9 constitutively sheds EphB4 in a manner not stimulated by phorbol esters, pervanadate, or calcium ionophores. ADAM9 is inhibited by TIMP-3 (10 nM) but not by TIMP-1 or TIMP-2 (up to 20 nM). Novel non-hydroxamate small-molecule inhibitors selectively inhibit ADAM9-dependent proteolysis over ADAM10 or ADAM17.","method":"Cell-based shedding assay with catalytically inactive ADAM9 E>A mutant as control, TIMP inhibitor profiling, small-molecule library screen","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based enzymatic assay with inactive mutant control, comprehensive TIMP and inhibitor profiling; multiple orthogonal methods","pmids":["28264989"],"is_preprint":false},{"year":2017,"finding":"ADAM9 promotes lung cancer progression through vascular remodeling by upregulating VEGFA, ANGPT2, and PLAT (tPA). Silencing ADAM9 in lung cancer cells decreases expression of these angiogenic factors, reduces angiogenesis and vascular remodeling, and inhibits tumor growth in vivo.","method":"ADAM9 siRNA knockdown, microarray, in vivo tumor model, angiogenesis assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined downstream gene expression and in vivo angiogenesis; single lab","pmids":["29118335"],"is_preprint":false},{"year":2017,"finding":"ADAM9 knockdown reduces EGFR signaling and increases miR-1 expression in lung cancer cells. miR-1 directly targets the 3'UTR of CDCP1, inhibiting its translation. Thus ADAM9 down-regulates miR-1 via EGFR signaling, which in turn enhances CDCP1 expression to promote lung cancer progression.","method":"Luciferase reporter assay, EGFR signaling analysis, miR-1 expression measurement, tumor metastasis mouse model, miR-1 overexpression","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter, signaling pathway analysis, and in vivo model; single lab with multiple orthogonal methods","pmids":["28537886"],"is_preprint":false},{"year":2017,"finding":"ADAM9 upregulates N-cadherin (CDH2) expression in aggressive lung adenocarcinoma cells by suppressing miR-218. miR-218 is generated from pri-miR-218-1 located in SLIT2. ADAM9 knockdown upregulates SLIT2 and miR-218, which then down-regulates CDH2.","method":"miRNA microarray, luciferase assay, Western blot, siRNA knockdown of ADAM9","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase assay confirming CDH2 as miR-218 target, ADAM9 knockdown with pathway analysis; single lab","pmids":["24705471"],"is_preprint":false},{"year":2018,"finding":"IL-6 upregulates ADAM9 expression in HCC cells via the JNK signaling pathway. ADAM9 promotes HCC cell invasion and EMT by interacting with NADPH oxidase 1 (NOX1) and inducing reactive oxygen species (ROS) generation. ADAM9 knockdown inhibits IL-6-induced EMT.","method":"JNK inhibitor treatment, siRNA knockdown, NOX1 interaction assay, ROS measurement, migration/invasion assay, EMT marker Western blot","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — signaling inhibitor, knockdown, protein interaction assay, and ROS measurement; single lab with multiple methods","pmids":["29432845"],"is_preprint":false},{"year":2018,"finding":"ADAM9 loss (siRNA knockdown) increases β1 integrin levels independently of protease activity. ADAM9 co-immunoprecipitates with β1 integrin. In ADAM9-silenced cells, β1 integrin internalization and degradation are significantly decreased (with no effect on recycling), altering focal adhesion formation, actin stress fibers, cell adhesion and migration.","method":"siRNA knockdown, co-immunoprecipitation, β1 integrin internalization/recycling/degradation assays, focal adhesion staining, migration assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, protease-independent mechanism established by specific mutant analysis, endocytosis/trafficking assays, and functional readouts; multiple orthogonal methods","pmids":["29142101"],"is_preprint":false},{"year":2019,"finding":"ADAM9 is required for the early stages (entry/genome delivery) of EMCV (encephalomyocarditis virus) infection. CRISPR-mediated deletion of ADAM9 renders cells highly resistant to EMCV. Bypassing entry by delivering viral RNA directly to the cytosol restores EMCV replication in ADAM9 KO cells, indicating ADAM9 is not required for post-entry replication. Reconstitution of catalytically inactive ADAM9 in KO cells restores susceptibility, indicating a proteinase-independent role.","method":"Genome-wide CRISPR-Cas9 KO screen, ADAM9 CRISPR deletion in multiple cell lines, viral RNA transfection bypass experiment, reconstitution with inactive ADAM9 mutant","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen with validation in multiple cell lines, mechanistic bypass experiment, and catalytic-dead reconstitution; multiple orthogonal methods","pmids":["30723129"],"is_preprint":false},{"year":2019,"finding":"ADAM9 facilitates attachment of EMCV to the cell surface, functioning as a receptor or cofactor for EMCV entry independent of its metalloproteinase activity (pharmacological metalloproteinase inhibition did not affect infection; catalytically inactive ADAM9 restored susceptibility in KO cells).","method":"Haploid genetic screen, CRISPR KO cell lines, neutralization assays with ADAM9-specific antiserum, soluble receptor proteins, cell-surface binding assays, catalytically inactive ADAM9 reconstitution","journal":"mBio","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple complementary approaches (screen, KO, neutralization, binding, catalytic mutant reconstitution); independent replication between two papers (PMID 30723129 and 31409686)","pmids":["31409686"],"is_preprint":false},{"year":2019,"finding":"ADAM9 contributes to vascular invasion in PDAC by mediating cell migration and adhesion to fibronectin, tenascin, and vitronectin (dependent on its catalytic activity). ADAM9 facilitates anchorage-independent growth. ADAM9 promotes angiogenesis in vitro and in vivo and regulates the levels of angiogenic factors including shed HB-EGF. ADAM9 post-translationally regulates integrin abundance in AsPC1 cells.","method":"siRNA gene silencing, migration and adhesion assays, anchorage-independent growth assay, HUVEC sprout formation with conditioned medium, orthotopic mouse model, immunoblotting","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple in vitro and in vivo readouts; single lab","pmids":["30556643"],"is_preprint":false},{"year":2020,"finding":"Naa10p (N-α-acetyltransferase 10 protein) forms a complex with ADAM9 to maintain ADAM9 protein stability, promoting AIPC (androgen-independent prostate cancer) invasive ability independently of Naa10p acetyltransferase activity. ADAM9 also exerts positive feedback regulation on Naa10p.","method":"Co-immunoprecipitation, siRNA knockdown, overexpression, in vitro/in vivo invasion assays, xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for complex formation, acetyltransferase mutant to distinguish mechanism; single lab","pmids":["32719332"],"is_preprint":false},{"year":2021,"finding":"ADAM9 cleaves the latency-associated peptide (LAP) of TGF-β1 to produce bioactive TGF-β1, which promotes SMAD2/3 phosphorylation and Th17 cell differentiation. Inducible cAMP early repressor (ICER) binds directly to the ADAM9 promoter and promotes its transcription. Adam9-deficient mice show mitigated experimental autoimmune encephalomyelitis (EAE).","method":"Adam9−/− mouse EAE model, T cell transfer assay, TGF-β1/LAP cleavage assay, SMAD2/3 phosphorylation assay, ICER promoter-binding (ChIP implied), Th17 differentiation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse model with T cell transfer assay, substrate cleavage assay, and downstream signaling; multiple orthogonal methods establishing mechanistic pathway","pmids":["33911034"],"is_preprint":false},{"year":2021,"finding":"USP39 promotes glioma cell migration and invasion by facilitating ADAM9 mRNA maturation (splicing), increasing ADAM9 expression. Overexpression of ADAM9 rescues the reduced migration/invasion caused by USP39 depletion.","method":"shRNA knockdown, gene expression profiling, mRNA maturation assay, rescue by ADAM9 overexpression, in vivo invasion model","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined mechanism (mRNA maturation) and genetic rescue; single lab","pmids":["33811456"],"is_preprint":false},{"year":2022,"finding":"ADAM9 cleaves ephrin-B1 and ephrin-B2 in mammalian (colorectal cancer) cells, can substitute for Xenopus ADAM13 in neural crest induction, and its knockdown reduces Akt kinase activity. ADAM9 KD differentially regulates Wnt and mTOR signaling downstream of Akt in a cell-line-dependent manner.","method":"ADAM9 KD in CRC cell lines, luciferase-based Wnt reporter, mTOR pathway assay, Akt kinase assay, Xenopus neural crest induction rescue experiment","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate cleavage (ephrin-B) with functional rescue in Xenopus and mammalian loss-of-function; single lab with multiple methods","pmids":["35780836"],"is_preprint":false},{"year":2022,"finding":"The secreted isoform of ADAM9 (ADAM9s) from cancer-associated fibroblasts (CAFs) with Immature desmoplastic reaction promotes CRC cell proliferation and migration. Knockdown of ADAM9s in these CAFs abrogates their tumor-promoting effects.","method":"CAF isolation from patient tissue, conditioned media assay, ADAM9s knockdown, CRC cell proliferation/migration assays, subcutaneous and orthotopic mouse models","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primary CAF isolation, knockdown with functional rescue, in vivo model; single lab","pmids":["35080810"],"is_preprint":false},{"year":2024,"finding":"ADAM9 stabilizes wild-type and mutant KRAS proteins in PDAC. ADAM9 loss increases interaction of KRAS with PAI-1 (plasminogen activator inhibitor 1), which functions as a selective autophagy receptor together with LC3, triggering lysosomal degradation of KRAS. A small-molecule ADAM9 inhibitor restricts PDAC disease progression in spontaneous models, and combination with gemcitabine elicits regression of patient-derived tumors.","method":"Co-immunoprecipitation (KRAS-PAI-1-LC3 complex), ADAM9 KO/inhibitor experiments, autophagy/lysosomal degradation assays, spontaneous PDAC mouse model, PDX model","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP defining complex, mechanistic autophagy assays, genetic KO and small-molecule inhibitor, multiple in vivo models; rigorous multi-method study","pmids":["38267627"],"is_preprint":false}],"current_model":"ADAM9 is a membrane-anchored metalloprotease-disintegrin whose prodomain is removed by a furin-type convertase in the secretory pathway; the mature enzyme sheds a broad range of cell-surface proteins (HB-EGF, EGF, FGFR2, EphB4, Tie-2, Flk-1, VE-cadherin, collagen XVII, ACE, ephrin-B1/B2, LAP-TGFβ1, and KRAS via autophagy) and is regulated by PKCδ binding to its cytoplasmic tail, ROS, and phosphorylation; its disintegrin-cysteine-rich domain directly engages multiple β1 integrins to control cell adhesion, migration, integrin endocytosis, and downstream ERK/Akt signaling; it also indirectly modulates alpha-secretase activity by controlling ADAM10 membrane localization, acts as a proteinase-independent entry factor/cofactor for EMCV, and cleaves LAP to generate bioactive TGFβ1 that drives Th17 differentiation."},"narrative":{"mechanistic_narrative":"ADAM9 is a membrane-anchored metalloprotease-disintegrin that controls cell-surface proteolysis and integrin-dependent adhesion across tissue remodeling, angiogenesis, and tumor progression [PMID:16230393, PMID:19273593]. Its prodomain is removed by a furin-type convertase in the secretory pathway to yield a catalytically active enzyme that cleaves insulin B-chain, is sensitive to hydroxamate inhibitors but not to TIMP-1/-2/-4 (and only weakly to TIMP-3), distinguishing it biochemically from related ADAMs [PMID:9920899, PMID:12135759, PMID:28264989]. As a sheddase it releases a broad substrate set including EGF and FGFR2 [PMID:16230393], EphB4, Tie-2, Flk-1, and VE-cadherin [PMID:19273593], collagen XVII [PMID:19574220], ACE [PMID:22480688], and ephrin-B1/B2 [PMID:35780836], and cleaves the latency-associated peptide of TGF-β1 to generate bioactive TGF-β1 that drives SMAD2/3 phosphorylation and Th17 differentiation [PMID:33911034]. Independent of its catalytic activity, the disintegrin–cysteine-rich domain is a polyvalent ligand for multiple β1 integrins, modulating cell–matrix adhesion, ERK signaling and MMP induction, and migration [PMID:15361064, PMID:17704059, PMID:21135106], while ADAM9 association with β1 integrin governs integrin internalization and degradation to remodel focal adhesions [PMID:29142101]. Shedding and adhesion functions are regulated through the cytoplasmic tail, which binds PKCδ to couple ectodomain shedding to signaling [PMID:9857183], and ADAM9 expression and activity are induced by reactive oxygen species [PMID:19273593]. ADAM9 also acts indirectly by controlling ADAM10 membrane localization and thereby alpha-secretase activity [PMID:21956108], and serves as a proteinase-independent entry factor/cofactor for encephalomyocarditis virus [PMID:30723129, PMID:31409686]. In cancer, ADAM9 stabilizes KRAS by preventing PAI-1/LC3-mediated selective autophagic degradation, and its small-molecule inhibition restricts PDAC progression [PMID:38267627]. Loss-of-function mutation of ADAM9 causes cone-rod dystrophy/CORD9, with the primary lesion being failure of retinal pigment epithelium apical microvilli to invest photoreceptor outer segments [PMID:20806078].","teleology":[{"year":1996,"claim":"Established that the ADAM9 cytoplasmic tail is a signaling adaptor by showing its proline-rich motifs bind the Src SH3 domain, framing the protein as more than a surface protease.","evidence":"Domain analysis, cell-surface biotinylation, and immunofluorescence of MDC9-expressing cells","pmids":["8647900"],"confidence":"Medium","gaps":["Functional consequence of Src binding not demonstrated","No catalytic activity tested yet"]},{"year":1998,"claim":"Linked ADAM9 to regulated ectodomain shedding by showing PKCδ binds its cytoplasmic tail and that ADAM9 mediates proHB-EGF shedding, coupling intracellular signaling to surface proteolysis.","evidence":"Reciprocal Co-IP, dominant-negative/active PKCδ constructs, domain-deletion mutants, shedding assay","pmids":["9857183"],"confidence":"High","gaps":["Physiological in vivo relevance not tested","Whether ADAM9 directly cleaves HB-EGF or acts via another sheddase unclear"]},{"year":1999,"claim":"Defined ADAM9 as a bona fide active metalloprotease processed by furin and regulated by cysteine-switch and phosphorylation, with a defined inhibitor sensitivity profile.","evidence":"Insulin B-chain cleavage, inhibitor profiling, cysteine-switch peptide assays, phosphorylation labeling","pmids":["9920899"],"confidence":"High","gaps":["Physiological substrates not yet defined","In vivo activation state unknown"]},{"year":1999,"claim":"Expanded the cytoplasmic interactome to endophilin I, SH3PX1, and a MAD2-related protein, indicating precursor-selective trafficking/regulatory partnerships.","evidence":"Yeast two-hybrid screens with GST pulldown and Co-IP","pmids":["10531379","10527948"],"confidence":"Medium","gaps":["Functional roles of endophilin/SH3PX1/MAD2β interactions not established","Precursor-selective binding mechanism unexplained"]},{"year":2002,"claim":"A genetic knockout showed ADAM9 is dispensable for HB-EGF shedding and APP processing in vivo, revealing functional redundancy and reframing earlier overexpression results.","evidence":"mdc9−/− mice with fibroblast shedding and neuronal Aβ/p3 assays","pmids":["11839819"],"confidence":"High","gaps":["Redundant ADAMs not identified","Does not exclude context-specific roles"]},{"year":2005,"claim":"Defined the disintegrin–cysteine-rich domain as a polyvalent β1-integrin ligand controlling cell-matrix adhesion, separating an adhesion function from catalysis.","evidence":"GST-disintegrin pulldown, adhesion assays with integrin-blocking antibodies, GFP-chimera expression","pmids":["15361064","10752518"],"confidence":"High","gaps":["Integrin selectivity rules not resolved","Signaling downstream of adhesion not yet mapped"]},{"year":2005,"claim":"Established ADAM9 substrates and tumor-promoting shedding (EGF, FGFR2, laminin) and showed secreted ADAM9 directly binds integrins to drive carcinoma invasion.","evidence":"W10 prostate cancer KO/overexpression mouse models, direct integrin-binding and laminin cleavage assays, protease-dead mutant","pmids":["16230393","15930291"],"confidence":"High","gaps":["Relative contribution of soluble vs membrane ADAM9 in vivo unclear","Tumor-stage specificity not defined"]},{"year":2005,"claim":"Revealed that ADAM9 acts indirectly on alpha-secretase substrates by requiring and promoting ADAM10, establishing an epistatic relationship rather than direct redundancy.","evidence":"ADAM10−/− complementation, antisense knockdown, fluorimetric substrate assays","pmids":["16236709"],"confidence":"High","gaps":["Mechanism of ADAM10 promotion not yet defined at this stage","Distinction from direct cleavage incomplete"]},{"year":2007,"claim":"Connected integrin engagement by the disintegrin–cysteine-rich domain to downstream ERK activation, MMP-9 induction, and motility, defining an outside-in signaling axis.","evidence":"Solid-phase binding, Co-IP, ERK phosphorylation, MMP-9 Western, keratinocyte migration assays","pmids":["17704059"],"confidence":"High","gaps":["Whether signaling occurs in trans or cis unclear","In vivo relevance to keratinocyte biology untested here"]},{"year":2009,"claim":"Showed ADAM9 drives pathological neovascularization and identified ROS as an upstream inducer of ADAM9 expression and shedding of vascular substrates.","evidence":"Adam9−/− OIR/CNV/tumor models, overexpression shedding assays, H2O2 stimulation","pmids":["19273593"],"confidence":"High","gaps":["Direct vs indirect cleavage of each vascular substrate not all confirmed","ROS-to-ADAM9 signaling mechanism not detailed"]},{"year":2009,"claim":"Defined ADAM9 as a major constitutive collagen XVII and ACE sheddase, tying its activity to keratinocyte basement-membrane biology and endothelial inflammation.","evidence":"Adam9−/− keratinocytes, ADAM10-selective inhibitor, LPS/HEK293 ACE shedding with catalytic mutant","pmids":["19574220","22480688"],"confidence":"High","gaps":["Stimulus-specific regulation of collagen XVII shedding incomplete","ACE shedding study lower confidence on direct cleavage"]},{"year":2010,"claim":"Separated the opposing roles of the secreted and membrane isoforms in migration and linked ADAM9-driven adhesion to tumor-stroma interactions and metastasis.","evidence":"Isoform-specific and domain-mutant constructs, recombinant DC-9 adhesion assays, siRNA, wound-repair and migration models","pmids":["20736367","21135106","20376065"],"confidence":"High","gaps":["Balance of isoform expression in tissues not quantified","How membrane ADAM9 suppresses migration mechanistically incomplete"]},{"year":2010,"claim":"Identified ADAM9 as the causative gene for cone-rod dystrophy/CORD9, establishing a Mendelian disease link and pointing to a role in RPE-photoreceptor microvillar interaction.","evidence":"Canine GWAS/sequencing of crd3, light/electron microscopy, electroretinography","pmids":["20806078"],"confidence":"Medium","gaps":["Molecular function of ADAM9 in RPE microvilli undefined","Ortholog (canine) study; human mechanism inferred"]},{"year":2011,"claim":"Mechanistically resolved the ADAM9-ADAM10 relationship by showing the ADAM9 prodomain is a selective inhibitor and that ADAM9 controls ADAM10 membrane localization and alpha-secretase output.","evidence":"Recombinant prodomain Ki measurement, cell-based ADAM10 localization and sAPPα/β quantification","pmids":["21956108"],"confidence":"High","gaps":["Whether ADAM9 sheds ADAM10 directly versus other mechanism unresolved","In vivo relevance to APP biology untested"]},{"year":2012,"claim":"Placed ADAM9 in a regulatory complex with MT1-MMP and FGFR2, where MT1-MMP inactivates ADAM9 to protect FGFR2 from shedding during skeletal development.","evidence":"Co-IP, Mmp14−/− and Adam9-depletion mice, genetic rescue, FGFR2 shedding and skeletal phenotyping","pmids":["22632802"],"confidence":"High","gaps":["Structural basis of MT1-MMP cleavage of ADAM9 not defined","Generality beyond osteoblasts unknown"]},{"year":2015,"claim":"Defined ADAM9 as a stored neutrophil ECM-degrading protease and a direct platelet α6β1 ligand, linking it to acute lung injury and metastatic dissemination.","evidence":"Subcellular fractionation, in vitro ECM degradation, Adam9−/− lung-injury models, recombinant DC-9 platelet adhesion and α6β1 KO metastasis models","pmids":["25063875","27699237","25646025"],"confidence":"High","gaps":["In vivo substrate spectrum during lung injury incompletely defined","Relative contribution of adhesion vs proteolysis to metastasis unresolved"]},{"year":2017,"claim":"Characterized constitutive EphB4 shedding and selective inhibitor profiles, and elaborated ADAM9-driven angiogenic and metastatic transcriptional programs in lung cancer.","evidence":"Cell-based shedding with E>A mutant, TIMP/small-molecule profiling, siRNA knockdown with microarray, tPA/CDCP1 cleavage, miR-1/miR-218 reporter assays, in vivo tumor models","pmids":["28264989","29118335","25060522","28537886","24705471"],"confidence":"High","gaps":["Direct vs transcriptionally indirect effects on angiogenic factors not fully separated","miRNA-axis findings are Medium-confidence single-lab"]},{"year":2018,"claim":"Resolved a protease-independent role in integrin trafficking and linked ADAM9 to ROS-generating NOX1 in driving EMT, broadening its mechanism beyond shedding.","evidence":"siRNA, Co-IP with β1 integrin, internalization/recycling/degradation assays, NOX1 interaction and ROS measurement, EMT markers","pmids":["29142101","29432845"],"confidence":"High","gaps":["Mechanism by which ADAM9 promotes integrin endocytosis undefined","NOX1 interaction is Medium-confidence single lab"]},{"year":2019,"claim":"Identified an entirely proteinase-independent function as an EMCV entry factor/cofactor mediating viral attachment and genome delivery.","evidence":"Genome-wide CRISPR and haploid screens, KO in multiple cell lines, RNA-transfection bypass, catalytic-dead reconstitution, neutralization and binding assays","pmids":["30723129","31409686"],"confidence":"High","gaps":["Structural basis of EMCV-ADAM9 binding not resolved","Whether other picornaviruses use ADAM9 not addressed"]},{"year":2021,"claim":"Established ADAM9 as a TGF-β1 activator that cleaves LAP to drive Th17 differentiation, with ICER as a direct transcriptional activator, defining an immunological role in autoimmunity.","evidence":"Adam9−/− EAE model, T cell transfer, LAP cleavage, SMAD2/3 phosphorylation, ICER promoter binding, Th17 assays","pmids":["33911034"],"confidence":"High","gaps":["Spatial control of latent TGF-β1 activation in vivo unclear","Other immune cell contributions not dissected"]},{"year":2022,"claim":"Demonstrated ephrin-B1/B2 cleavage and Akt/Wnt/mTOR modulation, with cross-species rescue of ADAM13 in neural crest induction, indicating conserved developmental signaling roles.","evidence":"ADAM9 KD in CRC lines, ephrin-B cleavage, Wnt/mTOR/Akt assays, Xenopus neural crest rescue","pmids":["35780836"],"confidence":"Medium","gaps":["Cell-line-dependent signaling outcomes not mechanistically explained","Single lab"]},{"year":2024,"claim":"Revealed a non-shedding oncogenic mechanism whereby ADAM9 stabilizes KRAS by blocking PAI-1/LC3-mediated selective autophagy, and validated ADAM9 as a druggable PDAC target.","evidence":"Co-IP of KRAS-PAI-1-LC3, ADAM9 KO/inhibitor, autophagy/lysosomal degradation assays, spontaneous PDAC and PDX models","pmids":["38267627"],"confidence":"High","gaps":["How ADAM9 physically prevents PAI-1-KRAS interaction undefined","Whether mechanism is shared across other RAS-driven tumors unknown"]},{"year":null,"claim":"How ADAM9 integrates its distinct catalytic-dependent shedding, catalytic-independent integrin/adhesion, viral-cofactor, and protein-stabilization functions into a unified regulatory logic, and how isoform/localization balance is controlled in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating disintegrin and protease functions","Mechanism switching between protease-dependent and -independent modes undefined","Regulation of secreted vs membrane isoform expression in tissues unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,9,15,17,18,30,40,42]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[2,9,30]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[13,16,20,28]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[13,16,35]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[36,37]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[24,44]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,16,27]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[27]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[10,12,22,43]}],"pathway":[{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[12,18,20,27,38]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,25,40,42]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[15,28,44]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[27,40]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,24]}],"complexes":["MT1-MMP–FGFR2–ADAM9 complex","ADAM9–Naa10p complex","KRAS–PAI-1–LC3 autophagy complex (ADAM9-regulated)"],"partners":["PRKCD","SRC","ITGB1","ITGA6","MMP14","FGFR2","NAA10","NOX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13443","full_name":"Disintegrin and metalloproteinase domain-containing protein 9","aliases":["Cellular disintegrin-related protein","Meltrin-gamma","Metalloprotease/disintegrin/cysteine-rich protein 9","Myeloma cell metalloproteinase"],"length_aa":819,"mass_kda":90.6,"function":"Metalloprotease that cleaves and releases a number of molecules with important roles in tumorigenesis and angiogenesis, such as TEK, KDR, EPHB4, CD40, VCAM1 and CDH5. May mediate cell-cell, cell-matrix interactions and regulate the motility of cells via interactions with integrins May act as alpha-secretase for amyloid precursor protein (APP)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q13443/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM9","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},{"gene":"DDOST","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADAM9","total_profiled":1310},"omim":[{"mim_id":"621000","title":"SORTING NEXIN 18; SNX18","url":"https://www.omim.org/entry/621000"},{"mim_id":"620561","title":"DENN DOMAIN-CONTAINING PROTEIN 6A; DENND6A","url":"https://www.omim.org/entry/620561"},{"mim_id":"614404","title":"RHOMBOID 5 HOMOLOG 2; RHBDF2","url":"https://www.omim.org/entry/614404"},{"mim_id":"612775","title":"CONE-ROD DYSTROPHY 9; CORD9","url":"https://www.omim.org/entry/612775"},{"mim_id":"605952","title":"SORTING NEXIN 9; SNX9","url":"https://www.omim.org/entry/605952"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADAM9"},"hgnc":{"alias_symbol":["MDC9","KIAA0021","MCMP","Mltng"],"prev_symbol":["CORD9"]},"alphafold":{"accession":"Q13443","domains":[{"cath_id":"-","chopping":"39-54_63-84_115-165","consensus_level":"high","plddt":88.4292,"start":39,"end":165},{"cath_id":"3.40.390.10","chopping":"207-397","consensus_level":"high","plddt":88.2874,"start":207,"end":397},{"cath_id":"-","chopping":"417-458","consensus_level":"medium","plddt":82.7626,"start":417,"end":458},{"cath_id":"-","chopping":"504-644","consensus_level":"high","plddt":87.3488,"start":504,"end":644}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13443","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13443-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13443-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM9","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM9"},"sequence":{"accession":"Q13443","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13443.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13443/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13443"}},"corpus_meta":[{"pmid":"9857183","id":"PMC_9857183","title":"A 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MDC9 is present on the plasma membrane of NIH 3T3 fibroblasts as an ~84 kDa glycoprotein.\",\n      \"method\": \"Protein domain analysis, cell surface biotinylation, 125I-labeling, immunofluorescence of COS-7 cells expressing MDC9\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical cell-surface experiments and SH3 binding demonstrated in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"8647900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PKCδ binds in vivo and in vitro to the cytoplasmic domain of MDC9/ADAM9. Constitutively active PKCδ or MDC9 overexpression induces ectodomain shedding of proHB-EGF, while MDC9 lacking the metalloprotease domain and kinase-negative PKCδ suppress TPA-induced HB-EGF ectodomain shedding.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro binding), dominant-negative/constitutively active mutant overexpression, ectodomain shedding assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vivo and in vitro Co-IP, domain deletion mutants and dominant-negative/active constructs, replicated with multiple approaches in a single rigorous study\",\n      \"pmids\": [\"9857183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The prodomain of MDC9/ADAM9 is removed by a furin-type proprotein convertase in the secretory pathway before cell surface emergence. Soluble MDC9 metalloprotease domain is catalytically active, cleaving insulin B-chain. MDC9 activity is inhibited by hydroxamic acid metalloprotease inhibitors (low nM range). Cysteine-switch peptides inhibit MDC9 in low µM range, providing evidence for cysteine-switch regulation. MDC9 becomes phosphorylated upon phorbol ester (PMA) treatment.\",\n      \"method\": \"Biochemical cleavage assays (insulin B-chain), inhibitor profiling, cysteine-switch peptide inhibition, metabolic labeling/phosphorylation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic activity assay with mutagenesis-equivalent prodomain removal, inhibitor characterization, and phosphorylation assay; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"9920899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The cytoplasmic domains of MDC9/ADAM9 interact with two SH3 domain-containing proteins: endophilin I (SH3GL2/SH3p4) and a novel protein SH3PX1 (containing SH3 and PX domains). Both proteins preferentially bind the precursor but not the processed form of MDC9 in COS-7 cells.\",\n      \"method\": \"Yeast two-hybrid screen, GST pulldown with bacterial fusion proteins, co-immunoprecipitation from eukaryotic cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by orthogonal pulldown and Co-IP; precursor vs. processed form selectivity demonstrated\",\n      \"pmids\": [\"10531379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"MDC9 co-expressed with APP695 in COS cells promotes exclusive alpha-secretory cleavage of APP upon phorbol ester treatment. Inhibition of MDC9 by the hydroxamate inhibitor SI-27 enhanced beta-secretase cleavage of APP.\",\n      \"method\": \"Co-expression in COS cells, APP cleavage assay (alpha-secretory site mutant), hydroxamate inhibitor treatment\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based overexpression and inhibitor assay, single lab, two orthogonal approaches (mutant substrate + inhibitor)\",\n      \"pmids\": [\"10510302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The cytoplasmic domain of MDC9/ADAM9 interacts with a novel MAD2-related protein, MAD2β (23% identity to MAD2, a spindle assembly checkpoint component). Interaction confirmed biochemically.\",\n      \"method\": \"Yeast two-hybrid screen, biochemical confirmation of interaction\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid with biochemical confirmation, single lab; functional consequence not established\",\n      \"pmids\": [\"10527948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MDC9/ADAM9 is localized to the basolateral surface of renal cortical tubule cells and glomerular visceral epithelial cells, co-localizing with β1 integrin. Expression of soluble disintegrin domain in glomerular epithelial cells causes cell rounding and detachment, indicating functional role in epithelial cell-matrix adhesion.\",\n      \"method\": \"Immunohistochemistry, GFP-chimera expression, Western blot of kidney fractions, cell morphology assay\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by multiple methods tied to functional consequence (cell detachment upon disintegrin domain expression)\",\n      \"pmids\": [\"10752518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAM9 is involved in monocyte fusion (multinucleated giant cell formation). Anti-ADAM9 antibody blocks CD98-mediated and RANKL-mediated multinucleated giant cell formation. The metalloprotease inhibitor SI-27 (which suppresses ADAM9 activity) also suppresses this fusion.\",\n      \"method\": \"Antibody blocking assay, metalloprotease inhibitor treatment, RT-PCR for expression\",\n      \"journal\": \"Cellular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — antibody blocking and inhibitor experiments in primary human monocytes, single lab, functional phenotype clearly defined\",\n      \"pmids\": [\"11831872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Loss of MDC9/ADAM9 (mdc9−/− mice) does not impair constitutive or stimulated HB-EGF ectodomain shedding in embryonic fibroblasts, nor does it alter APP alpha-secretase (p3) or beta/gamma-secretase (Aβ) processing in hippocampal neurons, arguing against essential non-redundant roles in these processes in vivo.\",\n      \"method\": \"Genetic knockout (mdc9−/− mice), ectodomain shedding assay in primary fibroblasts, Aβ/p3 measurement in hippocampal neurons\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic KO model with multiple specific substrate assays; negative results for HB-EGF shedding and APP processing are mechanistically informative\",\n      \"pmids\": [\"11839819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Soluble ADAM9 activity is not inhibited by TIMP-1, TIMP-2, TIMP-3, or TIMP-4 (tissue inhibitors of metalloproteinases), but can be inhibited by hydroxamate inhibitors, distinguishing it from ADAM10, ADAM12, ADAM17, and MT-MMPs.\",\n      \"method\": \"In vitro protease activity assay with TIMP inhibition profiling\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro enzymatic assay with defined substrates and inhibitor panel; single lab but rigorous biochemical method\",\n      \"pmids\": [\"12135759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"A secreted splice variant of human ADAM9 (hADAM9s), lacking the C-terminal transmembrane and cytoplasmic domains, is secreted from transfected COS cells and has alpha-secretase-like activity for APP upon phorbol ester treatment.\",\n      \"method\": \"Cloning of splice variant, COS cell transfection, APP cleavage assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based cleavage assay with defined splice variant; single lab, two orthogonal approaches (cloning + functional assay)\",\n      \"pmids\": [\"12054541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAM9, ADAM10, and ADAM17 each catalyze alpha-secretory cleavage of APP in COS-7 cells. Lipofection of dsRNA to suppress endogenous ADAM9 in A172 glioblastoma cells reduces alpha-secretase cleavage, indicating that endogenous ADAM9 contributes to constitutive and regulated alpha-secretase activity.\",\n      \"method\": \"Overexpression in COS-7 cells, RNAi knockdown in A172 cells, APP cleavage measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (RNAi) combined with gain-of-function (overexpression), single lab\",\n      \"pmids\": [\"12535668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A secreted form of ADAM9 (ADAM9-S) is secreted by hepatic stellate cells, binds directly to α6β4 and α2β1 integrins on colon carcinoma cells via its disintegrin domain, and promotes carcinoma invasion. ADAM9-S also cleaves laminin. Protease activity of ADAM9-S is required for invasion.\",\n      \"method\": \"Matrigel invasion assay, direct binding assay (disintegrin domain to integrins), laminin cleavage assay, protease-inactive mutant\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay, substrate cleavage (laminin), and protease-dead mutant all used in single study; multiple orthogonal methods\",\n      \"pmids\": [\"15930291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The disintegrin domain of ADAM9 is a polyvalent ligand for multiple β1 renal integrins (α1, α3, α6, αv, β1). Expression of ADAM9 on HEK-293 cells decreases adhesion to collagen I/IV, vitronectin, and laminin via competitive inhibition of cell-matrix binding through the disintegrin domain. The cysteine-rich domain alone has no effect on adhesion.\",\n      \"method\": \"Recombinant GST-disintegrin domain pulldown, adhesion assay with integrin-blocking antibodies, GFP-chimera expression, Western blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple adhesion and binding assays with antibody blocking and domain deletion constructs; multiple orthogonal methods\",\n      \"pmids\": [\"15361064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM9 participates in constitutive secretion of PrPc N1 fragment in HEK293 cells, TSM1 neurons, and fibroblasts; ADAM9 antisense reduces N1 and sAPPα recoveries. However, ADAM9 requires ADAM10 for this activity: ADAM9 cannot cleave alpha-secretase substrates in ADAM10−/− fibroblasts, but co-expression of ADAM9 and ADAM10 enhances activity beyond ADAM10 alone. ADAM9 contributes to PrPc processing indirectly by promoting shedding of ADAM10.\",\n      \"method\": \"Transient and stable transfection, antisense knockdown, ADAM10−/− fibroblasts, fluorimetric substrate assay, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic ADAM10 KO cells combined with complementation, antisense knockdown, and quantitative enzyme assays; multiple orthogonal methods revealing epistatic relationship\",\n      \"pmids\": [\"16236709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM9 loss in the W10 prostate cancer mouse model results in mostly well-differentiated tumors, while ADAM9-expressing controls develop poorly differentiated tumors. ADAM9 overexpression in mouse prostate epithelium causes hyperplasia and prostatic intraepithelial neoplasia. In cell-based assays, ADAM9 cleaves and releases EGF and FGFR2iiib from cells.\",\n      \"method\": \"Genetic KO in tumor mouse model (W10 × mdc9−/−), prostate-specific overexpression transgenic mice, cell-based shedding assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function genetic mouse models combined with cell-based shedding assays; multiple orthogonal approaches\",\n      \"pmids\": [\"16230393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The recombinant disintegrin-cysteine-rich domain of ADAM-9 specifically interacts with the β1 integrin subunit on keratinocytes (confirmed by solid-phase binding assay and co-immunoprecipitation). Engagement of integrin receptors by this domain induces ERK phosphorylation and increased MMP-9 synthesis. Keratinocytes adhering to immobilized ADAM-9 disintegrin-cysteine-rich domain show increased motility, partially dependent on MMP-9 induction.\",\n      \"method\": \"Solid-phase binding assay, antibody inhibition, Co-immunoprecipitation, ERK phosphorylation assay, MMP-9 Western blot, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, binding assay, signaling readout (ERK), and functional migration assay; multiple orthogonal methods in single study\",\n      \"pmids\": [\"17704059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM9 deficiency (Adam9−/−) significantly reduces pathological neovascularization in OIR (oxygen-induced retinopathy) and laser-induced choroidal neovascularization models, and reduces tumor growth from heterotopically injected melanoma cells. ADAM9 overexpression enhances shedding of EphB4, Tie-2, Flk-1, CD40, VCAM, and VE-cadherin. ADAM9 expression and shedding are upregulated by reactive oxygen species (H2O2).\",\n      \"method\": \"Adam9−/− mouse models (OIR, CNV, tumor xenograft), cell-based overexpression shedding assay, ROS stimulation assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in multiple in vivo models plus cell-based substrate shedding and ROS stimulation; multiple orthogonal methods\",\n      \"pmids\": [\"19273593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAMs 9 and 10 are the major collagen XVII sheddases in primary keratinocytes. Adam9−/− keratinocytes show a 55% decrease in constitutive collagen XVII ectodomain shedding. H2O2 enhances ADAM9 expression and stimulates collagen XVII shedding in wild-type but not Adam9−/− skin/keratinocytes.\",\n      \"method\": \"Adam9−/− and Adam10−/− primary keratinocyte cultures, ADAM10-selective inhibitor (GI254023X), phorbol ester treatment, H2O2 stimulation, collagen XVII shedding assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model with selective inhibitor, multiple substimuli, quantitative shedding assay; multiple orthogonal approaches\",\n      \"pmids\": [\"19574220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LPS activates ADAM9-dependent shedding of ACE from endothelial cells. ADAM9 requires both membrane anchorage and its catalytic domain to shed ACE, as shown by transient transfection of ADAM9 and ACE cDNAs in HEK293 cells.\",\n      \"method\": \"siRNA knockdown, inhibitor profiling (TIMP-based), HEK293 co-transfection with ADAM9 and ACE, catalytic domain mutant\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown confirmed by transfection with catalytic mutant; single lab, two orthogonal approaches\",\n      \"pmids\": [\"22480688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM9 expression in melanoma cells is required for adhesion to fibroblasts. The disintegrin-like and cysteine-rich domains of ADAM-9 mediate Mn2+-dependent integrin-mediated adhesion of melanoma cells and fibroblasts (via multiple β1 integrins, independent of RGD and ECD motifs). Interaction with soluble DC-9 induces MMP-1 and MMP-2 expression in fibroblasts and melanoma cells. ADAM9 silencing in fibroblasts abolishes cellular interactions and melanoma invasion.\",\n      \"method\": \"Recombinant DC-9 domain adhesion assay, integrin-blocking antibodies, siRNA knockdown, MMP expression assay, invasion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — recombinant domain adhesion assay, antibody blocking, siRNA knockdown with multiple functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"21135106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Adam9−/− mice show accelerated wound repair due to increased keratinocyte migration. Re-epithelialization is faster in Adam9−/− wounds, and increased migration (not proliferation) of keratinocytes is responsible. This is mechanistically linked to modulation of collagen XVII shedding by ADAM9.\",\n      \"method\": \"Adam9−/− genetic KO, excisional wound model, immunolocalization, keratinocyte migration assay, proliferation assay\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific in vivo and in vitro phenotypic readouts, mechanism linked to collagen XVII shedding\",\n      \"pmids\": [\"20376065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Secreted ADAM9 (ADAM9-S) promotes breast cancer cell migration via its metalloproteinase activity. Membrane-bound ADAM9 (ADAM9-L) suppresses migration independent of metalloproteinase activity but requiring a functional disintegrin domain and integrin binding. The two isoforms thus have opposing effects on migration.\",\n      \"method\": \"Isoform-specific overexpression, metalloproteinase-dead mutant, disintegrin domain mutant, migration assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isotype-specific constructs, catalytic and disintegrin domain mutants, functional migration assay; multiple orthogonal methods distinguishing two isoform mechanisms\",\n      \"pmids\": [\"20736367\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An ADAM9 deletion (removing exons 15 and 16, introducing a premature stop and removing critical domains) causes cone-rod dystrophy 3 (crd3) in Glen of Imaal Terriers, establishing homology to human CORD9. Light and electron microscopy show the primary lesion is failure of retinal pigment epithelium apical microvilli to invest photoreceptor outer segments.\",\n      \"method\": \"Genome-wide association, sequencing, light and electron microscopy, electroretinography\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutation identified with structural/histological characterization; ortholog (canine) study\",\n      \"pmids\": [\"20806078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The ADAM9 prodomain (proA9) is a competitive inhibitor of ADAM9 catalytic/disintegrin domain (Ki = 280 ± 34 nM) with high specificity. Inhibition of ADAM9 by proA9 in SY5Y neuroblastoma cells reduces ADAM10 shedding into the medium while increasing membrane-bound ADAM10, resulting in higher sAPPα and lower sAPPβ levels. This demonstrates that ADAM9 controls ADAM10 membrane localization and alpha-secretase activity.\",\n      \"method\": \"Recombinant prodomain expression from E. coli, competitive inhibition assay, Western blot, fluorescent peptide substrate assay (proteolytic activity matrix analysis), proteomic quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical inhibition with Ki measurement, cell-based mechanistic assay linking ADAM9 inhibition to ADAM10 localization and APP processing; multiple orthogonal methods\",\n      \"pmids\": [\"21956108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MT1-MMP (MMP14) forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9, protecting FGFR2 from ADAM9-mediated ectodomain shedding. In Mmp14−/− osteoblasts, ADAM9 is upregulated and FGFR2 shedding increases, compromising FGF-induced proliferation and signaling. Adam9 depletion completely rescues defective FGFR2 signaling and largely restores calvarial bone growth in Mmp14−/− embryos.\",\n      \"method\": \"Co-immunoprecipitation (complex formation), Mmp14−/− and Adam9 depletion mouse models, FGFR2 shedding assay, downstream signaling assay, skeletal phenotype analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genetic KO, genetic rescue (double KO), in vivo phenotype rescue; multiple orthogonal methods with rigorous controls\",\n      \"pmids\": [\"22632802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM9 enhances tissue plasminogen activator (tPA)-mediated cleavage and activation of the promigratory protein CDCP1, promoting lung cancer metastasis to the brain. Blocking this mechanism prolongs survival in tumor-bearing mice, and cooperates with dexamethasone and dasatinib treatment.\",\n      \"method\": \"In vivo tumor metastasis model, survival analysis, inhibitor combination studies, protein cleavage assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo tumor model with mechanistic substrate cleavage assay; single lab with multiple functional readouts\",\n      \"pmids\": [\"25060522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM9 is stored in gelatinase and specific granules and secretory vesicles of human PMNs (not synthesized de novo). PMN activation with degranulating agonists rapidly increases surface ADAM9. ADAM9 degrades ECM proteins (fibronectin, entactin, laminin, insoluble elastin) as potently as MMP-9, but does not degrade type I, III, or IV collagens or denatured collagens in vitro. Adam9 increases mortality and promotes alveolar-capillary barrier injury during LPS- and bleomycin-induced acute lung injury in mice; Adam9 does not regulate PMN/macrophage recruitment.\",\n      \"method\": \"Subcellular fractionation, flow cytometry, in vitro ECM degradation assays, Adam9−/− mouse lung injury models\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — subcellular fractionation defining storage granules, in vitro substrate assays (positive and negative), and genetic KO in vivo model; multiple orthogonal methods\",\n      \"pmids\": [\"25063875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Platelet integrin α6β1 directly binds to ADAM9 on tumor cell surfaces via the disintegrin-cysteine domain of ADAM9 (DC-9 recombinant protein). This platelet-tumor cell interaction promotes platelet activation, tumor cell extravasation, and efficient lung metastasis. Genetic deficiency of integrin α6β1 on platelets markedly decreases experimental and spontaneous lung metastasis.\",\n      \"method\": \"Knockdown approach (siRNA), static and flow-based adhesion assays with recombinant DC-9, α6β1 KO mouse model (experimental and spontaneous metastasis), pharmacological inhibition\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assay with recombinant domain, ADAM9 knockdown, and integrin KO mouse models with multiple metastasis readouts; multiple orthogonal methods\",\n      \"pmids\": [\"27699237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TNC (tenascin-C) stimulates BTIC (brain tumor-initiating cell) invasiveness in a metalloproteinase-dependent manner involving ADAM-9. TNC increases ADAM-9 protein expression in 4 BTIC lines. RNAi-mediated ADAM-9 knockdown and inhibition of JNK attenuate TNC-stimulated ADAM-9 expression, proteolytic activity, and BTIC invasiveness.\",\n      \"method\": \"Microarray gene expression screen, lentiviral RNAi knockdown, ADAM-9 activity assay, JNK inhibitor treatment, orthotopic xenograft\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined phenotypic readout and pathway inhibitor; single lab with multiple methods\",\n      \"pmids\": [\"25646025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM9 constitutively sheds EphB4 in a manner not stimulated by phorbol esters, pervanadate, or calcium ionophores. ADAM9 is inhibited by TIMP-3 (10 nM) but not by TIMP-1 or TIMP-2 (up to 20 nM). Novel non-hydroxamate small-molecule inhibitors selectively inhibit ADAM9-dependent proteolysis over ADAM10 or ADAM17.\",\n      \"method\": \"Cell-based shedding assay with catalytically inactive ADAM9 E>A mutant as control, TIMP inhibitor profiling, small-molecule library screen\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based enzymatic assay with inactive mutant control, comprehensive TIMP and inhibitor profiling; multiple orthogonal methods\",\n      \"pmids\": [\"28264989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM9 promotes lung cancer progression through vascular remodeling by upregulating VEGFA, ANGPT2, and PLAT (tPA). Silencing ADAM9 in lung cancer cells decreases expression of these angiogenic factors, reduces angiogenesis and vascular remodeling, and inhibits tumor growth in vivo.\",\n      \"method\": \"ADAM9 siRNA knockdown, microarray, in vivo tumor model, angiogenesis assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined downstream gene expression and in vivo angiogenesis; single lab\",\n      \"pmids\": [\"29118335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM9 knockdown reduces EGFR signaling and increases miR-1 expression in lung cancer cells. miR-1 directly targets the 3'UTR of CDCP1, inhibiting its translation. Thus ADAM9 down-regulates miR-1 via EGFR signaling, which in turn enhances CDCP1 expression to promote lung cancer progression.\",\n      \"method\": \"Luciferase reporter assay, EGFR signaling analysis, miR-1 expression measurement, tumor metastasis mouse model, miR-1 overexpression\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter, signaling pathway analysis, and in vivo model; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"28537886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ADAM9 upregulates N-cadherin (CDH2) expression in aggressive lung adenocarcinoma cells by suppressing miR-218. miR-218 is generated from pri-miR-218-1 located in SLIT2. ADAM9 knockdown upregulates SLIT2 and miR-218, which then down-regulates CDH2.\",\n      \"method\": \"miRNA microarray, luciferase assay, Western blot, siRNA knockdown of ADAM9\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase assay confirming CDH2 as miR-218 target, ADAM9 knockdown with pathway analysis; single lab\",\n      \"pmids\": [\"24705471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"IL-6 upregulates ADAM9 expression in HCC cells via the JNK signaling pathway. ADAM9 promotes HCC cell invasion and EMT by interacting with NADPH oxidase 1 (NOX1) and inducing reactive oxygen species (ROS) generation. ADAM9 knockdown inhibits IL-6-induced EMT.\",\n      \"method\": \"JNK inhibitor treatment, siRNA knockdown, NOX1 interaction assay, ROS measurement, migration/invasion assay, EMT marker Western blot\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — signaling inhibitor, knockdown, protein interaction assay, and ROS measurement; single lab with multiple methods\",\n      \"pmids\": [\"29432845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM9 loss (siRNA knockdown) increases β1 integrin levels independently of protease activity. ADAM9 co-immunoprecipitates with β1 integrin. In ADAM9-silenced cells, β1 integrin internalization and degradation are significantly decreased (with no effect on recycling), altering focal adhesion formation, actin stress fibers, cell adhesion and migration.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, β1 integrin internalization/recycling/degradation assays, focal adhesion staining, migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, protease-independent mechanism established by specific mutant analysis, endocytosis/trafficking assays, and functional readouts; multiple orthogonal methods\",\n      \"pmids\": [\"29142101\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM9 is required for the early stages (entry/genome delivery) of EMCV (encephalomyocarditis virus) infection. CRISPR-mediated deletion of ADAM9 renders cells highly resistant to EMCV. Bypassing entry by delivering viral RNA directly to the cytosol restores EMCV replication in ADAM9 KO cells, indicating ADAM9 is not required for post-entry replication. Reconstitution of catalytically inactive ADAM9 in KO cells restores susceptibility, indicating a proteinase-independent role.\",\n      \"method\": \"Genome-wide CRISPR-Cas9 KO screen, ADAM9 CRISPR deletion in multiple cell lines, viral RNA transfection bypass experiment, reconstitution with inactive ADAM9 mutant\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen with validation in multiple cell lines, mechanistic bypass experiment, and catalytic-dead reconstitution; multiple orthogonal methods\",\n      \"pmids\": [\"30723129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM9 facilitates attachment of EMCV to the cell surface, functioning as a receptor or cofactor for EMCV entry independent of its metalloproteinase activity (pharmacological metalloproteinase inhibition did not affect infection; catalytically inactive ADAM9 restored susceptibility in KO cells).\",\n      \"method\": \"Haploid genetic screen, CRISPR KO cell lines, neutralization assays with ADAM9-specific antiserum, soluble receptor proteins, cell-surface binding assays, catalytically inactive ADAM9 reconstitution\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple complementary approaches (screen, KO, neutralization, binding, catalytic mutant reconstitution); independent replication between two papers (PMID 30723129 and 31409686)\",\n      \"pmids\": [\"31409686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM9 contributes to vascular invasion in PDAC by mediating cell migration and adhesion to fibronectin, tenascin, and vitronectin (dependent on its catalytic activity). ADAM9 facilitates anchorage-independent growth. ADAM9 promotes angiogenesis in vitro and in vivo and regulates the levels of angiogenic factors including shed HB-EGF. ADAM9 post-translationally regulates integrin abundance in AsPC1 cells.\",\n      \"method\": \"siRNA gene silencing, migration and adhesion assays, anchorage-independent growth assay, HUVEC sprout formation with conditioned medium, orthotopic mouse model, immunoblotting\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple in vitro and in vivo readouts; single lab\",\n      \"pmids\": [\"30556643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Naa10p (N-α-acetyltransferase 10 protein) forms a complex with ADAM9 to maintain ADAM9 protein stability, promoting AIPC (androgen-independent prostate cancer) invasive ability independently of Naa10p acetyltransferase activity. ADAM9 also exerts positive feedback regulation on Naa10p.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, overexpression, in vitro/in vivo invasion assays, xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for complex formation, acetyltransferase mutant to distinguish mechanism; single lab\",\n      \"pmids\": [\"32719332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM9 cleaves the latency-associated peptide (LAP) of TGF-β1 to produce bioactive TGF-β1, which promotes SMAD2/3 phosphorylation and Th17 cell differentiation. Inducible cAMP early repressor (ICER) binds directly to the ADAM9 promoter and promotes its transcription. Adam9-deficient mice show mitigated experimental autoimmune encephalomyelitis (EAE).\",\n      \"method\": \"Adam9−/− mouse EAE model, T cell transfer assay, TGF-β1/LAP cleavage assay, SMAD2/3 phosphorylation assay, ICER promoter-binding (ChIP implied), Th17 differentiation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse model with T cell transfer assay, substrate cleavage assay, and downstream signaling; multiple orthogonal methods establishing mechanistic pathway\",\n      \"pmids\": [\"33911034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"USP39 promotes glioma cell migration and invasion by facilitating ADAM9 mRNA maturation (splicing), increasing ADAM9 expression. Overexpression of ADAM9 rescues the reduced migration/invasion caused by USP39 depletion.\",\n      \"method\": \"shRNA knockdown, gene expression profiling, mRNA maturation assay, rescue by ADAM9 overexpression, in vivo invasion model\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined mechanism (mRNA maturation) and genetic rescue; single lab\",\n      \"pmids\": [\"33811456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM9 cleaves ephrin-B1 and ephrin-B2 in mammalian (colorectal cancer) cells, can substitute for Xenopus ADAM13 in neural crest induction, and its knockdown reduces Akt kinase activity. ADAM9 KD differentially regulates Wnt and mTOR signaling downstream of Akt in a cell-line-dependent manner.\",\n      \"method\": \"ADAM9 KD in CRC cell lines, luciferase-based Wnt reporter, mTOR pathway assay, Akt kinase assay, Xenopus neural crest induction rescue experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate cleavage (ephrin-B) with functional rescue in Xenopus and mammalian loss-of-function; single lab with multiple methods\",\n      \"pmids\": [\"35780836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The secreted isoform of ADAM9 (ADAM9s) from cancer-associated fibroblasts (CAFs) with Immature desmoplastic reaction promotes CRC cell proliferation and migration. Knockdown of ADAM9s in these CAFs abrogates their tumor-promoting effects.\",\n      \"method\": \"CAF isolation from patient tissue, conditioned media assay, ADAM9s knockdown, CRC cell proliferation/migration assays, subcutaneous and orthotopic mouse models\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primary CAF isolation, knockdown with functional rescue, in vivo model; single lab\",\n      \"pmids\": [\"35080810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAM9 stabilizes wild-type and mutant KRAS proteins in PDAC. ADAM9 loss increases interaction of KRAS with PAI-1 (plasminogen activator inhibitor 1), which functions as a selective autophagy receptor together with LC3, triggering lysosomal degradation of KRAS. A small-molecule ADAM9 inhibitor restricts PDAC disease progression in spontaneous models, and combination with gemcitabine elicits regression of patient-derived tumors.\",\n      \"method\": \"Co-immunoprecipitation (KRAS-PAI-1-LC3 complex), ADAM9 KO/inhibitor experiments, autophagy/lysosomal degradation assays, spontaneous PDAC mouse model, PDX model\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP defining complex, mechanistic autophagy assays, genetic KO and small-molecule inhibitor, multiple in vivo models; rigorous multi-method study\",\n      \"pmids\": [\"38267627\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM9 is a membrane-anchored metalloprotease-disintegrin whose prodomain is removed by a furin-type convertase in the secretory pathway; the mature enzyme sheds a broad range of cell-surface proteins (HB-EGF, EGF, FGFR2, EphB4, Tie-2, Flk-1, VE-cadherin, collagen XVII, ACE, ephrin-B1/B2, LAP-TGFβ1, and KRAS via autophagy) and is regulated by PKCδ binding to its cytoplasmic tail, ROS, and phosphorylation; its disintegrin-cysteine-rich domain directly engages multiple β1 integrins to control cell adhesion, migration, integrin endocytosis, and downstream ERK/Akt signaling; it also indirectly modulates alpha-secretase activity by controlling ADAM10 membrane localization, acts as a proteinase-independent entry factor/cofactor for EMCV, and cleaves LAP to generate bioactive TGFβ1 that drives Th17 differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAM9 is a membrane-anchored metalloprotease-disintegrin that controls cell-surface proteolysis and integrin-dependent adhesion across tissue remodeling, angiogenesis, and tumor progression [#15, #17]. Its prodomain is removed by a furin-type convertase in the secretory pathway to yield a catalytically active enzyme that cleaves insulin B-chain, is sensitive to hydroxamate inhibitors but not to TIMP-1/-2/-4 (and only weakly to TIMP-3), distinguishing it biochemically from related ADAMs [#2, #9, #30]. As a sheddase it releases a broad substrate set including EGF and FGFR2 [#15], EphB4, Tie-2, Flk-1, and VE-cadherin [#17], collagen XVII [#18], ACE [#19], and ephrin-B1/B2 [#42], and cleaves the latency-associated peptide of TGF-\\u03b21 to generate bioactive TGF-\\u03b21 that drives SMAD2/3 phosphorylation and Th17 differentiation [#40]. Independent of its catalytic activity, the disintegrin\\u2013cysteine-rich domain is a polyvalent ligand for multiple \\u03b21 integrins, modulating cell\\u2013matrix adhesion, ERK signaling and MMP induction, and migration [#13, #16, #20], while ADAM9 association with \\u03b21 integrin governs integrin internalization and degradation to remodel focal adhesions [#35]. Shedding and adhesion functions are regulated through the cytoplasmic tail, which binds PKC\\u03b4 to couple ectodomain shedding to signaling [#1], and ADAM9 expression and activity are induced by reactive oxygen species [#17]. ADAM9 also acts indirectly by controlling ADAM10 membrane localization and thereby alpha-secretase activity [#24], and serves as a proteinase-independent entry factor/cofactor for encephalomyocarditis virus [#36, #37]. In cancer, ADAM9 stabilizes KRAS by preventing PAI-1/LC3-mediated selective autophagic degradation, and its small-molecule inhibition restricts PDAC progression [#44]. Loss-of-function mutation of ADAM9 causes cone-rod dystrophy/CORD9, with the primary lesion being failure of retinal pigment epithelium apical microvilli to invest photoreceptor outer segments [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that the ADAM9 cytoplasmic tail is a signaling adaptor by showing its proline-rich motifs bind the Src SH3 domain, framing the protein as more than a surface protease.\",\n      \"evidence\": \"Domain analysis, cell-surface biotinylation, and immunofluorescence of MDC9-expressing cells\",\n      \"pmids\": [\"8647900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Src binding not demonstrated\", \"No catalytic activity tested yet\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linked ADAM9 to regulated ectodomain shedding by showing PKC\\u03b4 binds its cytoplasmic tail and that ADAM9 mediates proHB-EGF shedding, coupling intracellular signaling to surface proteolysis.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant-negative/active PKC\\u03b4 constructs, domain-deletion mutants, shedding assay\",\n      \"pmids\": [\"9857183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological in vivo relevance not tested\", \"Whether ADAM9 directly cleaves HB-EGF or acts via another sheddase unclear\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined ADAM9 as a bona fide active metalloprotease processed by furin and regulated by cysteine-switch and phosphorylation, with a defined inhibitor sensitivity profile.\",\n      \"evidence\": \"Insulin B-chain cleavage, inhibitor profiling, cysteine-switch peptide assays, phosphorylation labeling\",\n      \"pmids\": [\"9920899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not yet defined\", \"In vivo activation state unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Expanded the cytoplasmic interactome to endophilin I, SH3PX1, and a MAD2-related protein, indicating precursor-selective trafficking/regulatory partnerships.\",\n      \"evidence\": \"Yeast two-hybrid screens with GST pulldown and Co-IP\",\n      \"pmids\": [\"10531379\", \"10527948\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional roles of endophilin/SH3PX1/MAD2\\u03b2 interactions not established\", \"Precursor-selective binding mechanism unexplained\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"A genetic knockout showed ADAM9 is dispensable for HB-EGF shedding and APP processing in vivo, revealing functional redundancy and reframing earlier overexpression results.\",\n      \"evidence\": \"mdc9\\u2212/\\u2212 mice with fibroblast shedding and neuronal A\\u03b2/p3 assays\",\n      \"pmids\": [\"11839819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundant ADAMs not identified\", \"Does not exclude context-specific roles\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the disintegrin\\u2013cysteine-rich domain as a polyvalent \\u03b21-integrin ligand controlling cell-matrix adhesion, separating an adhesion function from catalysis.\",\n      \"evidence\": \"GST-disintegrin pulldown, adhesion assays with integrin-blocking antibodies, GFP-chimera expression\",\n      \"pmids\": [\"15361064\", \"10752518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integrin selectivity rules not resolved\", \"Signaling downstream of adhesion not yet mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established ADAM9 substrates and tumor-promoting shedding (EGF, FGFR2, laminin) and showed secreted ADAM9 directly binds integrins to drive carcinoma invasion.\",\n      \"evidence\": \"W10 prostate cancer KO/overexpression mouse models, direct integrin-binding and laminin cleavage assays, protease-dead mutant\",\n      \"pmids\": [\"16230393\", \"15930291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of soluble vs membrane ADAM9 in vivo unclear\", \"Tumor-stage specificity not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Revealed that ADAM9 acts indirectly on alpha-secretase substrates by requiring and promoting ADAM10, establishing an epistatic relationship rather than direct redundancy.\",\n      \"evidence\": \"ADAM10\\u2212/\\u2212 complementation, antisense knockdown, fluorimetric substrate assays\",\n      \"pmids\": [\"16236709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ADAM10 promotion not yet defined at this stage\", \"Distinction from direct cleavage incomplete\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected integrin engagement by the disintegrin\\u2013cysteine-rich domain to downstream ERK activation, MMP-9 induction, and motility, defining an outside-in signaling axis.\",\n      \"evidence\": \"Solid-phase binding, Co-IP, ERK phosphorylation, MMP-9 Western, keratinocyte migration assays\",\n      \"pmids\": [\"17704059\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether signaling occurs in trans or cis unclear\", \"In vivo relevance to keratinocyte biology untested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed ADAM9 drives pathological neovascularization and identified ROS as an upstream inducer of ADAM9 expression and shedding of vascular substrates.\",\n      \"evidence\": \"Adam9\\u2212/\\u2212 OIR/CNV/tumor models, overexpression shedding assays, H2O2 stimulation\",\n      \"pmids\": [\"19273593\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect cleavage of each vascular substrate not all confirmed\", \"ROS-to-ADAM9 signaling mechanism not detailed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined ADAM9 as a major constitutive collagen XVII and ACE sheddase, tying its activity to keratinocyte basement-membrane biology and endothelial inflammation.\",\n      \"evidence\": \"Adam9\\u2212/\\u2212 keratinocytes, ADAM10-selective inhibitor, LPS/HEK293 ACE shedding with catalytic mutant\",\n      \"pmids\": [\"19574220\", \"22480688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus-specific regulation of collagen XVII shedding incomplete\", \"ACE shedding study lower confidence on direct cleavage\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Separated the opposing roles of the secreted and membrane isoforms in migration and linked ADAM9-driven adhesion to tumor-stroma interactions and metastasis.\",\n      \"evidence\": \"Isoform-specific and domain-mutant constructs, recombinant DC-9 adhesion assays, siRNA, wound-repair and migration models\",\n      \"pmids\": [\"20736367\", \"21135106\", \"20376065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Balance of isoform expression in tissues not quantified\", \"How membrane ADAM9 suppresses migration mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified ADAM9 as the causative gene for cone-rod dystrophy/CORD9, establishing a Mendelian disease link and pointing to a role in RPE-photoreceptor microvillar interaction.\",\n      \"evidence\": \"Canine GWAS/sequencing of crd3, light/electron microscopy, electroretinography\",\n      \"pmids\": [\"20806078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function of ADAM9 in RPE microvilli undefined\", \"Ortholog (canine) study; human mechanism inferred\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Mechanistically resolved the ADAM9-ADAM10 relationship by showing the ADAM9 prodomain is a selective inhibitor and that ADAM9 controls ADAM10 membrane localization and alpha-secretase output.\",\n      \"evidence\": \"Recombinant prodomain Ki measurement, cell-based ADAM10 localization and sAPP\\u03b1/\\u03b2 quantification\",\n      \"pmids\": [\"21956108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM9 sheds ADAM10 directly versus other mechanism unresolved\", \"In vivo relevance to APP biology untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed ADAM9 in a regulatory complex with MT1-MMP and FGFR2, where MT1-MMP inactivates ADAM9 to protect FGFR2 from shedding during skeletal development.\",\n      \"evidence\": \"Co-IP, Mmp14\\u2212/\\u2212 and Adam9-depletion mice, genetic rescue, FGFR2 shedding and skeletal phenotyping\",\n      \"pmids\": [\"22632802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of MT1-MMP cleavage of ADAM9 not defined\", \"Generality beyond osteoblasts unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined ADAM9 as a stored neutrophil ECM-degrading protease and a direct platelet \\u03b16\\u03b21 ligand, linking it to acute lung injury and metastatic dissemination.\",\n      \"evidence\": \"Subcellular fractionation, in vitro ECM degradation, Adam9\\u2212/\\u2212 lung-injury models, recombinant DC-9 platelet adhesion and \\u03b16\\u03b21 KO metastasis models\",\n      \"pmids\": [\"25063875\", \"27699237\", \"25646025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate spectrum during lung injury incompletely defined\", \"Relative contribution of adhesion vs proteolysis to metastasis unresolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterized constitutive EphB4 shedding and selective inhibitor profiles, and elaborated ADAM9-driven angiogenic and metastatic transcriptional programs in lung cancer.\",\n      \"evidence\": \"Cell-based shedding with E>A mutant, TIMP/small-molecule profiling, siRNA knockdown with microarray, tPA/CDCP1 cleavage, miR-1/miR-218 reporter assays, in vivo tumor models\",\n      \"pmids\": [\"28264989\", \"29118335\", \"25060522\", \"28537886\", \"24705471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs transcriptionally indirect effects on angiogenic factors not fully separated\", \"miRNA-axis findings are Medium-confidence single-lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved a protease-independent role in integrin trafficking and linked ADAM9 to ROS-generating NOX1 in driving EMT, broadening its mechanism beyond shedding.\",\n      \"evidence\": \"siRNA, Co-IP with \\u03b21 integrin, internalization/recycling/degradation assays, NOX1 interaction and ROS measurement, EMT markers\",\n      \"pmids\": [\"29142101\", \"29432845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ADAM9 promotes integrin endocytosis undefined\", \"NOX1 interaction is Medium-confidence single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified an entirely proteinase-independent function as an EMCV entry factor/cofactor mediating viral attachment and genome delivery.\",\n      \"evidence\": \"Genome-wide CRISPR and haploid screens, KO in multiple cell lines, RNA-transfection bypass, catalytic-dead reconstitution, neutralization and binding assays\",\n      \"pmids\": [\"30723129\", \"31409686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of EMCV-ADAM9 binding not resolved\", \"Whether other picornaviruses use ADAM9 not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established ADAM9 as a TGF-\\u03b21 activator that cleaves LAP to drive Th17 differentiation, with ICER as a direct transcriptional activator, defining an immunological role in autoimmunity.\",\n      \"evidence\": \"Adam9\\u2212/\\u2212 EAE model, T cell transfer, LAP cleavage, SMAD2/3 phosphorylation, ICER promoter binding, Th17 assays\",\n      \"pmids\": [\"33911034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial control of latent TGF-\\u03b21 activation in vivo unclear\", \"Other immune cell contributions not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated ephrin-B1/B2 cleavage and Akt/Wnt/mTOR modulation, with cross-species rescue of ADAM13 in neural crest induction, indicating conserved developmental signaling roles.\",\n      \"evidence\": \"ADAM9 KD in CRC lines, ephrin-B cleavage, Wnt/mTOR/Akt assays, Xenopus neural crest rescue\",\n      \"pmids\": [\"35780836\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-line-dependent signaling outcomes not mechanistically explained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed a non-shedding oncogenic mechanism whereby ADAM9 stabilizes KRAS by blocking PAI-1/LC3-mediated selective autophagy, and validated ADAM9 as a druggable PDAC target.\",\n      \"evidence\": \"Co-IP of KRAS-PAI-1-LC3, ADAM9 KO/inhibitor, autophagy/lysosomal degradation assays, spontaneous PDAC and PDX models\",\n      \"pmids\": [\"38267627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ADAM9 physically prevents PAI-1-KRAS interaction undefined\", \"Whether mechanism is shared across other RAS-driven tumors unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADAM9 integrates its distinct catalytic-dependent shedding, catalytic-independent integrin/adhesion, viral-cofactor, and protein-stabilization functions into a unified regulatory logic, and how isoform/localization balance is controlled in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model integrating disintegrin and protease functions\", \"Mechanism switching between protease-dependent and -independent modes undefined\", \"Regulation of secreted vs membrane isoform expression in tissues unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 9, 15, 17, 18, 30, 40, 42]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [2, 9, 30]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [13, 16, 20, 28]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [13, 16, 35]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [36, 37]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [24, 44]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 16, 27]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [10, 12, 22, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [12, 18, 20, 27, 38]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 25, 40, 42]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [15, 28, 44]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [27, 40]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 24]}\n    ],\n    \"complexes\": [\n      \"MT1-MMP\\u2013FGFR2\\u2013ADAM9 complex\",\n      \"ADAM9\\u2013Naa10p complex\",\n      \"KRAS\\u2013PAI-1\\u2013LC3 autophagy complex (ADAM9-regulated)\"\n    ],\n    \"partners\": [\n      \"PRKCD\",\n      \"SRC\",\n      \"ITGB1\",\n      \"ITGA6\",\n      \"MMP14\",\n      \"FGFR2\",\n      \"NAA10\",\n      \"NOX1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}