{"gene":"ADAM15","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1998,"finding":"The recombinant disintegrin-like domain of ADAM15 specifically binds integrin αvβ3 in an RGD-dependent manner; mutation of RGD to SGA abolishes binding, and the flanking sequence RPTRGD determines receptor specificity (αvβ3 vs αIIbβ3).","method":"GST fusion protein binding assay with recombinant integrins expressed in mammalian cells; site-directed mutagenesis of RGD motif","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro binding reconstitution with mutagenesis, replicated by multiple subsequent studies","pmids":["9516430"],"is_preprint":false},{"year":1999,"finding":"The extracellular domain of ADAM15 (metargidin) mediates cell adhesion to haemopoietic cells via integrin αvβ3 on U937 monocytic cells and integrin α5β1 on MOLT-4 T cells, in an RGD-dependent, divalent cation-dependent manner.","method":"Solid-phase cell-adhesion assays with chimeric ADAM15-Fc protein; anti-integrin antibody blocking; purified recombinant integrins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal adhesion assays with purified integrins and antibody blocking, replicated across two cell lines","pmids":["9914169"],"is_preprint":false},{"year":1998,"finding":"Mouse MDC15/ADAM15 pro-domain is removed by a pro-protein convertase (furin) in a late Golgi compartment; processed mature ADAM15 is endoglycosidase H-resistant, and the majority accumulates in a perinuclear/trans-Golgi network/endosomal compartment rather than at the cell surface.","method":"Pulse-chase experiments; brefeldin A/monensin treatment; in vitro furin cleavage assay; cell-surface trypsinization; immunolocalization in COS-7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including in vitro reconstitution with furin and pharmacological inhibitors","pmids":["9748307"],"is_preprint":false},{"year":1999,"finding":"The cytoplasmic domains of ADAM15 (MDC15) and MDC9 interact with the SH3 domain-containing proteins endophilin I (SH3GL2) and a novel SH3-PX domain protein (SH3PX1); these interactions are preferential for the precursor (pro-domain-containing) forms and were identified by yeast two-hybrid, bacterial fusion pulldown, and co-immunoprecipitation from eukaryotic cells.","method":"Yeast two-hybrid screen; bacterial GST fusion pulldown; co-immunoprecipitation from COS-7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; yeast two-hybrid confirmed by pulldown and co-IP","pmids":["10531379"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic domain of ADAM15 interacts with Src family kinases (Lck, Fyn, Abl, Src, Hck) via SH3 domain binding to proline-rich motifs, and with adaptor protein Grb2; interactions are phosphorylation-dependent (enhanced by tyrosine phosphorylation); Hck and Lck phosphorylate the ADAM15 cytoplasmic domain in vitro; Tyr715 and Tyr735 are regulatory residues.","method":"SH3 domain pulldowns; co-immunoprecipitation from hematopoietic cell lines; in vitro immune complex kinase assays; Far Western analysis; deletion and point mutation analysis; PMA stimulation and PP1 inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assays with mutagenesis, confirmed by multiple orthogonal methods in multiple cell lines","pmids":["11741929"],"is_preprint":false},{"year":2001,"finding":"ADAM15 overexpression in NIH3T3 cells enhances cell-cell interactions: it localizes to cell-cell contacts in epithelial cells, decreases monolayer permeability, and increases cell adhesion to ADAM15-expressing monolayers by 45%, while inhibiting cell migration on fibronectin.","method":"Tetracycline-regulated overexpression; Boyden chamber migration assay; scratch wound model; monolayer permeability assay; cell adhesion assay; epitope-tagged ADAM15 immunolocalization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — clean overexpression with specific cellular phenotype readouts, single lab","pmids":["11697891"],"is_preprint":false},{"year":2002,"finding":"ADAM15 localizes to adherens junctions in endothelial cells, colocalizing with VE-cadherin; VE-cadherin coexpression drives ADAM15 surface expression and translocation to the cell periphery in CHO cells.","method":"Immunofluorescence colocalization; ADAM15-GFP fusion protein imaging; flow cytometry for cell surface levels; co-expression of VE-cadherin and ADAM15 in CHO cells","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct localization with functional consequence (surface expression), single lab","pmids":["12243749"],"is_preprint":false},{"year":2003,"finding":"ADAM15-deficient (adam15-/-) mice show major reduction in pathological retinal neovascularization in a retinopathy of prematurity model, and reduced tumor growth of implanted B16F0 melanoma cells, demonstrating ADAM15 is required for pathological but not developmental neovascularization.","method":"Targeted gene deletion (knockout mice); mouse model of retinopathy of prematurity; heterotopic tumor implantation model; mRNA in situ hybridization for expression pattern","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean genetic loss-of-function with specific in vivo phenotypic readouts in multiple model systems","pmids":["12897135"],"is_preprint":false},{"year":2003,"finding":"Recombinant soluble ADAM15, ADAM8, and ADAM28 (MDC-L) cleave synthetic peptide substrates with distinct specificities from ADAM17, and catalyze ectodomain shedding of CD23 (low-affinity IgE receptor); shedding requires proteolytically active enzyme and is inhibited by hydroxamic acid metalloprotease inhibitor.","method":"Peptide substrate library screening with purified recombinant enzymes; ectodomain shedding assay; catalytically inactive mutant control; metalloprotease inhibitor treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with purified recombinant enzyme, mutagenesis control, and pharmacological inhibition","pmids":["12777399"],"is_preprint":false},{"year":2005,"finding":"ADAM15 deficiency in aging mice leads to accelerated osteoarthritic lesions; overexpression of ADAM15 in chondrocytes enhances adhesion to cartilage collagens (type II and VI) and promotes cell viability under serum starvation, indicating a chondroprotective/homeostatic role.","method":"ADAM15 knockout mice joint morphology analysis; stable transfection of T/C28a4 chondrocyte cell line; cell adhesion assays on fibronectin and collagens; cell viability under serum starvation","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 — complementary loss-of-function (KO mice) and gain-of-function (overexpression) with specific phenotypic readouts","pmids":["15818704"],"is_preprint":false},{"year":2005,"finding":"ADAM15 overexpression in cancer cells suppresses integrin αvβ3-mediated adhesion to vitronectin and reduces cell motility in an RGD-dependent manner; mutation of RGD to SGA abrogates these effects.","method":"Stable overexpression of ADAM15 and RGD→SGA mutant in OV-MZ-6 ovarian cancer cells; cell adhesion assay on vitronectin; cell motility assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — RGD mutagenesis with specific cellular phenotype, single lab","pmids":["15618016"],"is_preprint":false},{"year":2007,"finding":"ADAM15 gene contains 23 exons; alternative splicing of cytoplasmic-domain-encoding exons 19, 20a/b, and 21a/b generates at least 13 splice variants in normal human tissues with different combinations of regulatory protein interaction motifs; a GC-rich, TATA-less promoter with functional activity located within a CpG island proximal to the translation start was confirmed by reporter assays.","method":"Genomic characterization; RT-PCR splice variant analysis in human tissues; luciferase reporter expression experiments","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — reporter assays confirming promoter function; splice variant characterization across tissues","pmids":["17937806"],"is_preprint":false},{"year":2008,"finding":"ADAM15 catalytically cleaves E-cadherin ectodomain; the soluble E-cadherin fragment binds to and stabilizes HER2/HER3 heterodimerization, activating ERK signaling and promoting breast cancer cell migration and proliferation.","method":"ADAM15 overexpression and shRNA knockdown in breast cancer cells; metalloprotease inhibitor treatment; catalytically inactive ADAM15 mutant; co-immunoprecipitation of sE-cad with HER2/HER3; ERK pathway activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — catalytic mutant, inhibitor, shRNA, and co-IP with multiple orthogonal methods","pmids":["18434311"],"is_preprint":false},{"year":2008,"finding":"ADAM15 knockdown in PC-3 prostate cancer cells reduces N-cadherin cleavage at the cell surface, decreases αv integrin and CD44 surface expression, abrogates MMP9 secretion/activity, reduces adhesion and migration through vascular endothelial monolayers, and attenuates bone metastasis in SCID mice.","method":"Lentiviral shRNA knockdown; FACS for surface markers; MMP9 activity assay; transendothelial migration assay; SCID mouse bone metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — clean loss-of-function with multiple mechanistic readouts and in vivo validation","pmids":["18281484"],"is_preprint":false},{"year":2008,"finding":"ADAM15 splice variants differ only in their cytoplasmic domains; ADAM15A and ADAM15B variants show differential isoform-specific association with Nck, Src, and Brk tyrosine kinases (but equivalent binding to ERK, Grb2, and Tks5/Fish), leading to different effects on cell morphology, adhesion, migration, and invasion in breast cancer cells.","method":"Cloning and characterization of four alternatively spliced ADAM15 forms; GST pulldown assays; expression in MDA-MB-435 cells; adhesion, migration, invasion assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2-3 — pulldown with isoform-specific functional readouts, single lab","pmids":["18296648"],"is_preprint":false},{"year":2008,"finding":"ADAM15 suppresses cell motility by driving increased cell surface expression of integrin α5 (without directly interacting with α5β1) via downregulation of ERK1/2 phosphorylation; MEK inhibitor or ERK siRNA mimics this effect, and ADAM15 overexpression reduces lung metastatic nodules in a B16F10 model.","method":"CHO cell transfection with ADAM15; immunoprecipitation and immunofluorescence; MEK inhibitor PD98059; ERK1/2 siRNA; flow cytometry for integrin surface expression; B16F10 pulmonary metastasis model","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placement by pharmacological inhibition and siRNA, confirmed in vivo","pmids":["18387333"],"is_preprint":false},{"year":2008,"finding":"VEGF upregulates ADAM15 expression in retinal vascular endothelial cells in ischemic retina; ADAM15 and VEGF participate in an amplification loop, with ADAM15 increasing VEGF, VEGFR1, and VEGFR2 expression; ADAM15-deficient mice show reduced ischemia-induced retinal neovascularization and choroidal neovascularization.","method":"ADAM15 knockout mice; oxygen-induced retinopathy model; choroidal neovascularization model; VEGF knockdown in ischemic retina; VEGF overexpression in non-ischemic retina; mRNA quantification","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function in three in vivo model systems with defined molecular feedback loop","pmids":["18381816"],"is_preprint":false},{"year":2009,"finding":"Membrane-anchored ADAM15 sheds the ectodomain of fibroblast growth factor receptor 2iiib (FGFR2iiib) in cell-based assays; catalytically inactive ADAM15E→A mutant does not shed FGFR2iiib; shedding is inhibited by hydroxamate inhibitors (marimastat, TAPI-2, GM6001) and TIMP-3 (50 nM) but not TIMP-1 or TIMP-2; ADAM15 is not stimulated by phorbol esters or calcium ionophores.","method":"Overexpression of ADAM15 and catalytically inactive ADAM15E→A in cells; cell-based shedding assay; metalloprotease inhibitor panel; TIMP inhibitor panel","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1-2 — cell-based reconstitution with catalytic mutant, multiple inhibitors, and defined substrate","pmids":["19207106"],"is_preprint":false},{"year":2009,"finding":"ADAM15 splice variant ADAM15B (containing a Src-binding cytoplasmic site) has enhanced catalytic activity (FGFR2iiib shedding) compared to ADAM15A; this enhanced activity depends on Src kinase, as it is abolished by Src kinase inhibitors and in Src-/- cells but restored by Src rescue.","method":"Cell-based shedding assay; Src kinase inhibitors; Src-/- cells and rescue; comparison of ADAM15A vs ADAM15B splice variants","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — genetic (Src KO/rescue) and pharmacological evidence for Src-dependent enhancement of ADAM15B catalytic activity","pmids":["19487280"],"is_preprint":false},{"year":2009,"finding":"Alternative splicing of ADAM15 cytoplasmic exons profoundly influences selection of SH3-containing binding partners; isoforms containing exons 20 and/or 21 (with RxLPxxP motif) specifically bind nephrocystin; isoforms with the C-terminal proline cluster bind SNX33; these interactions were abolished by specific proline-cluster mutations.","method":"Co-precipitation from cell lysates; isoform-specific pull-downs; proline-cluster point mutations","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-precipitation with mutagenesis for multiple isoforms, single lab","pmids":["19718658"],"is_preprint":false},{"year":2010,"finding":"ADAM15 promotes endothelial hyperpermeability and neutrophil transendothelial migration via Src/ERK1/2 signaling, independent of junction molecule (VE-cadherin) shedding; both wild-type and catalytically dead ADAM15 increase ERK1/2 phosphorylation and permeability; Src or ERK inhibition reverses ADAM15-induced effects.","method":"siRNA knockdown; overexpression of wild-type and catalytically dead ADAM15 in HUVECs; transendothelial electric resistance and albumin flux assays; neutrophil migration assay; pharmacological Src/ERK inhibitors; ERK1/2 phosphorylation by Western blot","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — catalytic dead mutant establishes protease-independent mechanism; pharmacological pathway placement; multiple orthogonal readouts","pmids":["20189953"],"is_preprint":false},{"year":2010,"finding":"An ADAM15 metalloprotease domain-derived peptide (ADoPep1 containing HWRR sequence) activates GRP78 on endothelial cell membranes under hypoxia, inducing angiogenesis via Akt phosphorylation and ERK1/2 activation (VEGF-independent); GRP78 siRNA blocks this effect.","method":"Synthetic peptide derived from ADAM15 sequence; cell proliferation, migration, tube formation assays; mouse hind limb ischemia model; siRNA against GRP78; Western blot for Akt/ERK phosphorylation; VEGFR2 phosphorylation assay","journal":"Journal of vascular research","confidence":"Medium","confidence_rationale":"Tier 2-3 — peptide-based functional assay with siRNA validation and in vivo model; single lab","pmids":["20145413"],"is_preprint":false},{"year":2011,"finding":"Loss of ADAM15 in osteoblasts leads to increased nuclear β-catenin translocation (with increased cytoplasmic/membrane degradation), upregulation of cyclin D1 and c-Jun (downstream Wnt targets), and increased osteoblast proliferation, alkaline phosphatase activity, nodule deposition, and mineralization, resulting in higher trabecular and cortical bone mass in ADAM15-/- mice.","method":"ADAM15-/- mice bone analysis; primary ADAM15-/- osteoblast cultures; β-catenin immunoreactivity (nuclear vs cytoplasmic); cyclin D1 and c-Jun Western blot","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in vivo with mechanistic in vitro follow-up; single lab, moderate orthogonal methods","pmids":["21801086"],"is_preprint":false},{"year":2012,"finding":"ADAM15 is released from cells as an exosomal component in response to PKC activation; exosomal ADAM15 binds integrin αvβ3 in an RGD-dependent manner and suppresses vitronectin/fibronectin-induced cancer cell adhesion, growth, migration, and in vivo tumor growth; macrophage-derived ADAM15 exosomes have tumor inhibitory effects.","method":"Exosome isolation; phorbol ester (PMA/PKC activator) treatment; integrin αvβ3 binding assay; RGD mutation control; in vitro cancer cell adhesion, growth, migration assays; in vivo tumor growth model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — RGD mutagenesis control with multiple functional assays, single lab","pmids":["22505472"],"is_preprint":false},{"year":2012,"finding":"ADAM15 deficiency attenuates LPS-induced acute lung injury: loss of ADAM15 in endothelial cells reduces hyperpermeability response to LPS and decreases neutrophil chemotactic transmigration; rescue expression of ADAM15 in Adam15-/- ECs restores neutrophil transendothelial migration.","method":"Adam15-/- mice; LPS-induced acute lung injury model; primary mouse lung endothelial cell culture; albumin flux and TER assays; neutrophil transmigration assay; ADAM15 rescue expression","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function confirmed by rescue experiment, with specific mechanistic cellular readouts","pmids":["23161886"],"is_preprint":false},{"year":2012,"finding":"ADAM15 cytoplasmic domain directly binds the C-terminus of FAK; genotoxic stress (camptothecin) in ADAM15-transfected chondrocytes causes enhanced FAK phosphorylation at Tyr-397, Tyr-576, and Tyr-861 and concomitant Src activation; ADAM15 lacking its cytoplasmic tail loses this anti-apoptotic/FAK-activating property; Src binds FAK but not directly ADAM15, placing FAK as critical adaptor.","method":"Mammalian two-hybrid; pulldown; Far Western studies; chimeric IL-2Rα/ADAM15-cytoplasmic-tail construct; Western blot for phospho-FAK and phospho-Src; FAK/Src inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — multiple binding methods (two-hybrid, pulldown, Far Western) plus chimeric construct functional validation","pmids":["22544741"],"is_preprint":false},{"year":2013,"finding":"ADAM15 interacts with TRIF (TLR adaptor) following TLR3/TLR4 stimulation; ADAM15 acts as a negative regulator of TRIF-mediated NF-κB and IFN-β signaling, and mediates proteolytic cleavage of TRIF; ADAM15 suppression enhances proinflammatory cytokine production in response to poly I:C, LPS, rhinovirus 16, and VSV.","method":"Co-immunoprecipitation of TRIF signaling complex; LC-MS protein identification; ADAM15 knockdown; NF-κB and IFN-β reporter assays; cytokine production measurement; TRIF cleavage assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — MS-identified interaction confirmed by co-IP and proteolytic cleavage assay, with functional reporter assays","pmids":["23365087"],"is_preprint":false},{"year":2013,"finding":"ADAM15 adds to apoptosis resistance of rheumatoid arthritis synovial fibroblasts (RASFs) by activating Src/FAK signaling upon FasL stimulation; ADAM15 knockdown by siRNA increases caspase 3/7 activity and apoptosis upon camptothecin and FasL treatment; FasL-induced FAK/Src activation, PI3K activation, and NF-κB activity are ADAM15-dependent.","method":"siRNA knockdown of ADAM15 in RASFs; caspase 3/7 enzyme assays; annexin V staining; immunoblotting for phospho-FAK, phospho-Src, NF-κB; FAK inhibitor 14 and dasatinib treatment","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA with multiple mechanistic readouts and pharmacological validation, single lab","pmids":["23918525"],"is_preprint":false},{"year":2014,"finding":"Catalytic activity of ADAM15 is NOT required for pathological retinal neovascularization in the OIR model (Adam15E>A knock-in mice show WT-equivalent neovascularization), but catalytic activity contributes to suppression of tumor implantation; ADAM15 can process FGFR2iiib but not several angiogenesis-related receptors in cell-based assays.","method":"Adam15E>A catalytic point-mutation knock-in mice; OIR model; heterotopic melanoma tumor implantation; cell-based shedding assays for multiple angiogenesis receptors","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1-2 — knock-in catalytic mutant mice in multiple in vivo models, directly parsing catalytic vs non-catalytic functions","pmids":["25249606"],"is_preprint":false},{"year":2015,"finding":"ADAM15 proteolytically cleaves and activates pro-MMP9 in vitro; ADAM15 interacts with MMP9 in vivo; ADAM15 upregulates MMP9 expression via MEK-ERK pathway activation; MMP9 knockdown attenuates ADAM15-driven lung cancer cell invasion.","method":"In vitro pro-MMP9 cleavage assay; co-immunoprecipitation (in vivo interaction); MMP9 Western blot; MEK-ERK pathway analysis; shRNA knockdown; invasion assay","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — in vitro cleavage assay and co-IP, with epistasis by MMP9 knockdown; single lab","pmids":["26323669"],"is_preprint":false},{"year":2018,"finding":"ADAM15 converts FasL/Fas-death signals into prosurvival Src/FAK activation in RASFs via calmodulin (CaM) recruitment: FasL triggers CRAC/Orai1-dependent Ca2+ release, leading to CaM recruitment to Fas/CD95 and ADAM15 at the membrane, followed by Src-CaM engagement in the ADAM15/FAK complex; cytoplasmic ADAM15 domain is required for this prosurvival scaffolding.","method":"CaM-Sepharose pulldown; co-immunoprecipitation with anti-ADAM15 and anti-CD95 antibodies; recombinant CaM protein binding assay; immunofluorescence colocalization; CRAC/Orai1 inhibitor BTP-2; CaM inhibitor trifluoperazine; ADAM15 cytoplasmic domain deletion construct; caspase 3/7 assays; annexin V staining","journal":"Arthritis & rheumatology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple binding methods (pulldown, co-IP, recombinant protein assay), pharmacological pathway dissection, and cytoplasmic tail deletion control","pmids":["30003689"],"is_preprint":false},{"year":2018,"finding":"ADAM15 cytoplasmic domain transiently interacts with poly(A) binding protein 1 (PABP) via the PABP proline-rich linker during cell adhesion; this interaction recruits PABP to the cell membrane and promotes local mRNA translation (detected by puromycin-terminated polypeptides); loss of ADAM15 or its cytoplasmic tail reduces cell membrane-associated protein neosynthesis during adhesion.","method":"Co-immunoprecipitation; domain-mapping pulldown; immunostaining for PABP and puromycin-incorporated nascent proteins; ADAM15 siRNA and cytoplasmic-tail deletion mutant","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with domain mapping and functional puromycin assay; single lab","pmids":["30265671"],"is_preprint":false},{"year":2019,"finding":"ADAM15 isoform-specific, catalytic-function-dependent upregulation of Claudin-1 in breast cancer cells; ADAM15A (and to lesser extent C, E isoforms) increase Claudin-1 expression via PI3K/Akt/mTOR pathway; ADAM15 co-localizes with Claudin-1 and ZO1 at cell-cell junctions; ADAM15 forms a complex with ZO1/ZO2 as shown by co-immunoprecipitation.","method":"Isogenic cell panels expressing five ADAM15 variants (WT and catalytically inactive); shRNA knockdown; PI3K/Akt/mTOR pathway analysis; immunofluorescence; co-immunoprecipitation of ADAM15 with ZO1/ZO2","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — isoform and catalytic mutant panel with co-IP and pathway inhibition; single lab","pmids":["31467400"],"is_preprint":false},{"year":2019,"finding":"KLF2 transcription factor (induced by laminar shear stress) drives ADAM15 expression in endothelial cells; physiologic shear stress upregulates ADAM15 (~4-fold mRNA, 5.6-fold protein); ADAM15 promotes endothelial cell survival under growth factor depletion or TNF stimulation; KLF2 siRNA prevents shear-stress-induced ADAM15 upregulation.","method":"Flow culture of primary endothelial cells; transcriptomic analysis; KLF2 overexpression and siRNA; simvastatin induction; ADAM15 shRNA knockdown; endothelial survival assays","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — KLF2 overexpression/knockdown with ADAM15 readout, functional survival assay; single lab","pmids":["31271758"],"is_preprint":false},{"year":2021,"finding":"ADAM15 promotes a pro-inflammatory mechanosensing pathway in synovial fibroblasts: ADAM15 promotes cell membrane density of mechanosensitive TRPV4 calcium channels and reinforces Src-mediated pannexin-1 channel activation for ATP release; loss of ADAM15 abolishes Ca2+-dependent JNK activation, HOTAIR lncRNA downregulation, and sirtuin-1 upregulation in response to mechanical stimulation.","method":"ADAM15 loss-of-function in synovial fibroblasts; TRPV4 membrane density assay; pannexin-1 channel activity; JNK phosphorylation; HOTAIR and sirtuin-1 expression; Ca2+ signaling measurements","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2-3 — genetic loss-of-function with mechanistic pathway readouts; single lab","pmids":["34685689"],"is_preprint":false},{"year":2021,"finding":"ADAM15 participates in tick-borne encephalitis virus (TBEV) replication and assembly; ADAM15 subcellular localization changes during TBEV infection contributing to membrane reorganization and replication organelle formation; ADAM15 knockdown/knockout causes TBEV replication and assembly defects.","method":"siRNA knockdown; CRISPR knockout; RNA-seq; subcellular localization imaging; virus production and replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function by both siRNA and CRISPR with specific viral replication readouts; single lab","pmids":["33208450"],"is_preprint":false},{"year":2022,"finding":"ADAM15 is required for optimal collagen cross-linking and scar formation after myocardial infarction: Adam15-/- mice show higher rate of LV rupture post-MI, reduced fibrillar collagen density, lower insoluble collagen, reduced lysyl oxidase-1 (LOX-1) and fibronectin; ADAM15 loss reduces PAK1 levels in cardiac fibroblasts; PAK1 regulates fibronectin and LOX-1 expression.","method":"Adam15-/- mice; LAD ligation MI model; second harmonic generation imaging; soluble/insoluble collagen fractionation; LOX-1, fibronectin, PAK1 Western blot; primary cardiac fibroblast ischemia model; echocardiography","journal":"Matrix biology","confidence":"High","confidence_rationale":"Tier 2 — comprehensive in vivo KO with multiple mechanistic readouts and in vitro mechanistic follow-up; single lab but multiple orthogonal methods","pmids":["34995785"],"is_preprint":false},{"year":2022,"finding":"Loss of ADAM15 in pressure-overload cardiomyopathy (TAC) exacerbates eccentric hypertrophy and dilation through increased calcineurin/NFAT pathway activity; integrin-α7 expression increases more in Adam15-/- TAC hearts while integrin-laminin interaction decreases; calcineurin inhibition (cyclosporin-A) blocks excess hypertrophy in Adam15-/- TAC mice.","method":"Adam15-/- mice; TAC model; calcineurin activity assay; NFAT phosphorylation; integrin-α7 and laminin interaction; cyclosporin-A treatment; proteome profiling; echocardiography","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function with pathway rescue by cyclosporin-A and proteomic profiling; single lab but multiple orthogonal methods","pmids":["36330793"],"is_preprint":false},{"year":2022,"finding":"ADAM15 promotes FAK and EGFR signaling in lung cancer through interactions with integrins; integrin αV mediates ADAM15-FAK signaling; ADAM15 cooperates with CD151 to modulate integrin α3/α6-related EGFR signaling; miR-204-5p directly targets and suppresses ADAM15.","method":"Co-IP between ADAM15 and integrins; CD151 co-expression studies; FAK/EGFR signaling pathway assays; luciferase reporter assay for miR-204-5p targeting; nude mouse xenograft","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP for binding, reporter assay for miRNA targeting, in vivo model; single lab","pmids":["35597804"],"is_preprint":false},{"year":2025,"finding":"ADAM15 loss abrogates necroptosis induced by death ligands (TNF, TRAIL, FasL, TL1a) and a BH3 mimetic; loss of ADAM15 results in enhanced basal caspase-8 activity (non-cytotoxic) and partial RIPK1 degradation; ADAM15 is found in intracellular lysosomal compartments and enhanced TNF-R1 surface expression in ADAM15-KO cells suggests TNF-R1 as a potential substrate.","method":"CRISPR/Cas9 adam15 knockout in U937 and Jurkat cells; necroptosis/apoptosis assays; caspase-8 enzyme assay; Western blot for RIPK1; flow cytometry for TNF-R1 surface expression; immuno-magnetic fractionation for subcellular localization; bottom-up proteome analysis","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with multiple mechanistic readouts; TNF-R1 substrate hypothesis supported but not conclusively proven; single lab","pmids":["41340056"],"is_preprint":false},{"year":2025,"finding":"ADAM15 and N-cadherin (NCAD) co-localize in adherens junctions of synovial fibroblasts; mechanical strain triggers a pathway through this complex involving PAK2 phosphorylation and co-recruitment of Nck; this leads to downregulation of lncRNA H19 and miR-130a-3p, upregulation of cadherin-11, and enhanced cell invasion.","method":"Immunofluorescence co-localization; co-immunoprecipitation of ADAM15/NCAD complex; PAK2 phosphorylation assay; Nck recruitment assay; lncRNA H19 and miR-130a-3p expression; invasion assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP, phosphorylation assay, and functional invasion readout; mechanistic pathway placed but single lab","pmids":["40118917"],"is_preprint":false}],"current_model":"ADAM15 is a membrane-anchored multi-domain metalloprotease-disintegrin that functions through both catalytic and non-catalytic mechanisms: its extracellular disintegrin domain mediates RGD-dependent binding to integrins αvβ3 and α5β1 to regulate cell adhesion and migration; its metalloprotease domain sheds substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, and TRIF (with TIMP-3-sensitive, phorbol ester-insensitive catalytic properties); its cytoplasmic domain acts as a signaling scaffold that undergoes phosphorylation by Src family kinases (Hck, Lck) and interacts isoform-specifically with SH3-domain proteins (Grb2, Lck, Brk, Nck, nephrocystin, SNX33), FAK, calmodulin, and PABP to modulate ERK, FAK/Src, PI3K/Akt, calcineurin/NFAT, and purinergic signaling pathways; collectively, these functions govern pathological neovascularization, endothelial barrier integrity, chondrocyte survival, cardiac remodeling, and immune cell death decisions including necroptosis."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing that ADAM15 is an RGD-dependent integrin ligand resolved how a membrane metalloprotease could directly mediate cell adhesion: the disintegrin domain binds αvβ3 via a specific RPTRGD motif, and furin processes the pro-domain in the Golgi, with mature ADAM15 accumulating primarily in a perinuclear/TGN compartment rather than at the cell surface.","evidence":"Recombinant GST-disintegrin binding assays with RGD→SGA mutagenesis; pulse-chase, furin cleavage, and immunolocalization in COS-7 cells","pmids":["9516430","9748307"],"confidence":"High","gaps":["Crystal structure of ADAM15 disintegrin–integrin complex not determined","Mechanism controlling ADAM15 surface trafficking vs perinuclear retention unresolved"]},{"year":1999,"claim":"Demonstrating that ADAM15 engages both αvβ3 and α5β1 on haemopoietic cells and that its cytoplasmic domain interacts with SH3-domain proteins (endophilin I, SH3PX1) established ADAM15 as a dual-function molecule coupling extracellular adhesion with intracellular signaling scaffolds.","evidence":"Solid-phase adhesion assays with Fc-fusion protein and antibody blocking; yeast two-hybrid screen confirmed by co-IP from COS-7 cells","pmids":["9914169","10531379"],"confidence":"High","gaps":["Functional consequence of endophilin/SH3PX1 binding on ADAM15 biology not established","Whether pro-domain-preferential interaction reflects trafficking regulation is unknown"]},{"year":2001,"claim":"Identification of Src family kinases (Hck, Lck) as cytoplasmic-domain kinases and Grb2 as an adaptor partner, together with evidence that ADAM15 overexpression strengthens cell–cell contacts and suppresses migration, defined ADAM15 as a signaling-competent adhesion molecule at cell junctions.","evidence":"SH3 pulldowns, co-IP from hematopoietic lines, in vitro kinase assays with Tyr715/735 mutagenesis; overexpression in NIH3T3 with permeability, adhesion, and migration assays","pmids":["11741929","11697891"],"confidence":"High","gaps":["Which downstream pathways are activated by Hck/Lck-mediated ADAM15 phosphorylation was not yet mapped","Endogenous stoichiometry of ADAM15–kinase complexes not determined"]},{"year":2002,"claim":"Localizing ADAM15 to VE-cadherin-positive adherens junctions in endothelial cells, with VE-cadherin co-expression driving ADAM15 surface translocation, positioned ADAM15 within the junctional machinery controlling vascular integrity.","evidence":"Immunofluorescence colocalization and GFP-ADAM15 imaging in endothelial cells and CHO cells co-expressing VE-cadherin","pmids":["12243749"],"confidence":"Medium","gaps":["Direct molecular interaction between ADAM15 and VE-cadherin not demonstrated","Whether VE-cadherin-driven surface translocation involves specific sorting signals is unknown"]},{"year":2003,"claim":"Knockout mice revealed ADAM15 is required for pathological but not developmental neovascularization and tumor angiogenesis, while in vitro studies established ADAM15 as a bona fide sheddase for CD23, defining its first validated in vivo function and catalytic substrate.","evidence":"Adam15−/− mice in retinopathy of prematurity and B16F0 tumor models; recombinant ADAM15 peptide substrate profiling and CD23 shedding assay with catalytic-dead mutant control","pmids":["12897135","12777399"],"confidence":"High","gaps":["Whether CD23 shedding is relevant in vivo not tested","Catalytic vs non-catalytic contribution to neovascularization not yet resolved"]},{"year":2005,"claim":"ADAM15 knockout mice developing accelerated osteoarthritis, coupled with ADAM15 overexpression enhancing chondrocyte adhesion to cartilage collagens and viability, established a chondroprotective homeostatic role, while RGD-dependent suppression of αvβ3-mediated adhesion in cancer cells clarified the disintegrin domain's anti-migratory mechanism.","evidence":"Adam15−/− joint histomorphometry; chondrocyte overexpression with collagen adhesion and viability assays; cancer cell adhesion/motility with RGD→SGA mutant","pmids":["15818704","15618016"],"confidence":"High","gaps":["Molecular basis of ADAM15–collagen II/VI interaction unknown","Whether chondroprotection is catalytic or scaffolding-dependent not determined"]},{"year":2007,"claim":"Characterization of 13 cytoplasmic splice variants from a TATA-less CpG-island promoter explained the molecular basis for isoform-specific signaling diversity observed in subsequent functional studies.","evidence":"Genomic analysis, RT-PCR across human tissues, luciferase reporter assays for promoter","pmids":["17937806"],"confidence":"Medium","gaps":["Regulatory mechanisms governing tissue-specific splicing not identified","Epigenetic regulation of the CpG-island promoter not explored"]},{"year":2008,"claim":"Multiple studies resolved ADAM15's dual catalytic and scaffolding outputs: E-cadherin shedding activates HER2/HER3–ERK signaling in breast cancer; N-cadherin cleavage promotes prostate cancer transendothelial migration and bone metastasis; isoform-specific cytoplasmic domains differentially recruit Src, Nck, and Brk to control migration and invasion; and a VEGF–ADAM15 amplification loop drives ischemic retinal neovascularization.","evidence":"shRNA/overexpression with catalytic mutant in breast and prostate cancer cells; isoform-specific pulldowns; SCID mouse metastasis model; Adam15−/− mice in OIR and CNV models with VEGF pathway analysis","pmids":["18434311","18281484","18296648","18381816"],"confidence":"High","gaps":["Whether E-cadherin and N-cadherin are cleaved at the same or different sites unknown","In vivo relevance of isoform-specific signaling not tested in genetic models"]},{"year":2009,"claim":"Defining FGFR2iiib as a TIMP-3-sensitive, PMA-insensitive ADAM15 substrate with Src-dependent enhancement in the ADAM15B isoform established a paradigm in which cytoplasmic splice variation controls extracellular catalytic output, while nephrocystin and SNX33 were mapped as isoform-selective SH3-domain partners.","evidence":"Cell-based FGFR2iiib shedding with catalytic mutant, inhibitor panel, Src−/− cells with rescue; co-precipitation with proline-cluster mutations for nephrocystin/SNX33","pmids":["19207106","19487280","19718658"],"confidence":"High","gaps":["Physiological consequence of FGFR2iiib shedding in vivo not demonstrated","Whether nephrocystin interaction links ADAM15 to ciliopathy pathways untested"]},{"year":2010,"claim":"Demonstrating that catalytically dead ADAM15 still increases endothelial permeability and ERK phosphorylation via Src definitively separated the protease-independent scaffolding function from ectodomain shedding in vascular biology.","evidence":"Wild-type and catalytically dead ADAM15 overexpression in HUVECs; transendothelial resistance, albumin flux, neutrophil migration; Src/ERK inhibitors","pmids":["20189953"],"confidence":"High","gaps":["Structural basis of protease-independent Src/ERK activation unknown","Whether scaffolding and catalytic functions are spatially segregated at junctions not resolved"]},{"year":2012,"claim":"Three parallel advances solidified ADAM15's physiological roles: Adam15−/− endothelial rescue experiments confirmed its requirement for LPS-induced lung injury permeability; FAK was identified as a direct cytoplasmic-tail binding partner mediating anti-apoptotic Src activation; and exosomal ADAM15 release revealed a paracrine RGD-dependent mechanism suppressing cancer cell adhesion.","evidence":"Adam15−/− mice in LPS acute lung injury with rescue expression; mammalian two-hybrid, pulldown, Far Western for FAK binding with chimeric construct; exosome isolation with RGD mutant controls and tumor models","pmids":["23161886","22544741","22505472"],"confidence":"High","gaps":["Whether exosomal ADAM15 operates in non-cancer physiological contexts unknown","FAK binding site on ADAM15 cytoplasmic tail not mapped to specific residues"]},{"year":2013,"claim":"ADAM15 was found to cleave TRIF and suppress TLR3/TLR4-mediated NF-κB/IFN-β signaling, expanding its substrate repertoire to innate immune adaptors, while parallel work showed it confers apoptosis resistance in synovial fibroblasts via Src/FAK/PI3K/NF-κB signaling.","evidence":"LC-MS identification of TRIF interaction, co-IP, TRIF cleavage assay, NF-κB/IFN-β reporters with ADAM15 knockdown; RASF siRNA with caspase assays and FAK/Src/NF-κB pathway inhibitors","pmids":["23365087","23918525"],"confidence":"High","gaps":["TRIF cleavage site not identified","Whether TRIF cleavage is relevant in vivo during infection not tested"]},{"year":2014,"claim":"Adam15 catalytic-dead knock-in mice definitively showed that pathological retinal neovascularization is protease-independent while tumor suppression requires catalytic activity, parsing the in vivo contributions of ADAM15's two functional arms.","evidence":"Adam15E>A knock-in mice in OIR and tumor implantation models; cell-based shedding panel for angiogenesis receptors","pmids":["25249606"],"confidence":"High","gaps":["Identity of the non-catalytic mechanism driving neovascularization (which integrin or signaling partner) not defined","Limited substrate panel tested in cell-based assays"]},{"year":2018,"claim":"Calmodulin was identified as the calcium-sensing mediator linking FasL/Fas death signals to ADAM15-dependent prosurvival Src/FAK activation in synovial fibroblasts, while PABP recruitment to ADAM15's cytoplasmic tail during cell adhesion revealed an unexpected role in local mRNA translation at the membrane.","evidence":"CaM-Sepharose pulldown, co-IP, recombinant CaM binding, CRAC/Orai1 inhibitor, CaM inhibitor, cytoplasmic-tail deletion; co-IP/domain-mapping for PABP with puromycin incorporation assay","pmids":["30003689","30265671"],"confidence":"High","gaps":["Which mRNAs are locally translated at ADAM15/PABP sites unknown","Whether CaM–ADAM15 interaction is isoform-specific not tested"]},{"year":2019,"claim":"ADAM15 was placed downstream of shear-stress-induced KLF2 in endothelial cells to promote survival, and shown to upregulate Claudin-1 via PI3K/Akt/mTOR in an isoform- and catalysis-dependent manner while forming complexes with ZO1/ZO2 at tight junctions, broadening its junctional repertoire beyond adherens junctions.","evidence":"KLF2 overexpression/siRNA with ADAM15 readout under flow; isogenic ADAM15 isoform panel with PI3K/Akt/mTOR pathway analysis and ZO1/ZO2 co-IP","pmids":["31271758","31467400"],"confidence":"Medium","gaps":["Direct KLF2 binding to ADAM15 promoter not shown by ChIP","Functional consequence of ZO1/ZO2–ADAM15 complex on barrier integrity not tested"]},{"year":2021,"claim":"ADAM15 was identified as a mechanosensory scaffold in synovial fibroblasts promoting TRPV4 membrane density and Src-dependent pannexin-1 ATP release, and independently as a host factor required for tick-borne encephalitis virus replication and membrane reorganization.","evidence":"ADAM15 loss-of-function in synovial fibroblasts with TRPV4/pannexin-1/JNK pathway assays; CRISPR KO and siRNA in TBEV-infected cells with replication and assembly readouts","pmids":["34685689","33208450"],"confidence":"Medium","gaps":["Mechanism by which ADAM15 regulates TRPV4 surface density unclear","Whether ADAM15's role in TBEV replication involves its protease or scaffolding function not resolved"]},{"year":2022,"claim":"In vivo cardiac studies revealed ADAM15 is required for post-MI scar integrity through PAK1-dependent collagen cross-linking and for restraining calcineurin/NFAT-driven eccentric hypertrophy during pressure overload, establishing ADAM15 as a cardiac remodeling regulator.","evidence":"Adam15−/− mice in LAD ligation and TAC models; SHG imaging, collagen fractionation, LOX-1/PAK1 analysis; calcineurin activity assay with cyclosporin-A rescue","pmids":["34995785","36330793"],"confidence":"High","gaps":["Whether ADAM15's cardiac role is cell-autonomous to fibroblasts vs cardiomyocytes not resolved","Direct ADAM15–calcineurin interaction or intermediate not identified"]},{"year":2025,"claim":"ADAM15 was found essential for necroptosis competence: its loss enhances basal caspase-8 activity, partially degrades RIPK1, and increases TNF-R1 surface expression, while in synovial fibroblasts ADAM15 co-localizes with N-cadherin at adherens junctions to transduce mechanical strain via PAK2/Nck into epigenetic regulation of invasion.","evidence":"CRISPR KO in U937/Jurkat with necroptosis assays, caspase-8 activity, RIPK1 blots, TNF-R1 flow cytometry; co-IP of ADAM15/NCAD complex with PAK2/Nck recruitment and lncRNA H19/miR-130a-3p expression","pmids":["41340056","40118917"],"confidence":"Medium","gaps":["TNF-R1 as direct ADAM15 substrate not conclusively demonstrated","Whether RIPK1 degradation is a direct consequence of altered ADAM15-dependent trafficking unknown","In vivo validation of ADAM15 in necroptosis regulation lacking"]},{"year":null,"claim":"Key unresolved questions include: the structural basis for ADAM15 substrate selectivity; the in vivo relevance of most identified substrates beyond genetic models; how isoform-specific cytoplasmic splicing is regulated in disease; whether ADAM15's necroptosis role is relevant in inflammatory pathologies; and the molecular mechanism linking ADAM15 scaffolding to calcineurin/NFAT restraint in the heart.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of full-length ADAM15 available","Isoform-specific knockout mice not generated","In vivo substrate trapping has not been performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,12,13,17,26,29]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,25,30,31]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,6,20,32,40]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[39]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[23]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,12,15,20,25,37]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[5,6,32,40]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,39]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[27,30,39]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[36]}],"complexes":["ADAM15–FAK–Src complex","ADAM15–N-cadherin junctional complex","ADAM15–ZO1/ZO2 complex"],"partners":["ITGAV","FAK","GRB2","LCK","SRC","PABPC1","CALM1","NCK1"],"other_free_text":[]},"mechanistic_narrative":"ADAM15 is a membrane-anchored metalloprotease-disintegrin that integrates catalytic ectodomain shedding with non-catalytic cytoplasmic scaffolding to regulate cell adhesion, vascular permeability, neovascularization, tissue remodeling, and cell death decisions. Its extracellular disintegrin domain binds integrins αvβ3 and α5β1 in an RGD-dependent manner to modulate cell adhesion and migration [PMID:9516430, PMID:9914169], while its metalloprotease domain cleaves substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, and TRIF, with TIMP-3-sensitive but phorbol-ester-insensitive catalytic properties [PMID:19207106, PMID:18434311, PMID:23365087]; notably, pathological retinal neovascularization requires ADAM15 but not its catalytic activity, establishing a protease-independent scaffolding role in angiogenesis [PMID:25249606, PMID:20189953]. The cytoplasmic domain undergoes extensive alternative splicing generating isoform-specific interactions with Src family kinases, Grb2, FAK, calmodulin, Nck, nephrocystin, SNX33, and PABP, thereby activating FAK/Src, ERK, PI3K/Akt, and calcineurin/NFAT pathways to govern endothelial barrier function, chondrocyte survival, cardiac remodeling after injury, synovial fibroblast mechanosensing, and necroptosis competence [PMID:11741929, PMID:22544741, PMID:30003689, PMID:36330793, PMID:41340056]."},"prefetch_data":{"uniprot":{"accession":"Q13444","full_name":"Disintegrin and metalloproteinase domain-containing protein 15","aliases":["Metalloprotease RGD disintegrin protein","Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 15","MDC-15","Metargidin"],"length_aa":863,"mass_kda":93.0,"function":"Active metalloproteinase with gelatinolytic and collagenolytic activity. Plays a role in the wound healing process. Mediates both heterotypic intraepithelial cell/T-cell interactions and homotypic T-cell aggregation. Inhibits beta-1 integrin-mediated cell adhesion and migration of airway smooth muscle cells. Suppresses cell motility on or towards fibronectin possibly by driving alpha-v/beta-1 integrin (ITAGV-ITGB1) cell surface expression via ERK1/2 inactivation. Cleaves E-cadherin in response to growth factor deprivation. Plays a role in glomerular cell migration. Plays a role in pathological neovascularization. May play a role in cartilage remodeling. May be proteolytically processed, during sperm epididymal maturation and the acrosome reaction. May play a role in sperm-egg binding through its disintegrin domain","subcellular_location":"Endomembrane system; Cell junction, adherens junction; Cell projection, cilium, flagellum; Cytoplasmic vesicle, secretory vesicle, acrosome","url":"https://www.uniprot.org/uniprotkb/Q13444/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM15","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADAM15","total_profiled":1310},"omim":[{"mim_id":"620955","title":"SORTING NEXIN 30; SNX30","url":"https://www.omim.org/entry/620955"},{"mim_id":"619455","title":"SH3 AND PX DOMAINS-CONTAINING PROTEIN 2A; SH3PXD2A","url":"https://www.omim.org/entry/619455"},{"mim_id":"614404","title":"RHOMBOID 5 HOMOLOG 2; RHBDF2","url":"https://www.omim.org/entry/614404"},{"mim_id":"613293","title":"SH3 AND PX DOMAINS-CONTAINING PROTEIN 2B; SH3PXD2B","url":"https://www.omim.org/entry/613293"},{"mim_id":"606393","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN-LIKE PROTEIN DECYSIN 1; ADAMDEC1","url":"https://www.omim.org/entry/606393"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ADAM15"},"hgnc":{"alias_symbol":["MDC15"],"prev_symbol":[]},"alphafold":{"accession":"Q13444","domains":[{"cath_id":"-","chopping":"511-687","consensus_level":"medium","plddt":88.0573,"start":511,"end":687},{"cath_id":"-","chopping":"48-87_118-172","consensus_level":"high","plddt":82.1433,"start":48,"end":172},{"cath_id":"3.40.390.10","chopping":"209-412","consensus_level":"high","plddt":86.7854,"start":209,"end":412},{"cath_id":"4.10.70.10","chopping":"423-503","consensus_level":"medium","plddt":86.2838,"start":423,"end":503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13444","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13444-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13444-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM15","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM15"},"sequence":{"accession":"Q13444","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13444.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13444/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13444"}},"corpus_meta":[{"pmid":"9516430","id":"PMC_9516430","title":"Specific interaction of the recombinant disintegrin-like domain of MDC-15 (metargidin, ADAM-15) with integrin alphavbeta3.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9516430","citation_count":196,"is_preprint":false},{"pmid":"9914169","id":"PMC_9914169","title":"Interaction of metargidin (ADAM-15) with alphavbeta3 and alpha5beta1 integrins on different haemopoietic cells.","date":"1999","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9914169","citation_count":177,"is_preprint":false},{"pmid":"18434311","id":"PMC_18434311","title":"The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18434311","citation_count":160,"is_preprint":false},{"pmid":"12897135","id":"PMC_12897135","title":"Potential role for ADAM15 in pathological neovascularization in mice.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12897135","citation_count":154,"is_preprint":false},{"pmid":"10531379","id":"PMC_10531379","title":"Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10531379","citation_count":149,"is_preprint":false},{"pmid":"12777399","id":"PMC_12777399","title":"Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12777399","citation_count":147,"is_preprint":false},{"pmid":"15586220","id":"PMC_15586220","title":"The disintegrin-metalloproteinases ADAM9, ADAM12, and ADAM15 are upregulated in gastric cancer.","date":"2005","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/15586220","citation_count":147,"is_preprint":false},{"pmid":"9748307","id":"PMC_9748307","title":"Intracellular maturation of the mouse metalloprotease disintegrin MDC15.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9748307","citation_count":137,"is_preprint":false},{"pmid":"11741929","id":"PMC_11741929","title":"Phosphorylation-dependent interactions between ADAM15 cytoplasmic domain and Src family protein-tyrosine kinases.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11741929","citation_count":94,"is_preprint":false},{"pmid":"16756724","id":"PMC_16756724","title":"ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease.","date":"2006","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16756724","citation_count":86,"is_preprint":false},{"pmid":"18281484","id":"PMC_18281484","title":"ADAM15 supports prostate cancer metastasis by modulating tumor cell-endothelial cell interaction.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18281484","citation_count":74,"is_preprint":false},{"pmid":"19253070","id":"PMC_19253070","title":"ADAM-9, ADAM-15, and ADAM-17 are upregulated in macrophages in advanced human atherosclerotic plaques in aorta and carotid and femoral arteries--Tampere vascular study.","date":"2009","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19253070","citation_count":68,"is_preprint":false},{"pmid":"20189953","id":"PMC_20189953","title":"ADAM15 regulates endothelial permeability and neutrophil migration via Src/ERK1/2 signalling.","date":"2010","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/20189953","citation_count":65,"is_preprint":false},{"pmid":"17905725","id":"PMC_17905725","title":"ADAM-15: a metalloprotease that mediates inflammation.","date":"2007","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17905725","citation_count":59,"is_preprint":false},{"pmid":"11697891","id":"PMC_11697891","title":"ADAM15 overexpression in NIH3T3 cells enhances cell-cell interactions.","date":"2001","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/11697891","citation_count":56,"is_preprint":false},{"pmid":"12858346","id":"PMC_12858346","title":"Increased expression of disintegrin-metalloproteinases ADAM-15 and ADAM-9 following upregulation of integrins alpha5beta1 and alphavbeta3 in atherosclerosis.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12858346","citation_count":55,"is_preprint":false},{"pmid":"22505472","id":"PMC_22505472","title":"Exosome release of ADAM15 and the functional implications of human macrophage-derived ADAM15 exosomes.","date":"2012","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/22505472","citation_count":53,"is_preprint":false},{"pmid":"15818704","id":"PMC_15818704","title":"Homeostatic effects of the metalloproteinase disintegrin ADAM15 in degenerative cartilage remodeling.","date":"2005","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15818704","citation_count":53,"is_preprint":false},{"pmid":"18296648","id":"PMC_18296648","title":"Distinct functions of natural ADAM-15 cytoplasmic domain variants in human mammary carcinoma.","date":"2008","source":"Molecular cancer research : 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mutation of RGD to SGA abolishes binding, and the flanking sequence RPTRGD determines receptor specificity (αvβ3 vs αIIbβ3).\",\n      \"method\": \"GST fusion protein binding assay with recombinant integrins expressed in mammalian cells; site-directed mutagenesis of RGD motif\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro binding reconstitution with mutagenesis, replicated by multiple subsequent studies\",\n      \"pmids\": [\"9516430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The extracellular domain of ADAM15 (metargidin) mediates cell adhesion to haemopoietic cells via integrin αvβ3 on U937 monocytic cells and integrin α5β1 on MOLT-4 T cells, in an RGD-dependent, divalent cation-dependent manner.\",\n      \"method\": \"Solid-phase cell-adhesion assays with chimeric ADAM15-Fc protein; anti-integrin antibody blocking; purified recombinant integrins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal adhesion assays with purified integrins and antibody blocking, replicated across two cell lines\",\n      \"pmids\": [\"9914169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse MDC15/ADAM15 pro-domain is removed by a pro-protein convertase (furin) in a late Golgi compartment; processed mature ADAM15 is endoglycosidase H-resistant, and the majority accumulates in a perinuclear/trans-Golgi network/endosomal compartment rather than at the cell surface.\",\n      \"method\": \"Pulse-chase experiments; brefeldin A/monensin treatment; in vitro furin cleavage assay; cell-surface trypsinization; immunolocalization in COS-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including in vitro reconstitution with furin and pharmacological inhibitors\",\n      \"pmids\": [\"9748307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The cytoplasmic domains of ADAM15 (MDC15) and MDC9 interact with the SH3 domain-containing proteins endophilin I (SH3GL2) and a novel SH3-PX domain protein (SH3PX1); these interactions are preferential for the precursor (pro-domain-containing) forms and were identified by yeast two-hybrid, bacterial fusion pulldown, and co-immunoprecipitation from eukaryotic cells.\",\n      \"method\": \"Yeast two-hybrid screen; bacterial GST fusion pulldown; co-immunoprecipitation from COS-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; yeast two-hybrid confirmed by pulldown and co-IP\",\n      \"pmids\": [\"10531379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic domain of ADAM15 interacts with Src family kinases (Lck, Fyn, Abl, Src, Hck) via SH3 domain binding to proline-rich motifs, and with adaptor protein Grb2; interactions are phosphorylation-dependent (enhanced by tyrosine phosphorylation); Hck and Lck phosphorylate the ADAM15 cytoplasmic domain in vitro; Tyr715 and Tyr735 are regulatory residues.\",\n      \"method\": \"SH3 domain pulldowns; co-immunoprecipitation from hematopoietic cell lines; in vitro immune complex kinase assays; Far Western analysis; deletion and point mutation analysis; PMA stimulation and PP1 inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assays with mutagenesis, confirmed by multiple orthogonal methods in multiple cell lines\",\n      \"pmids\": [\"11741929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"ADAM15 overexpression in NIH3T3 cells enhances cell-cell interactions: it localizes to cell-cell contacts in epithelial cells, decreases monolayer permeability, and increases cell adhesion to ADAM15-expressing monolayers by 45%, while inhibiting cell migration on fibronectin.\",\n      \"method\": \"Tetracycline-regulated overexpression; Boyden chamber migration assay; scratch wound model; monolayer permeability assay; cell adhesion assay; epitope-tagged ADAM15 immunolocalization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — clean overexpression with specific cellular phenotype readouts, single lab\",\n      \"pmids\": [\"11697891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADAM15 localizes to adherens junctions in endothelial cells, colocalizing with VE-cadherin; VE-cadherin coexpression drives ADAM15 surface expression and translocation to the cell periphery in CHO cells.\",\n      \"method\": \"Immunofluorescence colocalization; ADAM15-GFP fusion protein imaging; flow cytometry for cell surface levels; co-expression of VE-cadherin and ADAM15 in CHO cells\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct localization with functional consequence (surface expression), single lab\",\n      \"pmids\": [\"12243749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAM15-deficient (adam15-/-) mice show major reduction in pathological retinal neovascularization in a retinopathy of prematurity model, and reduced tumor growth of implanted B16F0 melanoma cells, demonstrating ADAM15 is required for pathological but not developmental neovascularization.\",\n      \"method\": \"Targeted gene deletion (knockout mice); mouse model of retinopathy of prematurity; heterotopic tumor implantation model; mRNA in situ hybridization for expression pattern\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic loss-of-function with specific in vivo phenotypic readouts in multiple model systems\",\n      \"pmids\": [\"12897135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Recombinant soluble ADAM15, ADAM8, and ADAM28 (MDC-L) cleave synthetic peptide substrates with distinct specificities from ADAM17, and catalyze ectodomain shedding of CD23 (low-affinity IgE receptor); shedding requires proteolytically active enzyme and is inhibited by hydroxamic acid metalloprotease inhibitor.\",\n      \"method\": \"Peptide substrate library screening with purified recombinant enzymes; ectodomain shedding assay; catalytically inactive mutant control; metalloprotease inhibitor treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with purified recombinant enzyme, mutagenesis control, and pharmacological inhibition\",\n      \"pmids\": [\"12777399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM15 deficiency in aging mice leads to accelerated osteoarthritic lesions; overexpression of ADAM15 in chondrocytes enhances adhesion to cartilage collagens (type II and VI) and promotes cell viability under serum starvation, indicating a chondroprotective/homeostatic role.\",\n      \"method\": \"ADAM15 knockout mice joint morphology analysis; stable transfection of T/C28a4 chondrocyte cell line; cell adhesion assays on fibronectin and collagens; cell viability under serum starvation\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — complementary loss-of-function (KO mice) and gain-of-function (overexpression) with specific phenotypic readouts\",\n      \"pmids\": [\"15818704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM15 overexpression in cancer cells suppresses integrin αvβ3-mediated adhesion to vitronectin and reduces cell motility in an RGD-dependent manner; mutation of RGD to SGA abrogates these effects.\",\n      \"method\": \"Stable overexpression of ADAM15 and RGD→SGA mutant in OV-MZ-6 ovarian cancer cells; cell adhesion assay on vitronectin; cell motility assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RGD mutagenesis with specific cellular phenotype, single lab\",\n      \"pmids\": [\"15618016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ADAM15 gene contains 23 exons; alternative splicing of cytoplasmic-domain-encoding exons 19, 20a/b, and 21a/b generates at least 13 splice variants in normal human tissues with different combinations of regulatory protein interaction motifs; a GC-rich, TATA-less promoter with functional activity located within a CpG island proximal to the translation start was confirmed by reporter assays.\",\n      \"method\": \"Genomic characterization; RT-PCR splice variant analysis in human tissues; luciferase reporter expression experiments\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reporter assays confirming promoter function; splice variant characterization across tissues\",\n      \"pmids\": [\"17937806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 catalytically cleaves E-cadherin ectodomain; the soluble E-cadherin fragment binds to and stabilizes HER2/HER3 heterodimerization, activating ERK signaling and promoting breast cancer cell migration and proliferation.\",\n      \"method\": \"ADAM15 overexpression and shRNA knockdown in breast cancer cells; metalloprotease inhibitor treatment; catalytically inactive ADAM15 mutant; co-immunoprecipitation of sE-cad with HER2/HER3; ERK pathway activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — catalytic mutant, inhibitor, shRNA, and co-IP with multiple orthogonal methods\",\n      \"pmids\": [\"18434311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 knockdown in PC-3 prostate cancer cells reduces N-cadherin cleavage at the cell surface, decreases αv integrin and CD44 surface expression, abrogates MMP9 secretion/activity, reduces adhesion and migration through vascular endothelial monolayers, and attenuates bone metastasis in SCID mice.\",\n      \"method\": \"Lentiviral shRNA knockdown; FACS for surface markers; MMP9 activity assay; transendothelial migration assay; SCID mouse bone metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean loss-of-function with multiple mechanistic readouts and in vivo validation\",\n      \"pmids\": [\"18281484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 splice variants differ only in their cytoplasmic domains; ADAM15A and ADAM15B variants show differential isoform-specific association with Nck, Src, and Brk tyrosine kinases (but equivalent binding to ERK, Grb2, and Tks5/Fish), leading to different effects on cell morphology, adhesion, migration, and invasion in breast cancer cells.\",\n      \"method\": \"Cloning and characterization of four alternatively spliced ADAM15 forms; GST pulldown assays; expression in MDA-MB-435 cells; adhesion, migration, invasion assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pulldown with isoform-specific functional readouts, single lab\",\n      \"pmids\": [\"18296648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 suppresses cell motility by driving increased cell surface expression of integrin α5 (without directly interacting with α5β1) via downregulation of ERK1/2 phosphorylation; MEK inhibitor or ERK siRNA mimics this effect, and ADAM15 overexpression reduces lung metastatic nodules in a B16F10 model.\",\n      \"method\": \"CHO cell transfection with ADAM15; immunoprecipitation and immunofluorescence; MEK inhibitor PD98059; ERK1/2 siRNA; flow cytometry for integrin surface expression; B16F10 pulmonary metastasis model\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placement by pharmacological inhibition and siRNA, confirmed in vivo\",\n      \"pmids\": [\"18387333\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"VEGF upregulates ADAM15 expression in retinal vascular endothelial cells in ischemic retina; ADAM15 and VEGF participate in an amplification loop, with ADAM15 increasing VEGF, VEGFR1, and VEGFR2 expression; ADAM15-deficient mice show reduced ischemia-induced retinal neovascularization and choroidal neovascularization.\",\n      \"method\": \"ADAM15 knockout mice; oxygen-induced retinopathy model; choroidal neovascularization model; VEGF knockdown in ischemic retina; VEGF overexpression in non-ischemic retina; mRNA quantification\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in three in vivo model systems with defined molecular feedback loop\",\n      \"pmids\": [\"18381816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Membrane-anchored ADAM15 sheds the ectodomain of fibroblast growth factor receptor 2iiib (FGFR2iiib) in cell-based assays; catalytically inactive ADAM15E→A mutant does not shed FGFR2iiib; shedding is inhibited by hydroxamate inhibitors (marimastat, TAPI-2, GM6001) and TIMP-3 (50 nM) but not TIMP-1 or TIMP-2; ADAM15 is not stimulated by phorbol esters or calcium ionophores.\",\n      \"method\": \"Overexpression of ADAM15 and catalytically inactive ADAM15E→A in cells; cell-based shedding assay; metalloprotease inhibitor panel; TIMP inhibitor panel\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cell-based reconstitution with catalytic mutant, multiple inhibitors, and defined substrate\",\n      \"pmids\": [\"19207106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM15 splice variant ADAM15B (containing a Src-binding cytoplasmic site) has enhanced catalytic activity (FGFR2iiib shedding) compared to ADAM15A; this enhanced activity depends on Src kinase, as it is abolished by Src kinase inhibitors and in Src-/- cells but restored by Src rescue.\",\n      \"method\": \"Cell-based shedding assay; Src kinase inhibitors; Src-/- cells and rescue; comparison of ADAM15A vs ADAM15B splice variants\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic (Src KO/rescue) and pharmacological evidence for Src-dependent enhancement of ADAM15B catalytic activity\",\n      \"pmids\": [\"19487280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Alternative splicing of ADAM15 cytoplasmic exons profoundly influences selection of SH3-containing binding partners; isoforms containing exons 20 and/or 21 (with RxLPxxP motif) specifically bind nephrocystin; isoforms with the C-terminal proline cluster bind SNX33; these interactions were abolished by specific proline-cluster mutations.\",\n      \"method\": \"Co-precipitation from cell lysates; isoform-specific pull-downs; proline-cluster point mutations\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-precipitation with mutagenesis for multiple isoforms, single lab\",\n      \"pmids\": [\"19718658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM15 promotes endothelial hyperpermeability and neutrophil transendothelial migration via Src/ERK1/2 signaling, independent of junction molecule (VE-cadherin) shedding; both wild-type and catalytically dead ADAM15 increase ERK1/2 phosphorylation and permeability; Src or ERK inhibition reverses ADAM15-induced effects.\",\n      \"method\": \"siRNA knockdown; overexpression of wild-type and catalytically dead ADAM15 in HUVECs; transendothelial electric resistance and albumin flux assays; neutrophil migration assay; pharmacological Src/ERK inhibitors; ERK1/2 phosphorylation by Western blot\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — catalytic dead mutant establishes protease-independent mechanism; pharmacological pathway placement; multiple orthogonal readouts\",\n      \"pmids\": [\"20189953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An ADAM15 metalloprotease domain-derived peptide (ADoPep1 containing HWRR sequence) activates GRP78 on endothelial cell membranes under hypoxia, inducing angiogenesis via Akt phosphorylation and ERK1/2 activation (VEGF-independent); GRP78 siRNA blocks this effect.\",\n      \"method\": \"Synthetic peptide derived from ADAM15 sequence; cell proliferation, migration, tube formation assays; mouse hind limb ischemia model; siRNA against GRP78; Western blot for Akt/ERK phosphorylation; VEGFR2 phosphorylation assay\",\n      \"journal\": \"Journal of vascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — peptide-based functional assay with siRNA validation and in vivo model; single lab\",\n      \"pmids\": [\"20145413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Loss of ADAM15 in osteoblasts leads to increased nuclear β-catenin translocation (with increased cytoplasmic/membrane degradation), upregulation of cyclin D1 and c-Jun (downstream Wnt targets), and increased osteoblast proliferation, alkaline phosphatase activity, nodule deposition, and mineralization, resulting in higher trabecular and cortical bone mass in ADAM15-/- mice.\",\n      \"method\": \"ADAM15-/- mice bone analysis; primary ADAM15-/- osteoblast cultures; β-catenin immunoreactivity (nuclear vs cytoplasmic); cyclin D1 and c-Jun Western blot\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in vivo with mechanistic in vitro follow-up; single lab, moderate orthogonal methods\",\n      \"pmids\": [\"21801086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM15 is released from cells as an exosomal component in response to PKC activation; exosomal ADAM15 binds integrin αvβ3 in an RGD-dependent manner and suppresses vitronectin/fibronectin-induced cancer cell adhesion, growth, migration, and in vivo tumor growth; macrophage-derived ADAM15 exosomes have tumor inhibitory effects.\",\n      \"method\": \"Exosome isolation; phorbol ester (PMA/PKC activator) treatment; integrin αvβ3 binding assay; RGD mutation control; in vitro cancer cell adhesion, growth, migration assays; in vivo tumor growth model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — RGD mutagenesis control with multiple functional assays, single lab\",\n      \"pmids\": [\"22505472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM15 deficiency attenuates LPS-induced acute lung injury: loss of ADAM15 in endothelial cells reduces hyperpermeability response to LPS and decreases neutrophil chemotactic transmigration; rescue expression of ADAM15 in Adam15-/- ECs restores neutrophil transendothelial migration.\",\n      \"method\": \"Adam15-/- mice; LPS-induced acute lung injury model; primary mouse lung endothelial cell culture; albumin flux and TER assays; neutrophil transmigration assay; ADAM15 rescue expression\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function confirmed by rescue experiment, with specific mechanistic cellular readouts\",\n      \"pmids\": [\"23161886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM15 cytoplasmic domain directly binds the C-terminus of FAK; genotoxic stress (camptothecin) in ADAM15-transfected chondrocytes causes enhanced FAK phosphorylation at Tyr-397, Tyr-576, and Tyr-861 and concomitant Src activation; ADAM15 lacking its cytoplasmic tail loses this anti-apoptotic/FAK-activating property; Src binds FAK but not directly ADAM15, placing FAK as critical adaptor.\",\n      \"method\": \"Mammalian two-hybrid; pulldown; Far Western studies; chimeric IL-2Rα/ADAM15-cytoplasmic-tail construct; Western blot for phospho-FAK and phospho-Src; FAK/Src inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple binding methods (two-hybrid, pulldown, Far Western) plus chimeric construct functional validation\",\n      \"pmids\": [\"22544741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM15 interacts with TRIF (TLR adaptor) following TLR3/TLR4 stimulation; ADAM15 acts as a negative regulator of TRIF-mediated NF-κB and IFN-β signaling, and mediates proteolytic cleavage of TRIF; ADAM15 suppression enhances proinflammatory cytokine production in response to poly I:C, LPS, rhinovirus 16, and VSV.\",\n      \"method\": \"Co-immunoprecipitation of TRIF signaling complex; LC-MS protein identification; ADAM15 knockdown; NF-κB and IFN-β reporter assays; cytokine production measurement; TRIF cleavage assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — MS-identified interaction confirmed by co-IP and proteolytic cleavage assay, with functional reporter assays\",\n      \"pmids\": [\"23365087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM15 adds to apoptosis resistance of rheumatoid arthritis synovial fibroblasts (RASFs) by activating Src/FAK signaling upon FasL stimulation; ADAM15 knockdown by siRNA increases caspase 3/7 activity and apoptosis upon camptothecin and FasL treatment; FasL-induced FAK/Src activation, PI3K activation, and NF-κB activity are ADAM15-dependent.\",\n      \"method\": \"siRNA knockdown of ADAM15 in RASFs; caspase 3/7 enzyme assays; annexin V staining; immunoblotting for phospho-FAK, phospho-Src, NF-κB; FAK inhibitor 14 and dasatinib treatment\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with multiple mechanistic readouts and pharmacological validation, single lab\",\n      \"pmids\": [\"23918525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Catalytic activity of ADAM15 is NOT required for pathological retinal neovascularization in the OIR model (Adam15E>A knock-in mice show WT-equivalent neovascularization), but catalytic activity contributes to suppression of tumor implantation; ADAM15 can process FGFR2iiib but not several angiogenesis-related receptors in cell-based assays.\",\n      \"method\": \"Adam15E>A catalytic point-mutation knock-in mice; OIR model; heterotopic melanoma tumor implantation; cell-based shedding assays for multiple angiogenesis receptors\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — knock-in catalytic mutant mice in multiple in vivo models, directly parsing catalytic vs non-catalytic functions\",\n      \"pmids\": [\"25249606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAM15 proteolytically cleaves and activates pro-MMP9 in vitro; ADAM15 interacts with MMP9 in vivo; ADAM15 upregulates MMP9 expression via MEK-ERK pathway activation; MMP9 knockdown attenuates ADAM15-driven lung cancer cell invasion.\",\n      \"method\": \"In vitro pro-MMP9 cleavage assay; co-immunoprecipitation (in vivo interaction); MMP9 Western blot; MEK-ERK pathway analysis; shRNA knockdown; invasion assay\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vitro cleavage assay and co-IP, with epistasis by MMP9 knockdown; single lab\",\n      \"pmids\": [\"26323669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM15 converts FasL/Fas-death signals into prosurvival Src/FAK activation in RASFs via calmodulin (CaM) recruitment: FasL triggers CRAC/Orai1-dependent Ca2+ release, leading to CaM recruitment to Fas/CD95 and ADAM15 at the membrane, followed by Src-CaM engagement in the ADAM15/FAK complex; cytoplasmic ADAM15 domain is required for this prosurvival scaffolding.\",\n      \"method\": \"CaM-Sepharose pulldown; co-immunoprecipitation with anti-ADAM15 and anti-CD95 antibodies; recombinant CaM protein binding assay; immunofluorescence colocalization; CRAC/Orai1 inhibitor BTP-2; CaM inhibitor trifluoperazine; ADAM15 cytoplasmic domain deletion construct; caspase 3/7 assays; annexin V staining\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple binding methods (pulldown, co-IP, recombinant protein assay), pharmacological pathway dissection, and cytoplasmic tail deletion control\",\n      \"pmids\": [\"30003689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM15 cytoplasmic domain transiently interacts with poly(A) binding protein 1 (PABP) via the PABP proline-rich linker during cell adhesion; this interaction recruits PABP to the cell membrane and promotes local mRNA translation (detected by puromycin-terminated polypeptides); loss of ADAM15 or its cytoplasmic tail reduces cell membrane-associated protein neosynthesis during adhesion.\",\n      \"method\": \"Co-immunoprecipitation; domain-mapping pulldown; immunostaining for PABP and puromycin-incorporated nascent proteins; ADAM15 siRNA and cytoplasmic-tail deletion mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with domain mapping and functional puromycin assay; single lab\",\n      \"pmids\": [\"30265671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM15 isoform-specific, catalytic-function-dependent upregulation of Claudin-1 in breast cancer cells; ADAM15A (and to lesser extent C, E isoforms) increase Claudin-1 expression via PI3K/Akt/mTOR pathway; ADAM15 co-localizes with Claudin-1 and ZO1 at cell-cell junctions; ADAM15 forms a complex with ZO1/ZO2 as shown by co-immunoprecipitation.\",\n      \"method\": \"Isogenic cell panels expressing five ADAM15 variants (WT and catalytically inactive); shRNA knockdown; PI3K/Akt/mTOR pathway analysis; immunofluorescence; co-immunoprecipitation of ADAM15 with ZO1/ZO2\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform and catalytic mutant panel with co-IP and pathway inhibition; single lab\",\n      \"pmids\": [\"31467400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"KLF2 transcription factor (induced by laminar shear stress) drives ADAM15 expression in endothelial cells; physiologic shear stress upregulates ADAM15 (~4-fold mRNA, 5.6-fold protein); ADAM15 promotes endothelial cell survival under growth factor depletion or TNF stimulation; KLF2 siRNA prevents shear-stress-induced ADAM15 upregulation.\",\n      \"method\": \"Flow culture of primary endothelial cells; transcriptomic analysis; KLF2 overexpression and siRNA; simvastatin induction; ADAM15 shRNA knockdown; endothelial survival assays\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KLF2 overexpression/knockdown with ADAM15 readout, functional survival assay; single lab\",\n      \"pmids\": [\"31271758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM15 promotes a pro-inflammatory mechanosensing pathway in synovial fibroblasts: ADAM15 promotes cell membrane density of mechanosensitive TRPV4 calcium channels and reinforces Src-mediated pannexin-1 channel activation for ATP release; loss of ADAM15 abolishes Ca2+-dependent JNK activation, HOTAIR lncRNA downregulation, and sirtuin-1 upregulation in response to mechanical stimulation.\",\n      \"method\": \"ADAM15 loss-of-function in synovial fibroblasts; TRPV4 membrane density assay; pannexin-1 channel activity; JNK phosphorylation; HOTAIR and sirtuin-1 expression; Ca2+ signaling measurements\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — genetic loss-of-function with mechanistic pathway readouts; single lab\",\n      \"pmids\": [\"34685689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM15 participates in tick-borne encephalitis virus (TBEV) replication and assembly; ADAM15 subcellular localization changes during TBEV infection contributing to membrane reorganization and replication organelle formation; ADAM15 knockdown/knockout causes TBEV replication and assembly defects.\",\n      \"method\": \"siRNA knockdown; CRISPR knockout; RNA-seq; subcellular localization imaging; virus production and replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function by both siRNA and CRISPR with specific viral replication readouts; single lab\",\n      \"pmids\": [\"33208450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM15 is required for optimal collagen cross-linking and scar formation after myocardial infarction: Adam15-/- mice show higher rate of LV rupture post-MI, reduced fibrillar collagen density, lower insoluble collagen, reduced lysyl oxidase-1 (LOX-1) and fibronectin; ADAM15 loss reduces PAK1 levels in cardiac fibroblasts; PAK1 regulates fibronectin and LOX-1 expression.\",\n      \"method\": \"Adam15-/- mice; LAD ligation MI model; second harmonic generation imaging; soluble/insoluble collagen fractionation; LOX-1, fibronectin, PAK1 Western blot; primary cardiac fibroblast ischemia model; echocardiography\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive in vivo KO with multiple mechanistic readouts and in vitro mechanistic follow-up; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34995785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of ADAM15 in pressure-overload cardiomyopathy (TAC) exacerbates eccentric hypertrophy and dilation through increased calcineurin/NFAT pathway activity; integrin-α7 expression increases more in Adam15-/- TAC hearts while integrin-laminin interaction decreases; calcineurin inhibition (cyclosporin-A) blocks excess hypertrophy in Adam15-/- TAC mice.\",\n      \"method\": \"Adam15-/- mice; TAC model; calcineurin activity assay; NFAT phosphorylation; integrin-α7 and laminin interaction; cyclosporin-A treatment; proteome profiling; echocardiography\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with pathway rescue by cyclosporin-A and proteomic profiling; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36330793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ADAM15 promotes FAK and EGFR signaling in lung cancer through interactions with integrins; integrin αV mediates ADAM15-FAK signaling; ADAM15 cooperates with CD151 to modulate integrin α3/α6-related EGFR signaling; miR-204-5p directly targets and suppresses ADAM15.\",\n      \"method\": \"Co-IP between ADAM15 and integrins; CD151 co-expression studies; FAK/EGFR signaling pathway assays; luciferase reporter assay for miR-204-5p targeting; nude mouse xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP for binding, reporter assay for miRNA targeting, in vivo model; single lab\",\n      \"pmids\": [\"35597804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADAM15 loss abrogates necroptosis induced by death ligands (TNF, TRAIL, FasL, TL1a) and a BH3 mimetic; loss of ADAM15 results in enhanced basal caspase-8 activity (non-cytotoxic) and partial RIPK1 degradation; ADAM15 is found in intracellular lysosomal compartments and enhanced TNF-R1 surface expression in ADAM15-KO cells suggests TNF-R1 as a potential substrate.\",\n      \"method\": \"CRISPR/Cas9 adam15 knockout in U937 and Jurkat cells; necroptosis/apoptosis assays; caspase-8 enzyme assay; Western blot for RIPK1; flow cytometry for TNF-R1 surface expression; immuno-magnetic fractionation for subcellular localization; bottom-up proteome analysis\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with multiple mechanistic readouts; TNF-R1 substrate hypothesis supported but not conclusively proven; single lab\",\n      \"pmids\": [\"41340056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ADAM15 and N-cadherin (NCAD) co-localize in adherens junctions of synovial fibroblasts; mechanical strain triggers a pathway through this complex involving PAK2 phosphorylation and co-recruitment of Nck; this leads to downregulation of lncRNA H19 and miR-130a-3p, upregulation of cadherin-11, and enhanced cell invasion.\",\n      \"method\": \"Immunofluorescence co-localization; co-immunoprecipitation of ADAM15/NCAD complex; PAK2 phosphorylation assay; Nck recruitment assay; lncRNA H19 and miR-130a-3p expression; invasion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP, phosphorylation assay, and functional invasion readout; mechanistic pathway placed but single lab\",\n      \"pmids\": [\"40118917\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM15 is a membrane-anchored multi-domain metalloprotease-disintegrin that functions through both catalytic and non-catalytic mechanisms: its extracellular disintegrin domain mediates RGD-dependent binding to integrins αvβ3 and α5β1 to regulate cell adhesion and migration; its metalloprotease domain sheds substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, and TRIF (with TIMP-3-sensitive, phorbol ester-insensitive catalytic properties); its cytoplasmic domain acts as a signaling scaffold that undergoes phosphorylation by Src family kinases (Hck, Lck) and interacts isoform-specifically with SH3-domain proteins (Grb2, Lck, Brk, Nck, nephrocystin, SNX33), FAK, calmodulin, and PABP to modulate ERK, FAK/Src, PI3K/Akt, calcineurin/NFAT, and purinergic signaling pathways; collectively, these functions govern pathological neovascularization, endothelial barrier integrity, chondrocyte survival, cardiac remodeling, and immune cell death decisions including necroptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADAM15 is a membrane-anchored metalloprotease-disintegrin that integrates catalytic ectodomain shedding with non-catalytic cytoplasmic scaffolding to regulate cell adhesion, vascular permeability, neovascularization, tissue remodeling, and cell death decisions. Its extracellular disintegrin domain binds integrins αvβ3 and α5β1 in an RGD-dependent manner to modulate cell adhesion and migration [PMID:9516430, PMID:9914169], while its metalloprotease domain cleaves substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, and TRIF, with TIMP-3-sensitive but phorbol-ester-insensitive catalytic properties [PMID:19207106, PMID:18434311, PMID:23365087]; notably, pathological retinal neovascularization requires ADAM15 but not its catalytic activity, establishing a protease-independent scaffolding role in angiogenesis [PMID:25249606, PMID:20189953]. The cytoplasmic domain undergoes extensive alternative splicing generating isoform-specific interactions with Src family kinases, Grb2, FAK, calmodulin, Nck, nephrocystin, SNX33, and PABP, thereby activating FAK/Src, ERK, PI3K/Akt, and calcineurin/NFAT pathways to govern endothelial barrier function, chondrocyte survival, cardiac remodeling after injury, synovial fibroblast mechanosensing, and necroptosis competence [PMID:11741929, PMID:22544741, PMID:30003689, PMID:36330793, PMID:41340056].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing that ADAM15 is an RGD-dependent integrin ligand resolved how a membrane metalloprotease could directly mediate cell adhesion: the disintegrin domain binds αvβ3 via a specific RPTRGD motif, and furin processes the pro-domain in the Golgi, with mature ADAM15 accumulating primarily in a perinuclear/TGN compartment rather than at the cell surface.\",\n      \"evidence\": \"Recombinant GST-disintegrin binding assays with RGD→SGA mutagenesis; pulse-chase, furin cleavage, and immunolocalization in COS-7 cells\",\n      \"pmids\": [\"9516430\", \"9748307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of ADAM15 disintegrin–integrin complex not determined\", \"Mechanism controlling ADAM15 surface trafficking vs perinuclear retention unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that ADAM15 engages both αvβ3 and α5β1 on haemopoietic cells and that its cytoplasmic domain interacts with SH3-domain proteins (endophilin I, SH3PX1) established ADAM15 as a dual-function molecule coupling extracellular adhesion with intracellular signaling scaffolds.\",\n      \"evidence\": \"Solid-phase adhesion assays with Fc-fusion protein and antibody blocking; yeast two-hybrid screen confirmed by co-IP from COS-7 cells\",\n      \"pmids\": [\"9914169\", \"10531379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of endophilin/SH3PX1 binding on ADAM15 biology not established\", \"Whether pro-domain-preferential interaction reflects trafficking regulation is unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identification of Src family kinases (Hck, Lck) as cytoplasmic-domain kinases and Grb2 as an adaptor partner, together with evidence that ADAM15 overexpression strengthens cell–cell contacts and suppresses migration, defined ADAM15 as a signaling-competent adhesion molecule at cell junctions.\",\n      \"evidence\": \"SH3 pulldowns, co-IP from hematopoietic lines, in vitro kinase assays with Tyr715/735 mutagenesis; overexpression in NIH3T3 with permeability, adhesion, and migration assays\",\n      \"pmids\": [\"11741929\", \"11697891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream pathways are activated by Hck/Lck-mediated ADAM15 phosphorylation was not yet mapped\", \"Endogenous stoichiometry of ADAM15–kinase complexes not determined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Localizing ADAM15 to VE-cadherin-positive adherens junctions in endothelial cells, with VE-cadherin co-expression driving ADAM15 surface translocation, positioned ADAM15 within the junctional machinery controlling vascular integrity.\",\n      \"evidence\": \"Immunofluorescence colocalization and GFP-ADAM15 imaging in endothelial cells and CHO cells co-expressing VE-cadherin\",\n      \"pmids\": [\"12243749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular interaction between ADAM15 and VE-cadherin not demonstrated\", \"Whether VE-cadherin-driven surface translocation involves specific sorting signals is unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Knockout mice revealed ADAM15 is required for pathological but not developmental neovascularization and tumor angiogenesis, while in vitro studies established ADAM15 as a bona fide sheddase for CD23, defining its first validated in vivo function and catalytic substrate.\",\n      \"evidence\": \"Adam15−/− mice in retinopathy of prematurity and B16F0 tumor models; recombinant ADAM15 peptide substrate profiling and CD23 shedding assay with catalytic-dead mutant control\",\n      \"pmids\": [\"12897135\", \"12777399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD23 shedding is relevant in vivo not tested\", \"Catalytic vs non-catalytic contribution to neovascularization not yet resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"ADAM15 knockout mice developing accelerated osteoarthritis, coupled with ADAM15 overexpression enhancing chondrocyte adhesion to cartilage collagens and viability, established a chondroprotective homeostatic role, while RGD-dependent suppression of αvβ3-mediated adhesion in cancer cells clarified the disintegrin domain's anti-migratory mechanism.\",\n      \"evidence\": \"Adam15−/− joint histomorphometry; chondrocyte overexpression with collagen adhesion and viability assays; cancer cell adhesion/motility with RGD→SGA mutant\",\n      \"pmids\": [\"15818704\", \"15618016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of ADAM15–collagen II/VI interaction unknown\", \"Whether chondroprotection is catalytic or scaffolding-dependent not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Characterization of 13 cytoplasmic splice variants from a TATA-less CpG-island promoter explained the molecular basis for isoform-specific signaling diversity observed in subsequent functional studies.\",\n      \"evidence\": \"Genomic analysis, RT-PCR across human tissues, luciferase reporter assays for promoter\",\n      \"pmids\": [\"17937806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Regulatory mechanisms governing tissue-specific splicing not identified\", \"Epigenetic regulation of the CpG-island promoter not explored\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Multiple studies resolved ADAM15's dual catalytic and scaffolding outputs: E-cadherin shedding activates HER2/HER3–ERK signaling in breast cancer; N-cadherin cleavage promotes prostate cancer transendothelial migration and bone metastasis; isoform-specific cytoplasmic domains differentially recruit Src, Nck, and Brk to control migration and invasion; and a VEGF–ADAM15 amplification loop drives ischemic retinal neovascularization.\",\n      \"evidence\": \"shRNA/overexpression with catalytic mutant in breast and prostate cancer cells; isoform-specific pulldowns; SCID mouse metastasis model; Adam15−/− mice in OIR and CNV models with VEGF pathway analysis\",\n      \"pmids\": [\"18434311\", \"18281484\", \"18296648\", \"18381816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether E-cadherin and N-cadherin are cleaved at the same or different sites unknown\", \"In vivo relevance of isoform-specific signaling not tested in genetic models\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defining FGFR2iiib as a TIMP-3-sensitive, PMA-insensitive ADAM15 substrate with Src-dependent enhancement in the ADAM15B isoform established a paradigm in which cytoplasmic splice variation controls extracellular catalytic output, while nephrocystin and SNX33 were mapped as isoform-selective SH3-domain partners.\",\n      \"evidence\": \"Cell-based FGFR2iiib shedding with catalytic mutant, inhibitor panel, Src−/− cells with rescue; co-precipitation with proline-cluster mutations for nephrocystin/SNX33\",\n      \"pmids\": [\"19207106\", \"19487280\", \"19718658\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequence of FGFR2iiib shedding in vivo not demonstrated\", \"Whether nephrocystin interaction links ADAM15 to ciliopathy pathways untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrating that catalytically dead ADAM15 still increases endothelial permeability and ERK phosphorylation via Src definitively separated the protease-independent scaffolding function from ectodomain shedding in vascular biology.\",\n      \"evidence\": \"Wild-type and catalytically dead ADAM15 overexpression in HUVECs; transendothelial resistance, albumin flux, neutrophil migration; Src/ERK inhibitors\",\n      \"pmids\": [\"20189953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of protease-independent Src/ERK activation unknown\", \"Whether scaffolding and catalytic functions are spatially segregated at junctions not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Three parallel advances solidified ADAM15's physiological roles: Adam15−/− endothelial rescue experiments confirmed its requirement for LPS-induced lung injury permeability; FAK was identified as a direct cytoplasmic-tail binding partner mediating anti-apoptotic Src activation; and exosomal ADAM15 release revealed a paracrine RGD-dependent mechanism suppressing cancer cell adhesion.\",\n      \"evidence\": \"Adam15−/− mice in LPS acute lung injury with rescue expression; mammalian two-hybrid, pulldown, Far Western for FAK binding with chimeric construct; exosome isolation with RGD mutant controls and tumor models\",\n      \"pmids\": [\"23161886\", \"22544741\", \"22505472\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether exosomal ADAM15 operates in non-cancer physiological contexts unknown\", \"FAK binding site on ADAM15 cytoplasmic tail not mapped to specific residues\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"ADAM15 was found to cleave TRIF and suppress TLR3/TLR4-mediated NF-κB/IFN-β signaling, expanding its substrate repertoire to innate immune adaptors, while parallel work showed it confers apoptosis resistance in synovial fibroblasts via Src/FAK/PI3K/NF-κB signaling.\",\n      \"evidence\": \"LC-MS identification of TRIF interaction, co-IP, TRIF cleavage assay, NF-κB/IFN-β reporters with ADAM15 knockdown; RASF siRNA with caspase assays and FAK/Src/NF-κB pathway inhibitors\",\n      \"pmids\": [\"23365087\", \"23918525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TRIF cleavage site not identified\", \"Whether TRIF cleavage is relevant in vivo during infection not tested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Adam15 catalytic-dead knock-in mice definitively showed that pathological retinal neovascularization is protease-independent while tumor suppression requires catalytic activity, parsing the in vivo contributions of ADAM15's two functional arms.\",\n      \"evidence\": \"Adam15E>A knock-in mice in OIR and tumor implantation models; cell-based shedding panel for angiogenesis receptors\",\n      \"pmids\": [\"25249606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the non-catalytic mechanism driving neovascularization (which integrin or signaling partner) not defined\", \"Limited substrate panel tested in cell-based assays\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Calmodulin was identified as the calcium-sensing mediator linking FasL/Fas death signals to ADAM15-dependent prosurvival Src/FAK activation in synovial fibroblasts, while PABP recruitment to ADAM15's cytoplasmic tail during cell adhesion revealed an unexpected role in local mRNA translation at the membrane.\",\n      \"evidence\": \"CaM-Sepharose pulldown, co-IP, recombinant CaM binding, CRAC/Orai1 inhibitor, CaM inhibitor, cytoplasmic-tail deletion; co-IP/domain-mapping for PABP with puromycin incorporation assay\",\n      \"pmids\": [\"30003689\", \"30265671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which mRNAs are locally translated at ADAM15/PABP sites unknown\", \"Whether CaM–ADAM15 interaction is isoform-specific not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"ADAM15 was placed downstream of shear-stress-induced KLF2 in endothelial cells to promote survival, and shown to upregulate Claudin-1 via PI3K/Akt/mTOR in an isoform- and catalysis-dependent manner while forming complexes with ZO1/ZO2 at tight junctions, broadening its junctional repertoire beyond adherens junctions.\",\n      \"evidence\": \"KLF2 overexpression/siRNA with ADAM15 readout under flow; isogenic ADAM15 isoform panel with PI3K/Akt/mTOR pathway analysis and ZO1/ZO2 co-IP\",\n      \"pmids\": [\"31271758\", \"31467400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KLF2 binding to ADAM15 promoter not shown by ChIP\", \"Functional consequence of ZO1/ZO2–ADAM15 complex on barrier integrity not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"ADAM15 was identified as a mechanosensory scaffold in synovial fibroblasts promoting TRPV4 membrane density and Src-dependent pannexin-1 ATP release, and independently as a host factor required for tick-borne encephalitis virus replication and membrane reorganization.\",\n      \"evidence\": \"ADAM15 loss-of-function in synovial fibroblasts with TRPV4/pannexin-1/JNK pathway assays; CRISPR KO and siRNA in TBEV-infected cells with replication and assembly readouts\",\n      \"pmids\": [\"34685689\", \"33208450\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAM15 regulates TRPV4 surface density unclear\", \"Whether ADAM15's role in TBEV replication involves its protease or scaffolding function not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"In vivo cardiac studies revealed ADAM15 is required for post-MI scar integrity through PAK1-dependent collagen cross-linking and for restraining calcineurin/NFAT-driven eccentric hypertrophy during pressure overload, establishing ADAM15 as a cardiac remodeling regulator.\",\n      \"evidence\": \"Adam15−/− mice in LAD ligation and TAC models; SHG imaging, collagen fractionation, LOX-1/PAK1 analysis; calcineurin activity assay with cyclosporin-A rescue\",\n      \"pmids\": [\"34995785\", \"36330793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ADAM15's cardiac role is cell-autonomous to fibroblasts vs cardiomyocytes not resolved\", \"Direct ADAM15–calcineurin interaction or intermediate not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ADAM15 was found essential for necroptosis competence: its loss enhances basal caspase-8 activity, partially degrades RIPK1, and increases TNF-R1 surface expression, while in synovial fibroblasts ADAM15 co-localizes with N-cadherin at adherens junctions to transduce mechanical strain via PAK2/Nck into epigenetic regulation of invasion.\",\n      \"evidence\": \"CRISPR KO in U937/Jurkat with necroptosis assays, caspase-8 activity, RIPK1 blots, TNF-R1 flow cytometry; co-IP of ADAM15/NCAD complex with PAK2/Nck recruitment and lncRNA H19/miR-130a-3p expression\",\n      \"pmids\": [\"41340056\", \"40118917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TNF-R1 as direct ADAM15 substrate not conclusively demonstrated\", \"Whether RIPK1 degradation is a direct consequence of altered ADAM15-dependent trafficking unknown\", \"In vivo validation of ADAM15 in necroptosis regulation lacking\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis for ADAM15 substrate selectivity; the in vivo relevance of most identified substrates beyond genetic models; how isoform-specific cytoplasmic splicing is regulated in disease; whether ADAM15's necroptosis role is relevant in inflammatory pathologies; and the molecular mechanism linking ADAM15 scaffolding to calcineurin/NFAT restraint in the heart.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of full-length ADAM15 available\", \"Isoform-specific knockout mice not generated\", \"In vivo substrate trapping has not been performed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 12, 13, 17, 26, 29]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 25, 30, 31]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 6, 20, 32, 40]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [39]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 12, 15, 20, 25, 37]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [5, 6, 32, 40]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 39]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [27, 30, 39]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [36]}\n    ],\n    \"complexes\": [\n      \"ADAM15–FAK–Src complex\",\n      \"ADAM15–N-cadherin junctional complex\",\n      \"ADAM15–ZO1/ZO2 complex\"\n    ],\n    \"partners\": [\n      \"ITGAV\",\n      \"FAK\",\n      \"GRB2\",\n      \"LCK\",\n      \"SRC\",\n      \"PABPC1\",\n      \"CALM1\",\n      \"NCK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}