{"gene":"ADAM15","run_date":"2026-06-09T22:02:40","timeline":{"discoveries":[{"year":1998,"finding":"The recombinant disintegrin-like domain of ADAM15 (MDC-15) specifically binds integrin αvβ3 in an RGD-dependent manner; mutation of RGD to SGA completely blocks binding, and mutation of the flanking sequence RPTRGD to NWKRGD extends specificity to include αIIbβ3, demonstrating that the flanking sequence determines receptor binding specificity.","method":"GST fusion protein binding assay with recombinant integrins, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding reconstitution with mutagenesis, multiple integrin specificity controls, replicated in subsequent papers","pmids":["9516430"],"is_preprint":false},{"year":1999,"finding":"The extracellular domain of ADAM15 (metargidin) mediates cell adhesion to haemopoietic cell lines via αvβ3 (on U937 monocytic cells) and α5β1 (on MOLT-4 T cells) integrins; adhesion is divalent cation-dependent, Mn2+-enhanced, and inhibited by RGD-based peptides, consistent with integrin-mediated binding through the disintegrin domain.","method":"Solid-phase cell-adhesion assay using Fc-fusion extracellular domain, blocking antibodies, RGD peptide competition, purified recombinant integrins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cell adhesion, antibody blocking, RGD competition, purified integrin binding), independently consistent with PMID 9516430","pmids":["9914169"],"is_preprint":false},{"year":1998,"finding":"Mouse MDC15 (ADAM15) is processed by a furin-like pro-protein convertase in a late Golgi/trans-Golgi network compartment: brefeldin A and monensin block pro-domain removal, mature protein is endoglycosidase H-resistant, and recombinant furin cleaves mMDC15 in vitro. More than half of mature mMDC15 is intracellular, accumulating in a perinuclear region resembling the TGN/endosomal compartments.","method":"Pulse-chase experiments in transfected COS-7 cells, brefeldin A/monensin treatment, endoglycosidase H resistance assay, in vitro furin cleavage, cell-surface trypsinization, immunolocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal biochemical methods in one study establishing both processing mechanism and subcellular localization","pmids":["9748307"],"is_preprint":false},{"year":1999,"finding":"The cytoplasmic domains of MDC15 (ADAM15) and MDC9 interact with two SH3 domain-containing proteins, endophilin I (SH3GL2) and SH3PX1; both preferentially bind the precursor (not processed) form of ADAM15. Interactions were validated by yeast two-hybrid, bacterial fusion protein pulldown, and co-immunoprecipitation from COS-7 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 / Strong — three orthogonal methods (Y2H, pulldown, co-IP), precursor-specificity finding is mechanistically distinct","pmids":["10531379"],"is_preprint":false},{"year":2001,"finding":"The cytoplasmic domain of ADAM15 interacts with multiple Src family kinases (Lck, Fyn, Abl, Src, Hck) via their SH3 domains, and with adaptor Grb2; interactions are phosphorylation-dependent. Hck and Lck phosphorylate the ADAM15 cytoplasmic domain in vitro; PMA stimulation increases ADAM15 phosphorylation in Jurkat cells. Tyr715 and Tyr735 and proline-rich motifs are required for binding, established by deletion and point mutants.","method":"SH3-domain pulldown, co-immunoprecipitation from hematopoietic cells, in vitro kinase assay (immune complex), Far Western, dephosphorylation assay, deletion/point mutagenesis, PMA stimulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (IP, in vitro kinase, Far Western, mutagenesis) in one rigorous study","pmids":["11741929"],"is_preprint":false},{"year":2001,"finding":"Overexpression of ADAM15 in NIH3T3 cells decreases cell migration on fibronectin, reduces monolayer permeability, and increases cell-cell adhesion (~45% increase). ADAM15 localizes to cell-cell contacts in an epithelial cell line, suggesting it functions as an adhesion molecule at cell-cell contact structures.","method":"Tetracycline-regulated overexpression, Boyden chamber migration assay, scratch wound assay, permeability assay, retroviral transduction, cell adhesion assay, immunolocalization","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple functional assays in one lab, localization supported by imaging, no pathway placement","pmids":["11697891"],"is_preprint":false},{"year":2002,"finding":"ADAM15 co-localizes with VE-cadherin at endothelial cell adherens junctions; VE-cadherin-mediated adherens junction formation drives cell-surface expression of ADAM15. Co-expression of VE-cadherin with ADAM15-GFP in CHO cells causes translocation of ADAM15 to the cell periphery and increases surface ADAM15 levels.","method":"Immunofluorescence colocalization, ADAM15-GFP fusion protein live imaging, VE-cadherin co-transfection, flow cytometry for surface ADAM15","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct localization with functional consequence (surface expression driven by VE-cadherin), single lab","pmids":["12243749"],"is_preprint":false},{"year":2003,"finding":"ADAM15 catalyzes ectodomain shedding of CD23 (low affinity IgE receptor) in cell-based assays, similar to ADAM8 and ADAM28; ADAM8-dependent CD23 release requires proteolytically active enzyme and is associated with physical interaction of ADAM8 with membrane CD23. Screening of synthetic peptide substrates showed that ADAM15 has proteolytic substrate specificity distinct from ADAM17.","method":"Synthetic peptide substrate library screening with recombinant soluble ADAM15, cell-based CD23 ectodomain shedding assay, metalloprotease inhibitor blocking","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro substrate assay plus cell-based shedding, but most mechanistic detail about physical interaction established for ADAM8, not ADAM15 specifically","pmids":["12777399"],"is_preprint":false},{"year":2003,"finding":"ADAM15 knock-out (adam15−/−) mice show a major reduction in pathological retinal neovascularization in an oxygen-induced retinopathy model and significantly smaller tumors from implanted B16F0 melanoma cells compared to wild-type controls, demonstrating ADAM15 is required for pathological neovascularization but not developmental angiogenesis.","method":"Targeted gene deletion (adam15−/− mice), oxygen-induced retinopathy model, subcutaneous melanoma implantation model","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined phenotype in two independent in vivo models, consistent with later replication","pmids":["12897135"],"is_preprint":false},{"year":2005,"finding":"ADAM15 overexpression in chondrocytes (T/C28a4 cell line) specifically reinforces adhesion to type II and VI collagen (but not fibronectin) and enhances cell viability under serum starvation. ADAM15−/− mice develop accelerated osteoarthritic lesions compared to wild-type, demonstrating a homeostatic/chondroprotective role in cartilage.","method":"Stable transfection of T/C28a4 chondrocytes with full-length ADAM15 cDNA, adhesion assays on ECM proteins, cell viability assay, ADAM15−/− mouse aging study with histological analysis","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO animal phenotype corroborated by in vitro overexpression with specific functional readout, single lab but two orthogonal models","pmids":["15818704"],"is_preprint":false},{"year":2008,"finding":"ADAM15 cleaves E-cadherin ectodomain in response to growth factor deprivation in breast cancer cells; cleavage is abrogated by metalloproteinase inhibitor and by catalytically inactive ADAM15 mutant. The shed soluble E-cadherin fragment forms a complex with HER2 and HER3 receptors, stabilizes HER2/HER3 heterodimerization, and activates Erk signaling to support cell migration and proliferation.","method":"ADAM15 overexpression and shRNA knockdown in breast cancer cells, catalytically inactive ADAM15 mutant, metalloproteinase inhibitor treatment, co-immunoprecipitation of sE-cad with HER2/HER3, Erk phosphorylation assay, migration/proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — catalytic mutant plus inhibitor establish enzymatic substrate, co-IP establishes sE-cad/ErbB complex, multiple complementary models in one study","pmids":["18434311"],"is_preprint":false},{"year":2008,"finding":"ADAM15 knockdown in metastatic prostate cancer PC-3 cells reduces N-cadherin cleavage at the cell surface, decreases cell migration and adhesion to extracellular matrix proteins, reduces cell surface αv integrin and CD44, abrogates MMP9 secretion/activity, and reduces adhesion to and migration through vascular endothelial monolayers. In SCID mice, ADAM15 loss significantly attenuates bone metastasis.","method":"Lentiviral shRNA knockdown, N-cadherin shedding assay, FACS, Matrigel invasion, MMP9 zymography, in vitro vascular invasion assay, SCID mouse bone metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro assays with mechanistic readouts plus in vivo validation, loss-of-function approach","pmids":["18281484"],"is_preprint":false},{"year":2008,"finding":"An ADAM15 splice variant (ADAM15B) containing a cytoplasmic Src-binding site has enhanced catalytic activity (FGFR2iiib shedding) compared with ADAM15A (lacking Src-binding site); enhanced activity of ADAM15B is abolished by Src-kinase inhibitors and in Src−/− cells but restored by re-introduction of Src, establishing that Src-dependent phosphorylation of the cytoplasmic domain activates ADAM15B ectodomain shedding.","method":"Cell-based FGFR2iiib shedding assay, Src kinase inhibitors, Src−/− fibroblasts with and without Src rescue, comparison of ADAM15A vs ADAM15B splice variants","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — epistasis (Src−/− rescue), pharmacological inhibition, and splice-variant comparison in one rigorous study establish Src as activator","pmids":["19487280"],"is_preprint":false},{"year":2008,"finding":"ADAM15 splice variants (A, B, C) differ in isoform-specific interactions with Nck, Src, and Brk tyrosine kinases via their cytoplasmic domains (GST pulldown), while all interact equivalently with Grb2, Tks5/Fish, and ERK. Functionally, ADAM15A enhances adhesion, migration, and invasion whereas ADAM15B reduces adhesion in MDA-MB-435 cells.","method":"RT-PCR cloning of splice variants, GST-cytoplasmic domain pulldown assays, stable transfection of MDA-MB-435 cells, migration/invasion/adhesion assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pulldown identifies isoform-specific interactions, functional phenotypes demonstrated, single lab","pmids":["18296648"],"is_preprint":false},{"year":2009,"finding":"Soluble recombinant ADAM15 fails to cleave any tested synthetic peptide substrates. In cell-based assays, full-length membrane-anchored ADAM15 (but not catalytically inactive ADAM15 E→A mutant) increases shedding of FGFR2iiib; this activity is inhibited by hydroxamate metalloproteinase inhibitors (marimastat, TAPI-2, GM6001) and 50 nM TIMP-3, but not TIMP-1 or TIMP-2. ADAM15 is not stimulated by PMA or calcium ionophores.","method":"Peptide substrate library screening with purified soluble ADAM15, cell-based FGFR2iiib shedding assay, catalytic mutant (E→A), pharmacological inhibitors, TIMP titration","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution (negative peptide result) plus cell-based assay with mutagenesis and inhibitor profiling, multiple orthogonal methods","pmids":["19207106"],"is_preprint":false},{"year":2009,"finding":"ADAM15 alternative splicing generates isoforms with distinct SH3-binding profiles; isoforms i4, i5, i6 (containing exons 20/21 proline-rich regions) strongly co-precipitate nephrocystin from cell lysates via RxLPxxP motifs, while robust association with SNX33 is specific to isoforms containing the C-terminal proline cluster. Alternative exon use thus regulates selection of intracellular binding partners.","method":"Co-precipitation from cell lysates, mutagenesis of proline motifs, RT-PCR characterization of isoforms","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-precipitation with mutagenesis, single lab, establishes isoform-specific binding partners","pmids":["19718658"],"is_preprint":false},{"year":2009,"finding":"ADAM15 modulates outside-in signaling during chondrocyte-matrix interactions: the prodomain of ADAM15 is critical for enhancing type II collagen adhesion, and the cytoplasmic tail modulates FAK autophosphorylation at Y397 during chondrocyte-collagen interaction. ADAM15 cytoplasmic domain co-immunoprecipitates with FAK in this context.","method":"Stable transfection of T/C28a4 chondrocytes with ADAM15 deletion mutants, CII adhesion assay, Western blot for phospho-FAK, co-immunoprecipitation","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — deletion mutant analysis with phospho-signaling readout and co-IP, single lab","pmids":["18774960"],"is_preprint":false},{"year":2010,"finding":"ADAM15 regulates endothelial permeability and neutrophil transendothelial migration via Src/ERK1/2 signaling: both wild-type and catalytically dead ADAM15 increase basal and thrombin-induced permeability, showing the effect is protease-independent. ADAM15 overexpression promotes ERK1/2 phosphorylation; pharmacological inhibition of Src or ERK reverses ADAM15-induced hyperpermeability. ADAM15 does not cleave VE-cadherin.","method":"siRNA knockdown and overexpression (wild-type and catalytic mutant) in HUVECs, albumin transendothelial flux, TEER measurement, ERK1/2 phosphorylation Western blot, neutrophil transmigration assay, Src/ERK inhibitors","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — catalytic mutant distinguishes protease-independent mechanism, pharmacological epistasis, multiple orthogonal assays, single lab but rigorous","pmids":["20189953"],"is_preprint":false},{"year":2010,"finding":"An ADAM15-derived peptide containing the HWRR sequence activates GRP78 on endothelial cell membranes, inducing angiogenesis via Akt phosphorylation and ERK1/2 activation independently of VEGFR-2; siRNA knockdown of GRP78 blocks peptide-induced angiogenesis, identifying GRP78 as the receptor for this ADAM15 domain-derived peptide.","method":"Synthetic peptide assay, cell proliferation/migration/tube formation assays, siRNA knockdown of GRP78, Akt/ERK phosphorylation Western blot, mouse hind limb ischemia model","journal":"Journal of vascular research","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA epistasis identifies GRP78 as functional receptor, in vitro and in vivo validated, single lab","pmids":["20145413"],"is_preprint":false},{"year":2010,"finding":"ADAM15 exerts an anti-apoptotic effect in osteoarthritic chondrocytes by upregulating XIAP (~3-fold at protein and mRNA levels) upon genotoxic stress; siRNA knockdown of ADAM15 or XIAP sensitizes OA chondrocytes to camptothecin-induced caspase 3/7 activation. ADAM15 lacking its cytoplasmic tail loses anti-apoptotic activity.","method":"Stable ADAM15 transfection (full-length and cytoplasmic tail deletion) in T/C28a4 chondrocytes, siRNA knockdown, caspase 3/7 activity assay, ATP viability assay, Western blot, RT-PCR for XIAP, annexin V","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cytoplasmic tail deletion mutant localizes function, siRNA of both ADAM15 and XIAP used, single lab","pmids":["20213810"],"is_preprint":false},{"year":2012,"finding":"ADAM15 cytoplasmic domain directly binds the C-terminus of FAK (demonstrated by mammalian two-hybrid, GST pulldown, and Far Western assays); genotoxic stress triggers enhanced FAK phosphorylation at Y397, Y576, and Y861 plus Src Y416 activation in cells with full-length ADAM15 but not in cells expressing ADAM15 lacking the cytoplasmic tail. Src binds FAK but not ADAM15 directly, identifying FAK as the critical intracellular adaptor for ADAM15-dependent Src/FAK activation.","method":"Mammalian two-hybrid, GST pulldown, Far Western, Western blot for phospho-FAK/Src, chimeric IL-2Rα-ADAM15 cytoplasmic domain construct stimulated with IL-2, FAK/Src pharmacological inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — three orthogonal binding assays plus functional chimeric construct, mutant lacking cytoplasmic tail as control, rigorous mechanistic dissection","pmids":["22544741"],"is_preprint":false},{"year":2012,"finding":"ADAM15 is released as an exosomal component from various cell types including human macrophages; PMA (a PKC activator) stimulates ADAM15 exosome release with a corresponding decrease in plasma membrane ADAM15. Exosomal ADAM15 binds integrin αvβ3 in an RGD-dependent manner and suppresses vitronectin/fibronectin-induced cell adhesion, growth, migration, and in vivo tumor growth.","method":"Exosome isolation and characterization, PMA stimulation, RGD-dependent binding assay to αvβ3, cell adhesion/migration/growth assays, in vivo tumor growth assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — exosome characterization, RGD-dependence established, functional assays, single lab","pmids":["22505472"],"is_preprint":false},{"year":2013,"finding":"ADAM15 was identified as a TRIF-interacting partner by immunoprecipitation of the TRIF signaling complex followed by LC-MS/MS; ADAM15 negatively regulates TRIF-mediated NF-κB and IFN-β signaling. ADAM15 mediates proteolytic cleavage of TRIF; suppression of ADAM15 enhances LPS/poly(I:C)-mediated proinflammatory cytokine production and viral-induced cytokines.","method":"Co-immunoprecipitation of TRIF complex + LC-MS/MS protein ID, NF-κB and IFN-β reporter assays, ADAM15 siRNA knockdown, cytokine measurements","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP/MS identifies interaction, reporter and cytokine assays establish function, proteolytic cleavage of TRIF reported but not further dissected, single lab","pmids":["23365087"],"is_preprint":false},{"year":2013,"finding":"In rheumatoid arthritis synovial fibroblasts (RASFs), ADAM15 contributes to apoptosis resistance upon FasL stimulation by activating the FAK/Src/PI3K/NF-κB pathway; siRNA knockdown of ADAM15 increases caspase 3/7 activity after FasL or camptothecin exposure. FAK and Src inhibitors (FAK inhibitor 14, dasatinib) induce apoptosis potentiated by ADAM15 silencing.","method":"siRNA knockdown in RASFs, caspase 3/7 assay, annexin V staining, Western blot for phospho-FAK/Src/NF-κB, pharmacological inhibitors of FAK/Src","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with multiple signaling readouts, consistent with PMID 22544741, single lab","pmids":["23918525"],"is_preprint":false},{"year":2015,"finding":"ADAM15 upregulates MMP9 expression in lung cancer cells via activation of the MEK-ERK pathway; ADAM15 also proteolytically cleaves and activates pro-MMP9 in vitro, and interacts with MMP9 in vivo (co-immunoprecipitation). MMP9 knockdown attenuates ADAM15-overexpression-induced cell invasion.","method":"shRNA knockdown and overexpression, co-immunoprecipitation (ADAM15-MMP9 interaction), in vitro pro-MMP9 cleavage assay, MEK-ERK pathway analysis, Matrigel invasion assay, MMP9 siRNA rescue","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus in vitro cleavage establish direct interaction and proteolytic activity toward MMP9, functional epistasis, single lab","pmids":["26323669"],"is_preprint":false},{"year":2014,"finding":"The catalytic activity of ADAM15 (E→A knock-in mice) is NOT required for its role in promoting pathological neovascularization in the oxygen-induced retinopathy model; Adam15E>A mice show similar neovascularization to wild-type. However, tumor implantation was reduced in Adam15E>A mice. Cell-based assays show ADAM15 can process FGFR2iiib but not several angiogenesis-relevant receptors tested.","method":"Knock-in mice with inactivating E→A point mutation in catalytic site, oxygen-induced retinopathy model, heterotopic tumor model, cell-based receptor shedding assays","journal":"Investigative ophthalmology & visual science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — knock-in catalytic mutant in vivo dissects proteolytic vs. non-proteolytic functions, two model systems tested","pmids":["25249606"],"is_preprint":false},{"year":2018,"finding":"In RASFs, FasL-induced death signals trigger CRAC/Orai1 channel-dependent Ca2+ release, which drives CaM recruitment to both Fas/CD95 and ADAM15 at the cell membrane; Src associated with CaM becomes engaged in the ADAM15 complex also containing FAK, leading to Src/FAK phosphorylation and cell survival. ADAM15 cytoplasmic domain directly binds recombinant CaM (protein binding assay). An ADAM15 construct lacking the cytoplasmic domain loses anti-apoptotic activity.","method":"CaM-Sepharose pulldown, co-immunoprecipitation (ADAM15/Fas/CaM/Src/FAK), recombinant CaM binding assay, CaM inhibitor (trifluoperazine), CRAC/Orai1 inhibitor (BTP-2), ADAM15 tail-deletion mutant, caspase 3/7 assay, annexin V staining, siRNA, immunofluorescence colocalization","journal":"Arthritis & rheumatology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal binding assays, pharmacological epistasis of CaM and CRAC channels, functional cytoplasmic tail deletion mutant, mechanistically rigorous","pmids":["30003689"],"is_preprint":false},{"year":2018,"finding":"Upon cell adhesion, the cytoplasmic domain of ADAM15 transiently binds poly(A) binding protein 1 (PABP1) via the PABP proline-rich linker; ADAM15 recruits PABP to cell membrane foci coinciding with active mRNA translation (detected by puromycin-terminated polypeptides). Loss of ADAM15 by siRNA or use of a cytoplasmic-tail-deleted ADAM15 mutant reduces cell membrane-associated neosynthesis of proteins during induced adhesion.","method":"Co-immunoprecipitation (ADAM15-PABP1), GST-domain mapping of PABP proline-rich linker, immunostaining with puromycin-labeling of nascent proteins, siRNA knockdown, ADAM15 cytoplasmic tail deletion mutant","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus domain mapping, functional validation by puromycin labeling and mutant, single lab","pmids":["30265671"],"is_preprint":false},{"year":2019,"finding":"ADAM15 mediates upregulation of Claudin-1 in breast cancer cells in a catalytic-function-dependent and isoform-specific manner (ADAM15A > C and E >> B); ADAM15A co-localizes with Claudin-1 and ZO1 at cell-cell junctions; ADAM15 co-immunoprecipitates with ZO1 and ZO2. The PI3K/Akt/mTOR pathway is involved in Claudin-1 regulation downstream of ADAM15.","method":"Isogenic cell panels expressing ADAM15 wild-type and catalytically inactive isoforms (MDA-MB-231 and MCF-7), shRNA knockdown, Western blot, immunofluorescence, co-immunoprecipitation of ADAM15/ZO1/ZO2, PI3K/Akt/mTOR inhibitors","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant and co-IP with isoform-specific analysis, pathway epistasis, single lab","pmids":["31467400"],"is_preprint":false},{"year":2019,"finding":"Physiologic shear stress induces ADAM15 expression in endothelial cells (~4-fold mRNA, ~5.6-fold protein) through KLF2-dependent transcription; KLF2 overexpression increases ADAM15 expression and KLF2 siRNA prevents shear-induced ADAM15 upregulation. ADAM15 promotes endothelial survival under growth factor deprivation or TNF stimulation; shRNA knockdown of ADAM15 reduces survival specifically under flow conditions.","method":"Flow culture system, KLF2 overexpression and siRNA knockdown, promoter analysis (KLF2 consensus sites), simvastatin/geranylgeranyl pyrophosphate treatment, ADAM15 shRNA knockdown, cell viability assays under static and flow conditions","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter-based epistasis with KLF2 (knockdown + overexpression), functional shRNA knockdown, single lab","pmids":["31271758"],"is_preprint":false},{"year":2021,"finding":"ADAM15 promotes TRPV4 channel membrane density in synovial fibroblasts, thereby facilitating Ca2+-dependent JNK activation, HOTAIR lncRNA downregulation, and sirtuin-1 upregulation in response to mechanical stimuli. ADAM15 also reinforces Src-mediated pannexin-1 channel activation for ATP release (purinergic signaling); loss of ADAM15 completely abrogates this mechanosignaling pathway.","method":"ADAM15 siRNA knockdown in synovial fibroblasts, mechanical stimulation assay, TRPV4 surface expression quantification, JNK phosphorylation Western blot, HOTAIR lncRNA quantification, sirtuin-1 measurement, pannexin-1 channel assay, ATP release measurement","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — loss-of-function with multiple downstream readouts, mechanistic pathway defined, single lab","pmids":["34685689"],"is_preprint":false},{"year":2022,"finding":"ADAM15 is required for optimal collagen cross-linking and scar formation after myocardial infarction: Adam15−/− mice show markedly higher rates of left ventricular rupture (66% vs 15%), disorganized fibrillar collagen, reduced lysyl oxidase-1 (LOX-1) and fibronectin, and lower insoluble/higher soluble collagen fraction. ADAM15 deficiency is associated with reduced PAK1 levels (a regulator of fibronectin and LOX-1 expression). In vitro, Adam15−/− cardiac fibroblasts show suppressed activation under ischemia.","method":"Adam15−/− mice subjected to LAD ligation, echocardiography, second harmonic generation imaging of fibrillar collagen, Western blot for LOX-1/fibronectin/PAK1, collagen solubility fractionation, primary cardiac fibroblast hypoxia assay","journal":"Matrix biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple mechanistic readouts including specific downstream effectors, single lab","pmids":["34995785"],"is_preprint":false},{"year":2022,"finding":"Loss of ADAM15 worsens pressure-overload-induced eccentric hypertrophy and dilation in male mice via the calcineurin/NFAT pathway; Adam15−/− TAC mice show increased integrin-α7 expression with decreased integrin-laminin interaction and greater calcineurin activity; calcineurin inhibition (cyclosporin-A) blocks the excess hypertrophy in Adam15−/− mice. ADAM15 knockdown in vitro increases cardiomyocyte hypertrophy in response to mechanical stretch.","method":"Adam15−/− mice with transverse aortic constriction, echocardiography, calcineurin activity assay, NFAT phosphorylation, integrin-α7/β1/laminin Western blot and co-precipitation, cyclosporin-A pharmacological rescue, cardiomyocyte stretch assay, proteome profiling","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological rescue with cyclosporin-A provides pathway epistasis, multiple mechanistic readouts, single lab","pmids":["36330793"],"is_preprint":false},{"year":2025,"finding":"Loss of ADAM15 abrogates necroptosis (but not apoptosis or NF-κB/MAPK survival signaling) induced by TNF, TRAIL, FasL, TL1a, and Obatoclax in U937 and Jurkat cells; ADAM15-deficient cells show enhanced basal Caspase-8 activity and partial RIPK1 proteolysis. ADAM15 is found in intracellular compartments with lysosomal protein signatures, and TNF-R1 surface expression is enhanced in ADAM15-KO cells, suggesting TNF-R1 as a possible ADAM15 substrate involved in regulating receptor trafficking.","method":"CRISPR/Cas9 knockout, Western blot, flow cytometry for TNF-R1 surface expression, caspase-8 enzyme assay, RIPK1 Western blot, death ligand treatment (TNF/TRAIL/FasL/TL1a), bottom-up proteome analysis, immunomagnetic fractionation, microscopy for subcellular localization","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with multiple death stimuli, specific necroptosis vs apoptosis dissection, proteome screen supporting localization findings, single lab","pmids":["41340056"],"is_preprint":false},{"year":2008,"finding":"Mouse ADAM15 is present and post-translationally processed during epididymal sperm maturation and the acrosome reaction; Western blotting reveals proteolytic processing from 110/75 kDa forms to a 35 kDa form containing the disintegrin domain. A peptide from the ADAM15 disintegrin domain (RPPTDDCDLPEF) partially inhibits sperm-oolemma fusion and almost completely inhibits sperm-oolemma adhesion.","method":"Western blot of sperm at different epididymal segments, indirect immunofluorescence, disintegrin domain peptide inhibition assay of sperm-egg binding","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — direct peptide inhibition establishes functional role in sperm-egg binding, Western blot documents processing, single lab","pmids":["18390692"],"is_preprint":false},{"year":2014,"finding":"ADAM15 forms a complex with acrogranin on the surface of guinea pig spermatozoa; co-immunoprecipitation identified a 65 kDa protein co-precipitating with ADAM15 and N-terminal sequencing revealed it as acrogranin. Anti-acrogranin antibody inhibits sperm-egg adhesion. ADAM15 and acrogranin are also associated in two breast cancer cell lines.","method":"Co-immunoprecipitation, N-terminal protein sequencing, cell-surface labeling, heterologous fertilization inhibition assay with anti-acrogranin antibody","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP with protein identification by sequencing, functional antibody inhibition, single lab","pmids":["25392190"],"is_preprint":false},{"year":2011,"finding":"Adam15−/− mice have increased bone volume and thickness with increased osteoblast number and activity; ADAM15−/− osteoblasts show increased proliferation, ALP activity, mineralization, and nuclear β-catenin accumulation (with increased membrane/cytoplasmic β-catenin degradation). Downstream β-catenin targets cyclin D1 and c-Jun are upregulated in ADAM15-null osteoblasts, indicating ADAM15 normally suppresses Wnt/β-catenin-driven osteoblast activation.","method":"Adam15−/− mouse bone histomorphometry, osteoblast primary culture assays (proliferation, ALP, nodule mineralization), β-catenin immunolocalization (nuclear vs. membrane/cytoplasm), Western blot for cyclin D1 and c-Jun","journal":"Biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with multiple functional readouts and mechanistic pathway identification (β-catenin/cyclin D1/c-Jun), single lab","pmids":["21801086"],"is_preprint":false},{"year":2025,"finding":"In RASFs, mechanical strain triggers co-localization of ADAM15 with N-cadherin in adherens junctions and activates PAK2 phosphorylation; PAK2 and adaptor Nck are co-recruited to the NCAD/ADAM15 complex at the membrane. This leads to downregulation of lncRNA H19 and miR-130a-3p, and upregulation of cadherin-11 (CDH11), enhancing cell invasive properties. Disruption of ADAM15 abrogates the mechanosignaling response.","method":"ADAM15 siRNA/knockdown in RASFs, mechanical strain application, co-immunoprecipitation (ADAM15/NCAD/PAK2/Nck complex), Western blot for phospho-PAK2, RT-qPCR for H19/miR-130a-3p/CDH11, immunofluorescence colocalization, invasion assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP establishes complex, ADAM15 loss-of-function as epistasis, multiple downstream readouts, single lab","pmids":["40118917"],"is_preprint":false}],"current_model":"ADAM15 is a membrane-anchored multi-domain metalloprotease-disintegrin (ADAM family) whose RGD-containing disintegrin domain directly binds integrins αvβ3 and α5β1 to mediate cell adhesion and modulate migration; its prodomain is removed by furin in the trans-Golgi network to generate active protein; the metalloprotease domain catalyzes ectodomain shedding of substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, TRIF, and pro-MMP9 (inhibited by TIMP-3 and hydroxamate inhibitors but not by phorbol esters); the cytoplasmic domain acts as a scaffold that undergoes phosphorylation-dependent interactions with Src-family kinases (Hck, Lck, Fyn, Src), Grb2, FAK, calmodulin, and PABP1, enabling non-catalytic regulation of Src/FAK/ERK/PI3K signaling, endothelial barrier function, apoptosis resistance, mechanotransduction, and local mRNA translation; alternatively spliced cytoplasmic variants selectively recruit different SH3-containing partners (Nck, Brk, nephrocystin, SNX33) to tune these functions in a tissue- and isoform-specific manner; in vivo loss-of-function studies demonstrate roles in pathological neovascularization, cartilage homeostasis, post-infarction scar formation, cardiac hypertrophy suppression, and negative regulation of TLR/TRIF-mediated innate immune signaling."},"narrative":{"mechanistic_narrative":"ADAM15 is a furin-processed, membrane-anchored ADAM-family metalloprotease-disintegrin that bridges cell adhesion, ectodomain shedding, and intracellular signaling to control vascular, skeletal, cardiac, and inflammatory tissue homeostasis [PMID:9516430, PMID:12897135, PMID:25249606]. Its prodomain is removed by a furin-like convertase in the trans-Golgi network, generating mature protein that is both surface-displayed and substantially retained in a perinuclear TGN/endosomal pool [PMID:9748307]. The RGD-containing disintegrin domain directly engages integrins αvβ3 and α5β1 in a cation- and RGD-dependent manner, with flanking residues dictating receptor specificity, supporting cell adhesion at cell-cell contacts and modulating migration [PMID:9516430, PMID:9914169, PMID:11697891]. The metalloprotease domain catalyzes ectodomain shedding of membrane substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, and TRIF and activates pro-MMP9; this activity requires the full-length membrane-anchored enzyme (soluble ADAM15 is inactive against peptide substrates) and is blocked by hydroxamate inhibitors and TIMP-3 but not by phorbol esters [PMID:12777399, PMID:18434311, PMID:18281484, PMID:19207106, PMID:23365087, PMID:26323669]. Shed E-cadherin promotes HER2/HER3 heterodimerization and ERK signaling to drive tumor cell migration [PMID:18434311]. The cytoplasmic tail functions as a phosphorylation-dependent scaffold that recruits Src-family kinases, Grb2, FAK, calmodulin, and PABP1, enabling protease-independent activation of Src/FAK/ERK/PI3K signaling, endothelial barrier regulation, apoptosis resistance, mechanotransduction, and local membrane-associated mRNA translation [PMID:11741929, PMID:20189953, PMID:22544741, PMID:30003689, PMID:30265671]. Alternative splicing of the cytoplasmic domain selects distinct SH3-containing partners (Src, Brk, Nck, nephrocystin, SNX33) and tunes both catalytic activity and adhesion/invasion phenotypes in an isoform-specific manner [PMID:19487280, PMID:18296648, PMID:19718658]. In vivo loss-of-function studies establish ADAM15 as required for pathological neovascularization, cartilage and bone homeostasis, post-infarction scar formation, and suppression of pressure-overload cardiac hypertrophy, with catalytic activity dispensable for its angiogenic role [PMID:12897135, PMID:15818704, PMID:25249606, PMID:34995785, PMID:36330793, PMID:21801086].","teleology":[{"year":1998,"claim":"Established the molecular basis of ADAM15-integrin recognition, showing the disintegrin domain is a sequence-specific integrin ligand rather than a generic RGD motif.","evidence":"GST-fusion disintegrin domain binding to recombinant integrins with RGD and flanking-sequence mutagenesis","pmids":["9516430"],"confidence":"High","gaps":["Did not test integrin binding in native membrane context","Functional consequence of αvβ3 binding not assessed here"]},{"year":1998,"claim":"Defined how ADAM15 zymogen is activated, identifying furin-mediated prodomain removal in the TGN and revealing a large intracellular pool.","evidence":"Pulse-chase, brefeldin A/monensin block, endoglycosidase H resistance, and in vitro furin cleavage in transfected COS-7 cells","pmids":["9748307"],"confidence":"High","gaps":["Functional role of the intracellular pool unresolved","Whether processing gates catalytic activity not shown"]},{"year":1999,"claim":"Confirmed that ADAM15 mediates integrin-dependent cell adhesion on physiological cell types, extending in vitro binding to cellular function.","evidence":"Solid-phase cell-adhesion assays with Fc-fusion ectodomain, antibody blocking, and RGD competition","pmids":["9914169"],"confidence":"High","gaps":["Did not address signaling downstream of adhesion"]},{"year":1999,"claim":"First implicated the cytoplasmic tail as a protein-interaction scaffold, linking ADAM15 to SH3-domain proteins in a maturation-state-dependent way.","evidence":"Yeast two-hybrid, GST pulldown, and co-IP identifying endophilin I and SH3PX1 binding the precursor form","pmids":["10531379"],"confidence":"High","gaps":["Functional output of these interactions undefined","Precursor-specificity mechanism unexplained"]},{"year":2001,"claim":"Connected the cytoplasmic tail to tyrosine-kinase signaling, showing it is a phosphorylation-dependent docking site for Src-family kinases and Grb2.","evidence":"SH3 pulldown, co-IP, in vitro kinase assays, Far Western, and tyrosine/proline-motif mutagenesis in hematopoietic cells","pmids":["11741929"],"confidence":"High","gaps":["Downstream signaling outputs not yet mapped","In vivo relevance unaddressed"]},{"year":2001,"claim":"Demonstrated a cellular adhesion phenotype, positioning ADAM15 at cell-cell contacts where it restrains migration and reinforces junctions.","evidence":"Regulated overexpression in NIH3T3, migration/permeability/adhesion assays, and junctional immunolocalization","pmids":["11697891"],"confidence":"Medium","gaps":["No molecular pathway placement","Single overexpression system"]},{"year":2002,"claim":"Linked ADAM15 to endothelial junctions, showing VE-cadherin engagement drives its surface delivery.","evidence":"Immunofluorescence colocalization and VE-cadherin co-transfection with ADAM15-GFP in CHO cells","pmids":["12243749"],"confidence":"Medium","gaps":["Mechanism of VE-cadherin-driven trafficking unknown","No loss-of-function validation"]},{"year":2003,"claim":"Provided the first substrate evidence for ADAM15 proteolysis with a specificity distinct from ADAM17.","evidence":"Synthetic peptide library screening with recombinant ADAM15 and cell-based CD23 shedding assays","pmids":["12777399"],"confidence":"Medium","gaps":["Much mechanistic detail was for ADAM8, not ADAM15","Physical ADAM15-CD23 interaction not directly shown"]},{"year":2003,"claim":"First in vivo demonstration that ADAM15 is selectively required for pathological, not developmental, neovascularization.","evidence":"adam15−/− mice in oxygen-induced retinopathy and melanoma implantation models","pmids":["12897135"],"confidence":"High","gaps":["Molecular mechanism of the angiogenic requirement undefined","Catalytic vs non-catalytic contribution not separated"]},{"year":2005,"claim":"Established a chondroprotective homeostatic role, linking ADAM15 to ECM adhesion and chondrocyte survival.","evidence":"ADAM15 overexpression in chondrocytes with collagen adhesion/viability assays and aging study of ADAM15−/− mice","pmids":["15818704"],"confidence":"High","gaps":["Signaling pathway behind chondroprotection not yet identified"]},{"year":2008,"claim":"Identified a catalytic substrate (E-cadherin) whose shed fragment activates ErbB receptor signaling, defining a tumor-promoting proteolytic axis.","evidence":"Overexpression/knockdown, catalytic-dead mutant, inhibitor treatment, and sE-cad/HER2/HER3 co-IP in breast cancer cells","pmids":["18434311"],"confidence":"High","gaps":["In vivo relevance of the sE-cad/ErbB axis not tested here"]},{"year":2008,"claim":"Defined a pro-metastatic role through N-cadherin shedding, MMP9 activity, and integrin/CD44 surface regulation.","evidence":"shRNA knockdown in PC-3 cells with multiple invasion/adhesion assays plus SCID bone-metastasis model","pmids":["18281484"],"confidence":"High","gaps":["Direct catalytic cleavage of N-cadherin by ADAM15 not isolated from indirect effects"]},{"year":2008,"claim":"Showed alternative cytoplasmic splicing controls catalytic output via Src, establishing inside-out regulation of shedding.","evidence":"FGFR2iiib shedding compared across ADAM15A/B, Src inhibitors, and Src−/− rescue","pmids":["19487280"],"confidence":"High","gaps":["How Src phosphorylation mechanistically activates the ectodomain remains unresolved"]},{"year":2008,"claim":"Mapped isoform-specific SH3 partner selection to opposing adhesion/invasion phenotypes between splice variants.","evidence":"Splice-variant cloning, GST-cytoplasmic-domain pulldowns, and functional assays in MDA-MB-435 cells","pmids":["18296648"],"confidence":"Medium","gaps":["Single cell line","Direct binding not validated by reciprocal co-IP"]},{"year":2008,"claim":"Extended ADAM15 function to reproduction, implicating its disintegrin domain in sperm-egg adhesion and fusion.","evidence":"Western blot of sperm processing and disintegrin-peptide inhibition of sperm-oolemma binding","pmids":["18390692"],"confidence":"Medium","gaps":["Receptor partner on the oolemma not identified","Peptide inhibition is indirect evidence"]},{"year":2009,"claim":"Clarified that membrane anchoring is essential for catalysis and defined the inhibitor/TIMP profile distinguishing ADAM15 from other sheddases.","evidence":"Negative peptide reconstitution plus cell-based FGFR2iiib shedding with E→A mutant, hydroxamates, and TIMP titration","pmids":["19207106"],"confidence":"High","gaps":["Structural basis for membrane-dependence of activity unknown"]},{"year":2009,"claim":"Showed alternative exon usage selects distinct intracellular partners (nephrocystin, SNX33) through specific proline motifs.","evidence":"Co-precipitation and proline-motif mutagenesis across ADAM15 isoforms","pmids":["19718658"],"confidence":"Medium","gaps":["Functional consequences of nephrocystin/SNX33 recruitment untested"]},{"year":2009,"claim":"Linked ADAM15 to outside-in chondrocyte signaling, assigning prodomain and cytoplasmic-tail roles in FAK activation.","evidence":"ADAM15 deletion mutants in chondrocytes with phospho-FAK Western blot and FAK co-IP","pmids":["18774960"],"confidence":"Medium","gaps":["Whether ADAM15-FAK binding is direct not resolved here"]},{"year":2010,"claim":"Demonstrated a protease-independent endothelial barrier function driven by the cytoplasmic tail through Src/ERK.","evidence":"Wild-type and catalytic-dead ADAM15 in HUVECs, permeability/TEER/transmigration assays, and Src/ERK inhibitors","pmids":["20189953"],"confidence":"High","gaps":["Upstream trigger of ADAM15-driven Src/ERK activation in endothelium unclear"]},{"year":2010,"claim":"Identified GRP78 as the receptor for an ADAM15-derived angiogenic peptide acting via Akt/ERK independent of VEGFR-2.","evidence":"Synthetic HWRR peptide, GRP78 siRNA epistasis, and hind-limb ischemia model","pmids":["20145413"],"confidence":"Medium","gaps":["Whether full-length ADAM15 generates this peptide physiologically is unknown"]},{"year":2010,"claim":"Defined an anti-apoptotic mechanism via cytoplasmic-tail-dependent XIAP upregulation in chondrocytes.","evidence":"Full-length vs tail-deleted ADAM15 transfection, ADAM15/XIAP siRNA, and caspase 3/7 assays","pmids":["20213810"],"confidence":"Medium","gaps":["Signaling link between ADAM15 tail and XIAP transcription unmapped"]},{"year":2011,"claim":"Revealed that ADAM15 restrains osteoblast activation by suppressing Wnt/β-catenin signaling, defining a skeletal homeostatic role.","evidence":"ADAM15−/− mouse bone histomorphometry and osteoblast assays with β-catenin/cyclin D1/c-Jun readouts","pmids":["21801086"],"confidence":"Medium","gaps":["Mechanism by which ADAM15 modulates β-catenin stability unidentified"]},{"year":2012,"claim":"Identified FAK as the direct adaptor coupling the ADAM15 tail to Src activation under genotoxic stress.","evidence":"Mammalian two-hybrid, GST pulldown, Far Western, and IL-2Rα-ADAM15 chimeric activation construct","pmids":["22544741"],"confidence":"High","gaps":["Stimulus-specificity of the ADAM15-FAK-Src axis beyond genotoxic stress not defined"]},{"year":2012,"claim":"Showed ADAM15 is exported as exosomal cargo that acts as a soluble αvβ3 ligand suppressing adhesion and tumor growth.","evidence":"Exosome isolation, PKC-stimulated release, RGD-dependent binding, and in vivo tumor assays","pmids":["22505472"],"confidence":"Medium","gaps":["Mechanism sorting ADAM15 into exosomes unknown"]},{"year":2013,"claim":"Placed ADAM15 as a negative regulator of innate immune TRIF signaling and a TRIF interactor/substrate.","evidence":"TRIF complex co-IP/LC-MS/MS, NF-κB/IFN-β reporters, and ADAM15 siRNA cytokine assays","pmids":["23365087"],"confidence":"Medium","gaps":["TRIF cleavage reported but not biochemically dissected","Single lab"]},{"year":2013,"claim":"Extended ADAM15-FAK/Src signaling to apoptosis resistance in rheumatoid synovial fibroblasts via PI3K/NF-κB.","evidence":"siRNA knockdown in RASFs with caspase assays and FAK/Src inhibitors","pmids":["23918525"],"confidence":"Medium","gaps":["Direct receptor input to the ADAM15 complex not defined here"]},{"year":2014,"claim":"Identified acrogranin as a surface partner of ADAM15 functionally implicated in sperm-egg adhesion.","evidence":"Co-IP, N-terminal sequencing, and anti-acrogranin inhibition of fertilization","pmids":["25392190"],"confidence":"Medium","gaps":["Functional consequence of the ADAM15-acrogranin complex in cancer cells untested"]},{"year":2015,"claim":"Established ADAM15 as both a transcriptional inducer and direct activator of pro-MMP9, promoting invasion.","evidence":"Knockdown/overexpression, ADAM15-MMP9 co-IP, in vitro pro-MMP9 cleavage, and MMP9 rescue in lung cancer cells","pmids":["26323669"],"confidence":"Medium","gaps":["Relative contribution of transcriptional vs proteolytic MMP9 activation unresolved"]},{"year":2014,"claim":"Genetically separated catalytic from non-catalytic functions in vivo, showing protease activity is dispensable for pathological retinal neovascularization.","evidence":"Adam15 E→A knock-in mice in oxygen-induced retinopathy and tumor models","pmids":["25249606"],"confidence":"High","gaps":["Which non-catalytic activity drives neovascularization not pinpointed"]},{"year":2018,"claim":"Defined a Ca2+/calmodulin-gated assembly of the ADAM15/Fas/Src/FAK survival complex in synovial fibroblasts.","evidence":"CaM pulldown, recombinant CaM binding, CRAC/CaM inhibitors, and tail-deletion mutant with caspase assays","pmids":["30003689"],"confidence":"High","gaps":["Stoichiometry and order of complex assembly not fully resolved"]},{"year":2018,"claim":"Uncovered a novel role coupling adhesion to local translation through transient PABP1 recruitment to membrane foci.","evidence":"ADAM15-PABP1 co-IP, GST domain mapping, puromycin labeling of nascent proteins, and tail-deletion mutant","pmids":["30265671"],"confidence":"Medium","gaps":["Identity of locally translated mRNAs unknown","Single lab"]},{"year":2019,"claim":"Showed catalytic and isoform-specific ADAM15 regulates tight-junction Claudin-1 via PI3K/Akt/mTOR and ZO1/ZO2 association.","evidence":"Isogenic ADAM15 wild-type/catalytic-dead isoform panels, co-IP, and pathway inhibitors in breast cancer cells","pmids":["31467400"],"confidence":"Medium","gaps":["Direct catalytic substrate driving Claudin-1 induction not identified"]},{"year":2019,"claim":"Identified shear stress/KLF2 as a transcriptional driver of ADAM15 supporting flow-dependent endothelial survival.","evidence":"Flow culture, KLF2 overexpression/siRNA, promoter analysis, and ADAM15 shRNA survival assays","pmids":["31271758"],"confidence":"Medium","gaps":["Downstream survival effector under flow not defined"]},{"year":2021,"claim":"Defined ADAM15 as a mechanotransduction hub regulating TRPV4 surface density and pannexin-1/ATP purinergic signaling.","evidence":"ADAM15 siRNA in synovial fibroblasts with mechanical stimulation and multiple channel/signaling readouts","pmids":["34685689"],"confidence":"Medium","gaps":["Mechanism by which ADAM15 controls TRPV4 trafficking unknown"]},{"year":2022,"claim":"Established ADAM15 as required for organized post-infarction collagen cross-linking and scar integrity via PAK1/LOX-1/fibronectin.","evidence":"Adam15−/− mice after LAD ligation with collagen imaging, solubility fractionation, and effector Western blots","pmids":["34995785"],"confidence":"Medium","gaps":["Whether ADAM15 acts catalytically or as scaffold in fibroblast activation unresolved"]},{"year":2022,"claim":"Showed ADAM15 suppresses pressure-overload cardiac hypertrophy through integrin-α7/laminin and calcineurin/NFAT control.","evidence":"Adam15−/− TAC mice, calcineurin activity assays, cyclosporin-A rescue, and cardiomyocyte stretch assay","pmids":["36330793"],"confidence":"Medium","gaps":["Direct molecular link between ADAM15 and integrin-α7 regulation unclear"]},{"year":2025,"claim":"Assigned ADAM15 a selective role in death-receptor necroptosis and TNF-R1 trafficking, distinct from apoptosis control.","evidence":"CRISPR knockout in U937/Jurkat, multiple death ligands, caspase-8/RIPK1 analysis, and TNF-R1 surface flow cytometry","pmids":["41340056"],"confidence":"Medium","gaps":["TNF-R1 proposed but not confirmed as a catalytic substrate","Mechanism of necroptosis regulation undefined"]},{"year":2025,"claim":"Defined a strain-induced ADAM15/N-cadherin/PAK2/Nck mechanosignaling complex driving invasive gene expression in synovial fibroblasts.","evidence":"ADAM15 knockdown in RASFs, complex co-IP, phospho-PAK2 blots, and lncRNA/miRNA/CDH11 readouts","pmids":["40118917"],"confidence":"Medium","gaps":["Whether ADAM15 catalytic activity contributes to this complex untested"]},{"year":null,"claim":"How ADAM15 isoform-specific cytoplasmic scaffolding, catalytic shedding, and integrin adhesion are integrated and prioritized within a single cell, and which functions dominate in each tissue context, remains unresolved.","evidence":"No single study integrates the catalytic, adhesive, and scaffold functions in a unified physiological model","pmids":[],"confidence":"Low","gaps":["No structural model of the full-length protein in its membrane context","Endogenous substrate repertoire incompletely defined","Relative in vivo contribution of catalytic vs scaffold activity unresolved across tissues"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[7,10,11,14,22,24]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[10,14,24]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[4,20,26]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,20,27]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5,6,21]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[21,33]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[33]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,17,20,26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,10,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[22,33]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[19,20,23,26,33]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[9,31]}],"complexes":[],"partners":["ITGAV","ITGB3","ITGB1","SRC","PTK2","GRB2","CALM1","PABPC1"],"other_free_text":[]}},"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":163,"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":155,"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":149,"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 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Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38607341","citation_count":0,"is_preprint":false},{"pmid":"41986445","id":"PMC_41986445","title":"ADAM15 promotes the progression and metastasis of hepatocellular carcinoma by activating the JNK/p38 pathway.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41986445","citation_count":0,"is_preprint":false},{"pmid":"39815900","id":"PMC_39815900","title":"TFDP1 overexpression promotes apoptosis of nucleus pulposus cells in intervertebral disc degeneration through regulating ADAM15/MMP9 axis.","date":"2025","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/39815900","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.05.25329068","title":"Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity","date":"2025-06-06","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.05.25329068","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51069,"output_tokens":11303,"usd":0.161376,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22454,"output_tokens":9084,"usd":0.169685,"stage2_stop_reason":"end_turn"},"total_usd":0.331061,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"The recombinant disintegrin-like domain of ADAM15 (MDC-15) specifically binds integrin αvβ3 in an RGD-dependent manner; mutation of RGD to SGA completely blocks binding, and mutation of the flanking sequence RPTRGD to NWKRGD extends specificity to include αIIbβ3, demonstrating that the flanking sequence determines receptor binding specificity.\",\n      \"method\": \"GST fusion protein binding assay with recombinant integrins, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding reconstitution with mutagenesis, multiple integrin specificity controls, replicated in subsequent papers\",\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 cell lines via αvβ3 (on U937 monocytic cells) and α5β1 (on MOLT-4 T cells) integrins; adhesion is divalent cation-dependent, Mn2+-enhanced, and inhibited by RGD-based peptides, consistent with integrin-mediated binding through the disintegrin domain.\",\n      \"method\": \"Solid-phase cell-adhesion assay using Fc-fusion extracellular domain, blocking antibodies, RGD peptide competition, purified recombinant integrins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cell adhesion, antibody blocking, RGD competition, purified integrin binding), independently consistent with PMID 9516430\",\n      \"pmids\": [\"9914169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mouse MDC15 (ADAM15) is processed by a furin-like pro-protein convertase in a late Golgi/trans-Golgi network compartment: brefeldin A and monensin block pro-domain removal, mature protein is endoglycosidase H-resistant, and recombinant furin cleaves mMDC15 in vitro. More than half of mature mMDC15 is intracellular, accumulating in a perinuclear region resembling the TGN/endosomal compartments.\",\n      \"method\": \"Pulse-chase experiments in transfected COS-7 cells, brefeldin A/monensin treatment, endoglycosidase H resistance assay, in vitro furin cleavage, cell-surface trypsinization, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal biochemical methods in one study establishing both processing mechanism and subcellular localization\",\n      \"pmids\": [\"9748307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The cytoplasmic domains of MDC15 (ADAM15) and MDC9 interact with two SH3 domain-containing proteins, endophilin I (SH3GL2) and SH3PX1; both preferentially bind the precursor (not processed) form of ADAM15. Interactions were validated by yeast two-hybrid, bacterial fusion protein pulldown, and co-immunoprecipitation from COS-7 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 / Strong — three orthogonal methods (Y2H, pulldown, co-IP), precursor-specificity finding is mechanistically distinct\",\n      \"pmids\": [\"10531379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The cytoplasmic domain of ADAM15 interacts with multiple Src family kinases (Lck, Fyn, Abl, Src, Hck) via their SH3 domains, and with adaptor Grb2; interactions are phosphorylation-dependent. Hck and Lck phosphorylate the ADAM15 cytoplasmic domain in vitro; PMA stimulation increases ADAM15 phosphorylation in Jurkat cells. Tyr715 and Tyr735 and proline-rich motifs are required for binding, established by deletion and point mutants.\",\n      \"method\": \"SH3-domain pulldown, co-immunoprecipitation from hematopoietic cells, in vitro kinase assay (immune complex), Far Western, dephosphorylation assay, deletion/point mutagenesis, PMA stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (IP, in vitro kinase, Far Western, mutagenesis) in one rigorous study\",\n      \"pmids\": [\"11741929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Overexpression of ADAM15 in NIH3T3 cells decreases cell migration on fibronectin, reduces monolayer permeability, and increases cell-cell adhesion (~45% increase). ADAM15 localizes to cell-cell contacts in an epithelial cell line, suggesting it functions as an adhesion molecule at cell-cell contact structures.\",\n      \"method\": \"Tetracycline-regulated overexpression, Boyden chamber migration assay, scratch wound assay, permeability assay, retroviral transduction, cell adhesion assay, immunolocalization\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple functional assays in one lab, localization supported by imaging, no pathway placement\",\n      \"pmids\": [\"11697891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ADAM15 co-localizes with VE-cadherin at endothelial cell adherens junctions; VE-cadherin-mediated adherens junction formation drives cell-surface expression of ADAM15. Co-expression of VE-cadherin with ADAM15-GFP in CHO cells causes translocation of ADAM15 to the cell periphery and increases surface ADAM15 levels.\",\n      \"method\": \"Immunofluorescence colocalization, ADAM15-GFP fusion protein live imaging, VE-cadherin co-transfection, flow cytometry for surface ADAM15\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct localization with functional consequence (surface expression driven by VE-cadherin), single lab\",\n      \"pmids\": [\"12243749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAM15 catalyzes ectodomain shedding of CD23 (low affinity IgE receptor) in cell-based assays, similar to ADAM8 and ADAM28; ADAM8-dependent CD23 release requires proteolytically active enzyme and is associated with physical interaction of ADAM8 with membrane CD23. Screening of synthetic peptide substrates showed that ADAM15 has proteolytic substrate specificity distinct from ADAM17.\",\n      \"method\": \"Synthetic peptide substrate library screening with recombinant soluble ADAM15, cell-based CD23 ectodomain shedding assay, metalloprotease inhibitor blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro substrate assay plus cell-based shedding, but most mechanistic detail about physical interaction established for ADAM8, not ADAM15 specifically\",\n      \"pmids\": [\"12777399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ADAM15 knock-out (adam15−/−) mice show a major reduction in pathological retinal neovascularization in an oxygen-induced retinopathy model and significantly smaller tumors from implanted B16F0 melanoma cells compared to wild-type controls, demonstrating ADAM15 is required for pathological neovascularization but not developmental angiogenesis.\",\n      \"method\": \"Targeted gene deletion (adam15−/− mice), oxygen-induced retinopathy model, subcutaneous melanoma implantation model\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined phenotype in two independent in vivo models, consistent with later replication\",\n      \"pmids\": [\"12897135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ADAM15 overexpression in chondrocytes (T/C28a4 cell line) specifically reinforces adhesion to type II and VI collagen (but not fibronectin) and enhances cell viability under serum starvation. ADAM15−/− mice develop accelerated osteoarthritic lesions compared to wild-type, demonstrating a homeostatic/chondroprotective role in cartilage.\",\n      \"method\": \"Stable transfection of T/C28a4 chondrocytes with full-length ADAM15 cDNA, adhesion assays on ECM proteins, cell viability assay, ADAM15−/− mouse aging study with histological analysis\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO animal phenotype corroborated by in vitro overexpression with specific functional readout, single lab but two orthogonal models\",\n      \"pmids\": [\"15818704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 cleaves E-cadherin ectodomain in response to growth factor deprivation in breast cancer cells; cleavage is abrogated by metalloproteinase inhibitor and by catalytically inactive ADAM15 mutant. The shed soluble E-cadherin fragment forms a complex with HER2 and HER3 receptors, stabilizes HER2/HER3 heterodimerization, and activates Erk signaling to support cell migration and proliferation.\",\n      \"method\": \"ADAM15 overexpression and shRNA knockdown in breast cancer cells, catalytically inactive ADAM15 mutant, metalloproteinase inhibitor treatment, co-immunoprecipitation of sE-cad with HER2/HER3, Erk phosphorylation assay, migration/proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — catalytic mutant plus inhibitor establish enzymatic substrate, co-IP establishes sE-cad/ErbB complex, multiple complementary models in one study\",\n      \"pmids\": [\"18434311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 knockdown in metastatic prostate cancer PC-3 cells reduces N-cadherin cleavage at the cell surface, decreases cell migration and adhesion to extracellular matrix proteins, reduces cell surface αv integrin and CD44, abrogates MMP9 secretion/activity, and reduces adhesion to and migration through vascular endothelial monolayers. In SCID mice, ADAM15 loss significantly attenuates bone metastasis.\",\n      \"method\": \"Lentiviral shRNA knockdown, N-cadherin shedding assay, FACS, Matrigel invasion, MMP9 zymography, in vitro vascular invasion assay, SCID mouse bone metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro assays with mechanistic readouts plus in vivo validation, loss-of-function approach\",\n      \"pmids\": [\"18281484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"An ADAM15 splice variant (ADAM15B) containing a cytoplasmic Src-binding site has enhanced catalytic activity (FGFR2iiib shedding) compared with ADAM15A (lacking Src-binding site); enhanced activity of ADAM15B is abolished by Src-kinase inhibitors and in Src−/− cells but restored by re-introduction of Src, establishing that Src-dependent phosphorylation of the cytoplasmic domain activates ADAM15B ectodomain shedding.\",\n      \"method\": \"Cell-based FGFR2iiib shedding assay, Src kinase inhibitors, Src−/− fibroblasts with and without Src rescue, comparison of ADAM15A vs ADAM15B splice variants\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — epistasis (Src−/− rescue), pharmacological inhibition, and splice-variant comparison in one rigorous study establish Src as activator\",\n      \"pmids\": [\"19487280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM15 splice variants (A, B, C) differ in isoform-specific interactions with Nck, Src, and Brk tyrosine kinases via their cytoplasmic domains (GST pulldown), while all interact equivalently with Grb2, Tks5/Fish, and ERK. Functionally, ADAM15A enhances adhesion, migration, and invasion whereas ADAM15B reduces adhesion in MDA-MB-435 cells.\",\n      \"method\": \"RT-PCR cloning of splice variants, GST-cytoplasmic domain pulldown assays, stable transfection of MDA-MB-435 cells, migration/invasion/adhesion assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pulldown identifies isoform-specific interactions, functional phenotypes demonstrated, single lab\",\n      \"pmids\": [\"18296648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Soluble recombinant ADAM15 fails to cleave any tested synthetic peptide substrates. In cell-based assays, full-length membrane-anchored ADAM15 (but not catalytically inactive ADAM15 E→A mutant) increases shedding of FGFR2iiib; this activity is inhibited by hydroxamate metalloproteinase inhibitors (marimastat, TAPI-2, GM6001) and 50 nM TIMP-3, but not TIMP-1 or TIMP-2. ADAM15 is not stimulated by PMA or calcium ionophores.\",\n      \"method\": \"Peptide substrate library screening with purified soluble ADAM15, cell-based FGFR2iiib shedding assay, catalytic mutant (E→A), pharmacological inhibitors, TIMP titration\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution (negative peptide result) plus cell-based assay with mutagenesis and inhibitor profiling, multiple orthogonal methods\",\n      \"pmids\": [\"19207106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM15 alternative splicing generates isoforms with distinct SH3-binding profiles; isoforms i4, i5, i6 (containing exons 20/21 proline-rich regions) strongly co-precipitate nephrocystin from cell lysates via RxLPxxP motifs, while robust association with SNX33 is specific to isoforms containing the C-terminal proline cluster. Alternative exon use thus regulates selection of intracellular binding partners.\",\n      \"method\": \"Co-precipitation from cell lysates, mutagenesis of proline motifs, RT-PCR characterization of isoforms\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-precipitation with mutagenesis, single lab, establishes isoform-specific binding partners\",\n      \"pmids\": [\"19718658\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM15 modulates outside-in signaling during chondrocyte-matrix interactions: the prodomain of ADAM15 is critical for enhancing type II collagen adhesion, and the cytoplasmic tail modulates FAK autophosphorylation at Y397 during chondrocyte-collagen interaction. ADAM15 cytoplasmic domain co-immunoprecipitates with FAK in this context.\",\n      \"method\": \"Stable transfection of T/C28a4 chondrocytes with ADAM15 deletion mutants, CII adhesion assay, Western blot for phospho-FAK, co-immunoprecipitation\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — deletion mutant analysis with phospho-signaling readout and co-IP, single lab\",\n      \"pmids\": [\"18774960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM15 regulates endothelial permeability and neutrophil transendothelial migration via Src/ERK1/2 signaling: both wild-type and catalytically dead ADAM15 increase basal and thrombin-induced permeability, showing the effect is protease-independent. ADAM15 overexpression promotes ERK1/2 phosphorylation; pharmacological inhibition of Src or ERK reverses ADAM15-induced hyperpermeability. ADAM15 does not cleave VE-cadherin.\",\n      \"method\": \"siRNA knockdown and overexpression (wild-type and catalytic mutant) in HUVECs, albumin transendothelial flux, TEER measurement, ERK1/2 phosphorylation Western blot, neutrophil transmigration assay, Src/ERK inhibitors\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — catalytic mutant distinguishes protease-independent mechanism, pharmacological epistasis, multiple orthogonal assays, single lab but rigorous\",\n      \"pmids\": [\"20189953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"An ADAM15-derived peptide containing the HWRR sequence activates GRP78 on endothelial cell membranes, inducing angiogenesis via Akt phosphorylation and ERK1/2 activation independently of VEGFR-2; siRNA knockdown of GRP78 blocks peptide-induced angiogenesis, identifying GRP78 as the receptor for this ADAM15 domain-derived peptide.\",\n      \"method\": \"Synthetic peptide assay, cell proliferation/migration/tube formation assays, siRNA knockdown of GRP78, Akt/ERK phosphorylation Western blot, mouse hind limb ischemia model\",\n      \"journal\": \"Journal of vascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA epistasis identifies GRP78 as functional receptor, in vitro and in vivo validated, single lab\",\n      \"pmids\": [\"20145413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ADAM15 exerts an anti-apoptotic effect in osteoarthritic chondrocytes by upregulating XIAP (~3-fold at protein and mRNA levels) upon genotoxic stress; siRNA knockdown of ADAM15 or XIAP sensitizes OA chondrocytes to camptothecin-induced caspase 3/7 activation. ADAM15 lacking its cytoplasmic tail loses anti-apoptotic activity.\",\n      \"method\": \"Stable ADAM15 transfection (full-length and cytoplasmic tail deletion) in T/C28a4 chondrocytes, siRNA knockdown, caspase 3/7 activity assay, ATP viability assay, Western blot, RT-PCR for XIAP, annexin V\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cytoplasmic tail deletion mutant localizes function, siRNA of both ADAM15 and XIAP used, single lab\",\n      \"pmids\": [\"20213810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM15 cytoplasmic domain directly binds the C-terminus of FAK (demonstrated by mammalian two-hybrid, GST pulldown, and Far Western assays); genotoxic stress triggers enhanced FAK phosphorylation at Y397, Y576, and Y861 plus Src Y416 activation in cells with full-length ADAM15 but not in cells expressing ADAM15 lacking the cytoplasmic tail. Src binds FAK but not ADAM15 directly, identifying FAK as the critical intracellular adaptor for ADAM15-dependent Src/FAK activation.\",\n      \"method\": \"Mammalian two-hybrid, GST pulldown, Far Western, Western blot for phospho-FAK/Src, chimeric IL-2Rα-ADAM15 cytoplasmic domain construct stimulated with IL-2, FAK/Src pharmacological inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — three orthogonal binding assays plus functional chimeric construct, mutant lacking cytoplasmic tail as control, rigorous mechanistic dissection\",\n      \"pmids\": [\"22544741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM15 is released as an exosomal component from various cell types including human macrophages; PMA (a PKC activator) stimulates ADAM15 exosome release with a corresponding decrease in plasma membrane ADAM15. Exosomal ADAM15 binds integrin αvβ3 in an RGD-dependent manner and suppresses vitronectin/fibronectin-induced cell adhesion, growth, migration, and in vivo tumor growth.\",\n      \"method\": \"Exosome isolation and characterization, PMA stimulation, RGD-dependent binding assay to αvβ3, cell adhesion/migration/growth assays, in vivo tumor growth assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — exosome characterization, RGD-dependence established, functional assays, single lab\",\n      \"pmids\": [\"22505472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ADAM15 was identified as a TRIF-interacting partner by immunoprecipitation of the TRIF signaling complex followed by LC-MS/MS; ADAM15 negatively regulates TRIF-mediated NF-κB and IFN-β signaling. ADAM15 mediates proteolytic cleavage of TRIF; suppression of ADAM15 enhances LPS/poly(I:C)-mediated proinflammatory cytokine production and viral-induced cytokines.\",\n      \"method\": \"Co-immunoprecipitation of TRIF complex + LC-MS/MS protein ID, NF-κB and IFN-β reporter assays, ADAM15 siRNA knockdown, cytokine measurements\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP/MS identifies interaction, reporter and cytokine assays establish function, proteolytic cleavage of TRIF reported but not further dissected, single lab\",\n      \"pmids\": [\"23365087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In rheumatoid arthritis synovial fibroblasts (RASFs), ADAM15 contributes to apoptosis resistance upon FasL stimulation by activating the FAK/Src/PI3K/NF-κB pathway; siRNA knockdown of ADAM15 increases caspase 3/7 activity after FasL or camptothecin exposure. FAK and Src inhibitors (FAK inhibitor 14, dasatinib) induce apoptosis potentiated by ADAM15 silencing.\",\n      \"method\": \"siRNA knockdown in RASFs, caspase 3/7 assay, annexin V staining, Western blot for phospho-FAK/Src/NF-κB, pharmacological inhibitors of FAK/Src\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with multiple signaling readouts, consistent with PMID 22544741, single lab\",\n      \"pmids\": [\"23918525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ADAM15 upregulates MMP9 expression in lung cancer cells via activation of the MEK-ERK pathway; ADAM15 also proteolytically cleaves and activates pro-MMP9 in vitro, and interacts with MMP9 in vivo (co-immunoprecipitation). MMP9 knockdown attenuates ADAM15-overexpression-induced cell invasion.\",\n      \"method\": \"shRNA knockdown and overexpression, co-immunoprecipitation (ADAM15-MMP9 interaction), in vitro pro-MMP9 cleavage assay, MEK-ERK pathway analysis, Matrigel invasion assay, MMP9 siRNA rescue\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus in vitro cleavage establish direct interaction and proteolytic activity toward MMP9, functional epistasis, single lab\",\n      \"pmids\": [\"26323669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The catalytic activity of ADAM15 (E→A knock-in mice) is NOT required for its role in promoting pathological neovascularization in the oxygen-induced retinopathy model; Adam15E>A mice show similar neovascularization to wild-type. However, tumor implantation was reduced in Adam15E>A mice. Cell-based assays show ADAM15 can process FGFR2iiib but not several angiogenesis-relevant receptors tested.\",\n      \"method\": \"Knock-in mice with inactivating E→A point mutation in catalytic site, oxygen-induced retinopathy model, heterotopic tumor model, cell-based receptor shedding assays\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — knock-in catalytic mutant in vivo dissects proteolytic vs. non-proteolytic functions, two model systems tested\",\n      \"pmids\": [\"25249606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In RASFs, FasL-induced death signals trigger CRAC/Orai1 channel-dependent Ca2+ release, which drives CaM recruitment to both Fas/CD95 and ADAM15 at the cell membrane; Src associated with CaM becomes engaged in the ADAM15 complex also containing FAK, leading to Src/FAK phosphorylation and cell survival. ADAM15 cytoplasmic domain directly binds recombinant CaM (protein binding assay). An ADAM15 construct lacking the cytoplasmic domain loses anti-apoptotic activity.\",\n      \"method\": \"CaM-Sepharose pulldown, co-immunoprecipitation (ADAM15/Fas/CaM/Src/FAK), recombinant CaM binding assay, CaM inhibitor (trifluoperazine), CRAC/Orai1 inhibitor (BTP-2), ADAM15 tail-deletion mutant, caspase 3/7 assay, annexin V staining, siRNA, immunofluorescence colocalization\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal binding assays, pharmacological epistasis of CaM and CRAC channels, functional cytoplasmic tail deletion mutant, mechanistically rigorous\",\n      \"pmids\": [\"30003689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Upon cell adhesion, the cytoplasmic domain of ADAM15 transiently binds poly(A) binding protein 1 (PABP1) via the PABP proline-rich linker; ADAM15 recruits PABP to cell membrane foci coinciding with active mRNA translation (detected by puromycin-terminated polypeptides). Loss of ADAM15 by siRNA or use of a cytoplasmic-tail-deleted ADAM15 mutant reduces cell membrane-associated neosynthesis of proteins during induced adhesion.\",\n      \"method\": \"Co-immunoprecipitation (ADAM15-PABP1), GST-domain mapping of PABP proline-rich linker, immunostaining with puromycin-labeling of nascent proteins, siRNA knockdown, ADAM15 cytoplasmic tail deletion mutant\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus domain mapping, functional validation by puromycin labeling and mutant, single lab\",\n      \"pmids\": [\"30265671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM15 mediates upregulation of Claudin-1 in breast cancer cells in a catalytic-function-dependent and isoform-specific manner (ADAM15A > C and E >> B); ADAM15A co-localizes with Claudin-1 and ZO1 at cell-cell junctions; ADAM15 co-immunoprecipitates with ZO1 and ZO2. The PI3K/Akt/mTOR pathway is involved in Claudin-1 regulation downstream of ADAM15.\",\n      \"method\": \"Isogenic cell panels expressing ADAM15 wild-type and catalytically inactive isoforms (MDA-MB-231 and MCF-7), shRNA knockdown, Western blot, immunofluorescence, co-immunoprecipitation of ADAM15/ZO1/ZO2, PI3K/Akt/mTOR inhibitors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant and co-IP with isoform-specific analysis, pathway epistasis, single lab\",\n      \"pmids\": [\"31467400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Physiologic shear stress induces ADAM15 expression in endothelial cells (~4-fold mRNA, ~5.6-fold protein) through KLF2-dependent transcription; KLF2 overexpression increases ADAM15 expression and KLF2 siRNA prevents shear-induced ADAM15 upregulation. ADAM15 promotes endothelial survival under growth factor deprivation or TNF stimulation; shRNA knockdown of ADAM15 reduces survival specifically under flow conditions.\",\n      \"method\": \"Flow culture system, KLF2 overexpression and siRNA knockdown, promoter analysis (KLF2 consensus sites), simvastatin/geranylgeranyl pyrophosphate treatment, ADAM15 shRNA knockdown, cell viability assays under static and flow conditions\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter-based epistasis with KLF2 (knockdown + overexpression), functional shRNA knockdown, single lab\",\n      \"pmids\": [\"31271758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM15 promotes TRPV4 channel membrane density in synovial fibroblasts, thereby facilitating Ca2+-dependent JNK activation, HOTAIR lncRNA downregulation, and sirtuin-1 upregulation in response to mechanical stimuli. ADAM15 also reinforces Src-mediated pannexin-1 channel activation for ATP release (purinergic signaling); loss of ADAM15 completely abrogates this mechanosignaling pathway.\",\n      \"method\": \"ADAM15 siRNA knockdown in synovial fibroblasts, mechanical stimulation assay, TRPV4 surface expression quantification, JNK phosphorylation Western blot, HOTAIR lncRNA quantification, sirtuin-1 measurement, pannexin-1 channel assay, ATP release measurement\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — loss-of-function with multiple downstream readouts, mechanistic pathway defined, single lab\",\n      \"pmids\": [\"34685689\"],\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 markedly higher rates of left ventricular rupture (66% vs 15%), disorganized fibrillar collagen, reduced lysyl oxidase-1 (LOX-1) and fibronectin, and lower insoluble/higher soluble collagen fraction. ADAM15 deficiency is associated with reduced PAK1 levels (a regulator of fibronectin and LOX-1 expression). In vitro, Adam15−/− cardiac fibroblasts show suppressed activation under ischemia.\",\n      \"method\": \"Adam15−/− mice subjected to LAD ligation, echocardiography, second harmonic generation imaging of fibrillar collagen, Western blot for LOX-1/fibronectin/PAK1, collagen solubility fractionation, primary cardiac fibroblast hypoxia assay\",\n      \"journal\": \"Matrix biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple mechanistic readouts including specific downstream effectors, single lab\",\n      \"pmids\": [\"34995785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of ADAM15 worsens pressure-overload-induced eccentric hypertrophy and dilation in male mice via the calcineurin/NFAT pathway; Adam15−/− TAC mice show increased integrin-α7 expression with decreased integrin-laminin interaction and greater calcineurin activity; calcineurin inhibition (cyclosporin-A) blocks the excess hypertrophy in Adam15−/− mice. ADAM15 knockdown in vitro increases cardiomyocyte hypertrophy in response to mechanical stretch.\",\n      \"method\": \"Adam15−/− mice with transverse aortic constriction, echocardiography, calcineurin activity assay, NFAT phosphorylation, integrin-α7/β1/laminin Western blot and co-precipitation, cyclosporin-A pharmacological rescue, cardiomyocyte stretch assay, proteome profiling\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological rescue with cyclosporin-A provides pathway epistasis, multiple mechanistic readouts, single lab\",\n      \"pmids\": [\"36330793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of ADAM15 abrogates necroptosis (but not apoptosis or NF-κB/MAPK survival signaling) induced by TNF, TRAIL, FasL, TL1a, and Obatoclax in U937 and Jurkat cells; ADAM15-deficient cells show enhanced basal Caspase-8 activity and partial RIPK1 proteolysis. ADAM15 is found in intracellular compartments with lysosomal protein signatures, and TNF-R1 surface expression is enhanced in ADAM15-KO cells, suggesting TNF-R1 as a possible ADAM15 substrate involved in regulating receptor trafficking.\",\n      \"method\": \"CRISPR/Cas9 knockout, Western blot, flow cytometry for TNF-R1 surface expression, caspase-8 enzyme assay, RIPK1 Western blot, death ligand treatment (TNF/TRAIL/FasL/TL1a), bottom-up proteome analysis, immunomagnetic fractionation, microscopy for subcellular localization\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with multiple death stimuli, specific necroptosis vs apoptosis dissection, proteome screen supporting localization findings, single lab\",\n      \"pmids\": [\"41340056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mouse ADAM15 is present and post-translationally processed during epididymal sperm maturation and the acrosome reaction; Western blotting reveals proteolytic processing from 110/75 kDa forms to a 35 kDa form containing the disintegrin domain. A peptide from the ADAM15 disintegrin domain (RPPTDDCDLPEF) partially inhibits sperm-oolemma fusion and almost completely inhibits sperm-oolemma adhesion.\",\n      \"method\": \"Western blot of sperm at different epididymal segments, indirect immunofluorescence, disintegrin domain peptide inhibition assay of sperm-egg binding\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — direct peptide inhibition establishes functional role in sperm-egg binding, Western blot documents processing, single lab\",\n      \"pmids\": [\"18390692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADAM15 forms a complex with acrogranin on the surface of guinea pig spermatozoa; co-immunoprecipitation identified a 65 kDa protein co-precipitating with ADAM15 and N-terminal sequencing revealed it as acrogranin. Anti-acrogranin antibody inhibits sperm-egg adhesion. ADAM15 and acrogranin are also associated in two breast cancer cell lines.\",\n      \"method\": \"Co-immunoprecipitation, N-terminal protein sequencing, cell-surface labeling, heterologous fertilization inhibition assay with anti-acrogranin antibody\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP with protein identification by sequencing, functional antibody inhibition, single lab\",\n      \"pmids\": [\"25392190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Adam15−/− mice have increased bone volume and thickness with increased osteoblast number and activity; ADAM15−/− osteoblasts show increased proliferation, ALP activity, mineralization, and nuclear β-catenin accumulation (with increased membrane/cytoplasmic β-catenin degradation). Downstream β-catenin targets cyclin D1 and c-Jun are upregulated in ADAM15-null osteoblasts, indicating ADAM15 normally suppresses Wnt/β-catenin-driven osteoblast activation.\",\n      \"method\": \"Adam15−/− mouse bone histomorphometry, osteoblast primary culture assays (proliferation, ALP, nodule mineralization), β-catenin immunolocalization (nuclear vs. membrane/cytoplasm), Western blot for cyclin D1 and c-Jun\",\n      \"journal\": \"Biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with multiple functional readouts and mechanistic pathway identification (β-catenin/cyclin D1/c-Jun), single lab\",\n      \"pmids\": [\"21801086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In RASFs, mechanical strain triggers co-localization of ADAM15 with N-cadherin in adherens junctions and activates PAK2 phosphorylation; PAK2 and adaptor Nck are co-recruited to the NCAD/ADAM15 complex at the membrane. This leads to downregulation of lncRNA H19 and miR-130a-3p, and upregulation of cadherin-11 (CDH11), enhancing cell invasive properties. Disruption of ADAM15 abrogates the mechanosignaling response.\",\n      \"method\": \"ADAM15 siRNA/knockdown in RASFs, mechanical strain application, co-immunoprecipitation (ADAM15/NCAD/PAK2/Nck complex), Western blot for phospho-PAK2, RT-qPCR for H19/miR-130a-3p/CDH11, immunofluorescence colocalization, invasion assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP establishes complex, ADAM15 loss-of-function as epistasis, multiple downstream readouts, single lab\",\n      \"pmids\": [\"40118917\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM15 is a membrane-anchored multi-domain metalloprotease-disintegrin (ADAM family) whose RGD-containing disintegrin domain directly binds integrins αvβ3 and α5β1 to mediate cell adhesion and modulate migration; its prodomain is removed by furin in the trans-Golgi network to generate active protein; the metalloprotease domain catalyzes ectodomain shedding of substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, TRIF, and pro-MMP9 (inhibited by TIMP-3 and hydroxamate inhibitors but not by phorbol esters); the cytoplasmic domain acts as a scaffold that undergoes phosphorylation-dependent interactions with Src-family kinases (Hck, Lck, Fyn, Src), Grb2, FAK, calmodulin, and PABP1, enabling non-catalytic regulation of Src/FAK/ERK/PI3K signaling, endothelial barrier function, apoptosis resistance, mechanotransduction, and local mRNA translation; alternatively spliced cytoplasmic variants selectively recruit different SH3-containing partners (Nck, Brk, nephrocystin, SNX33) to tune these functions in a tissue- and isoform-specific manner; in vivo loss-of-function studies demonstrate roles in pathological neovascularization, cartilage homeostasis, post-infarction scar formation, cardiac hypertrophy suppression, and negative regulation of TLR/TRIF-mediated innate immune signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAM15 is a furin-processed, membrane-anchored ADAM-family metalloprotease-disintegrin that bridges cell adhesion, ectodomain shedding, and intracellular signaling to control vascular, skeletal, cardiac, and inflammatory tissue homeostasis [#0, #8, #25]. Its prodomain is removed by a furin-like convertase in the trans-Golgi network, generating mature protein that is both surface-displayed and substantially retained in a perinuclear TGN/endosomal pool [#2]. The RGD-containing disintegrin domain directly engages integrins \\u03b1v\\u03b23 and \\u03b15\\u03b21 in a cation- and RGD-dependent manner, with flanking residues dictating receptor specificity, supporting cell adhesion at cell-cell contacts and modulating migration [#0, #1, #5]. The metalloprotease domain catalyzes ectodomain shedding of membrane substrates including E-cadherin, N-cadherin, FGFR2iiib, CD23, and TRIF and activates pro-MMP9; this activity requires the full-length membrane-anchored enzyme (soluble ADAM15 is inactive against peptide substrates) and is blocked by hydroxamate inhibitors and TIMP-3 but not by phorbol esters [#7, #10, #11, #14, #22, #24]. Shed E-cadherin promotes HER2/HER3 heterodimerization and ERK signaling to drive tumor cell migration [#10]. The cytoplasmic tail functions as a phosphorylation-dependent scaffold that recruits Src-family kinases, Grb2, FAK, calmodulin, and PABP1, enabling protease-independent activation of Src/FAK/ERK/PI3K signaling, endothelial barrier regulation, apoptosis resistance, mechanotransduction, and local membrane-associated mRNA translation [#4, #17, #20, #26, #27]. Alternative splicing of the cytoplasmic domain selects distinct SH3-containing partners (Src, Brk, Nck, nephrocystin, SNX33) and tunes both catalytic activity and adhesion/invasion phenotypes in an isoform-specific manner [#12, #13, #15]. In vivo loss-of-function studies establish ADAM15 as required for pathological neovascularization, cartilage and bone homeostasis, post-infarction scar formation, and suppression of pressure-overload cardiac hypertrophy, with catalytic activity dispensable for its angiogenic role [#8, #9, #25, #31, #32, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the molecular basis of ADAM15-integrin recognition, showing the disintegrin domain is a sequence-specific integrin ligand rather than a generic RGD motif.\",\n      \"evidence\": \"GST-fusion disintegrin domain binding to recombinant integrins with RGD and flanking-sequence mutagenesis\",\n      \"pmids\": [\"9516430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test integrin binding in native membrane context\", \"Functional consequence of \\u03b1v\\u03b23 binding not assessed here\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined how ADAM15 zymogen is activated, identifying furin-mediated prodomain removal in the TGN and revealing a large intracellular pool.\",\n      \"evidence\": \"Pulse-chase, brefeldin A/monensin block, endoglycosidase H resistance, and in vitro furin cleavage in transfected COS-7 cells\",\n      \"pmids\": [\"9748307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the intracellular pool unresolved\", \"Whether processing gates catalytic activity not shown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Confirmed that ADAM15 mediates integrin-dependent cell adhesion on physiological cell types, extending in vitro binding to cellular function.\",\n      \"evidence\": \"Solid-phase cell-adhesion assays with Fc-fusion ectodomain, antibody blocking, and RGD competition\",\n      \"pmids\": [\"9914169\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address signaling downstream of adhesion\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"First implicated the cytoplasmic tail as a protein-interaction scaffold, linking ADAM15 to SH3-domain proteins in a maturation-state-dependent way.\",\n      \"evidence\": \"Yeast two-hybrid, GST pulldown, and co-IP identifying endophilin I and SH3PX1 binding the precursor form\",\n      \"pmids\": [\"10531379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional output of these interactions undefined\", \"Precursor-specificity mechanism unexplained\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected the cytoplasmic tail to tyrosine-kinase signaling, showing it is a phosphorylation-dependent docking site for Src-family kinases and Grb2.\",\n      \"evidence\": \"SH3 pulldown, co-IP, in vitro kinase assays, Far Western, and tyrosine/proline-motif mutagenesis in hematopoietic cells\",\n      \"pmids\": [\"11741929\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling outputs not yet mapped\", \"In vivo relevance unaddressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Demonstrated a cellular adhesion phenotype, positioning ADAM15 at cell-cell contacts where it restrains migration and reinforces junctions.\",\n      \"evidence\": \"Regulated overexpression in NIH3T3, migration/permeability/adhesion assays, and junctional immunolocalization\",\n      \"pmids\": [\"11697891\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular pathway placement\", \"Single overexpression system\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked ADAM15 to endothelial junctions, showing VE-cadherin engagement drives its surface delivery.\",\n      \"evidence\": \"Immunofluorescence colocalization and VE-cadherin co-transfection with ADAM15-GFP in CHO cells\",\n      \"pmids\": [\"12243749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of VE-cadherin-driven trafficking unknown\", \"No loss-of-function validation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Provided the first substrate evidence for ADAM15 proteolysis with a specificity distinct from ADAM17.\",\n      \"evidence\": \"Synthetic peptide library screening with recombinant ADAM15 and cell-based CD23 shedding assays\",\n      \"pmids\": [\"12777399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Much mechanistic detail was for ADAM8, not ADAM15\", \"Physical ADAM15-CD23 interaction not directly shown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"First in vivo demonstration that ADAM15 is selectively required for pathological, not developmental, neovascularization.\",\n      \"evidence\": \"adam15\\u2212/\\u2212 mice in oxygen-induced retinopathy and melanoma implantation models\",\n      \"pmids\": [\"12897135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of the angiogenic requirement undefined\", \"Catalytic vs non-catalytic contribution not separated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Established a chondroprotective homeostatic role, linking ADAM15 to ECM adhesion and chondrocyte survival.\",\n      \"evidence\": \"ADAM15 overexpression in chondrocytes with collagen adhesion/viability assays and aging study of ADAM15\\u2212/\\u2212 mice\",\n      \"pmids\": [\"15818704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway behind chondroprotection not yet identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified a catalytic substrate (E-cadherin) whose shed fragment activates ErbB receptor signaling, defining a tumor-promoting proteolytic axis.\",\n      \"evidence\": \"Overexpression/knockdown, catalytic-dead mutant, inhibitor treatment, and sE-cad/HER2/HER3 co-IP in breast cancer cells\",\n      \"pmids\": [\"18434311\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the sE-cad/ErbB axis not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined a pro-metastatic role through N-cadherin shedding, MMP9 activity, and integrin/CD44 surface regulation.\",\n      \"evidence\": \"shRNA knockdown in PC-3 cells with multiple invasion/adhesion assays plus SCID bone-metastasis model\",\n      \"pmids\": [\"18281484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct catalytic cleavage of N-cadherin by ADAM15 not isolated from indirect effects\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed alternative cytoplasmic splicing controls catalytic output via Src, establishing inside-out regulation of shedding.\",\n      \"evidence\": \"FGFR2iiib shedding compared across ADAM15A/B, Src inhibitors, and Src\\u2212/\\u2212 rescue\",\n      \"pmids\": [\"19487280\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Src phosphorylation mechanistically activates the ectodomain remains unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped isoform-specific SH3 partner selection to opposing adhesion/invasion phenotypes between splice variants.\",\n      \"evidence\": \"Splice-variant cloning, GST-cytoplasmic-domain pulldowns, and functional assays in MDA-MB-435 cells\",\n      \"pmids\": [\"18296648\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line\", \"Direct binding not validated by reciprocal co-IP\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended ADAM15 function to reproduction, implicating its disintegrin domain in sperm-egg adhesion and fusion.\",\n      \"evidence\": \"Western blot of sperm processing and disintegrin-peptide inhibition of sperm-oolemma binding\",\n      \"pmids\": [\"18390692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor partner on the oolemma not identified\", \"Peptide inhibition is indirect evidence\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Clarified that membrane anchoring is essential for catalysis and defined the inhibitor/TIMP profile distinguishing ADAM15 from other sheddases.\",\n      \"evidence\": \"Negative peptide reconstitution plus cell-based FGFR2iiib shedding with E\\u2192A mutant, hydroxamates, and TIMP titration\",\n      \"pmids\": [\"19207106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for membrane-dependence of activity unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed alternative exon usage selects distinct intracellular partners (nephrocystin, SNX33) through specific proline motifs.\",\n      \"evidence\": \"Co-precipitation and proline-motif mutagenesis across ADAM15 isoforms\",\n      \"pmids\": [\"19718658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences of nephrocystin/SNX33 recruitment untested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked ADAM15 to outside-in chondrocyte signaling, assigning prodomain and cytoplasmic-tail roles in FAK activation.\",\n      \"evidence\": \"ADAM15 deletion mutants in chondrocytes with phospho-FAK Western blot and FAK co-IP\",\n      \"pmids\": [\"18774960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ADAM15-FAK binding is direct not resolved here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated a protease-independent endothelial barrier function driven by the cytoplasmic tail through Src/ERK.\",\n      \"evidence\": \"Wild-type and catalytic-dead ADAM15 in HUVECs, permeability/TEER/transmigration assays, and Src/ERK inhibitors\",\n      \"pmids\": [\"20189953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream trigger of ADAM15-driven Src/ERK activation in endothelium unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified GRP78 as the receptor for an ADAM15-derived angiogenic peptide acting via Akt/ERK independent of VEGFR-2.\",\n      \"evidence\": \"Synthetic HWRR peptide, GRP78 siRNA epistasis, and hind-limb ischemia model\",\n      \"pmids\": [\"20145413\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether full-length ADAM15 generates this peptide physiologically is unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined an anti-apoptotic mechanism via cytoplasmic-tail-dependent XIAP upregulation in chondrocytes.\",\n      \"evidence\": \"Full-length vs tail-deleted ADAM15 transfection, ADAM15/XIAP siRNA, and caspase 3/7 assays\",\n      \"pmids\": [\"20213810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling link between ADAM15 tail and XIAP transcription unmapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed that ADAM15 restrains osteoblast activation by suppressing Wnt/\\u03b2-catenin signaling, defining a skeletal homeostatic role.\",\n      \"evidence\": \"ADAM15\\u2212/\\u2212 mouse bone histomorphometry and osteoblast assays with \\u03b2-catenin/cyclin D1/c-Jun readouts\",\n      \"pmids\": [\"21801086\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAM15 modulates \\u03b2-catenin stability unidentified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified FAK as the direct adaptor coupling the ADAM15 tail to Src activation under genotoxic stress.\",\n      \"evidence\": \"Mammalian two-hybrid, GST pulldown, Far Western, and IL-2R\\u03b1-ADAM15 chimeric activation construct\",\n      \"pmids\": [\"22544741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus-specificity of the ADAM15-FAK-Src axis beyond genotoxic stress not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed ADAM15 is exported as exosomal cargo that acts as a soluble \\u03b1v\\u03b23 ligand suppressing adhesion and tumor growth.\",\n      \"evidence\": \"Exosome isolation, PKC-stimulated release, RGD-dependent binding, and in vivo tumor assays\",\n      \"pmids\": [\"22505472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism sorting ADAM15 into exosomes unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placed ADAM15 as a negative regulator of innate immune TRIF signaling and a TRIF interactor/substrate.\",\n      \"evidence\": \"TRIF complex co-IP/LC-MS/MS, NF-\\u03baB/IFN-\\u03b2 reporters, and ADAM15 siRNA cytokine assays\",\n      \"pmids\": [\"23365087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRIF cleavage reported but not biochemically dissected\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ADAM15-FAK/Src signaling to apoptosis resistance in rheumatoid synovial fibroblasts via PI3K/NF-\\u03baB.\",\n      \"evidence\": \"siRNA knockdown in RASFs with caspase assays and FAK/Src inhibitors\",\n      \"pmids\": [\"23918525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor input to the ADAM15 complex not defined here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified acrogranin as a surface partner of ADAM15 functionally implicated in sperm-egg adhesion.\",\n      \"evidence\": \"Co-IP, N-terminal sequencing, and anti-acrogranin inhibition of fertilization\",\n      \"pmids\": [\"25392190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the ADAM15-acrogranin complex in cancer cells untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established ADAM15 as both a transcriptional inducer and direct activator of pro-MMP9, promoting invasion.\",\n      \"evidence\": \"Knockdown/overexpression, ADAM15-MMP9 co-IP, in vitro pro-MMP9 cleavage, and MMP9 rescue in lung cancer cells\",\n      \"pmids\": [\"26323669\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of transcriptional vs proteolytic MMP9 activation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetically separated catalytic from non-catalytic functions in vivo, showing protease activity is dispensable for pathological retinal neovascularization.\",\n      \"evidence\": \"Adam15 E\\u2192A knock-in mice in oxygen-induced retinopathy and tumor models\",\n      \"pmids\": [\"25249606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which non-catalytic activity drives neovascularization not pinpointed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a Ca2+/calmodulin-gated assembly of the ADAM15/Fas/Src/FAK survival complex in synovial fibroblasts.\",\n      \"evidence\": \"CaM pulldown, recombinant CaM binding, CRAC/CaM inhibitors, and tail-deletion mutant with caspase assays\",\n      \"pmids\": [\"30003689\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and order of complex assembly not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Uncovered a novel role coupling adhesion to local translation through transient PABP1 recruitment to membrane foci.\",\n      \"evidence\": \"ADAM15-PABP1 co-IP, GST domain mapping, puromycin labeling of nascent proteins, and tail-deletion mutant\",\n      \"pmids\": [\"30265671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of locally translated mRNAs unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed catalytic and isoform-specific ADAM15 regulates tight-junction Claudin-1 via PI3K/Akt/mTOR and ZO1/ZO2 association.\",\n      \"evidence\": \"Isogenic ADAM15 wild-type/catalytic-dead isoform panels, co-IP, and pathway inhibitors in breast cancer cells\",\n      \"pmids\": [\"31467400\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalytic substrate driving Claudin-1 induction not identified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified shear stress/KLF2 as a transcriptional driver of ADAM15 supporting flow-dependent endothelial survival.\",\n      \"evidence\": \"Flow culture, KLF2 overexpression/siRNA, promoter analysis, and ADAM15 shRNA survival assays\",\n      \"pmids\": [\"31271758\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream survival effector under flow not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined ADAM15 as a mechanotransduction hub regulating TRPV4 surface density and pannexin-1/ATP purinergic signaling.\",\n      \"evidence\": \"ADAM15 siRNA in synovial fibroblasts with mechanical stimulation and multiple channel/signaling readouts\",\n      \"pmids\": [\"34685689\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAM15 controls TRPV4 trafficking unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established ADAM15 as required for organized post-infarction collagen cross-linking and scar integrity via PAK1/LOX-1/fibronectin.\",\n      \"evidence\": \"Adam15\\u2212/\\u2212 mice after LAD ligation with collagen imaging, solubility fractionation, and effector Western blots\",\n      \"pmids\": [\"34995785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ADAM15 acts catalytically or as scaffold in fibroblast activation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ADAM15 suppresses pressure-overload cardiac hypertrophy through integrin-\\u03b17/laminin and calcineurin/NFAT control.\",\n      \"evidence\": \"Adam15\\u2212/\\u2212 TAC mice, calcineurin activity assays, cyclosporin-A rescue, and cardiomyocyte stretch assay\",\n      \"pmids\": [\"36330793\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between ADAM15 and integrin-\\u03b17 regulation unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Assigned ADAM15 a selective role in death-receptor necroptosis and TNF-R1 trafficking, distinct from apoptosis control.\",\n      \"evidence\": \"CRISPR knockout in U937/Jurkat, multiple death ligands, caspase-8/RIPK1 analysis, and TNF-R1 surface flow cytometry\",\n      \"pmids\": [\"41340056\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TNF-R1 proposed but not confirmed as a catalytic substrate\", \"Mechanism of necroptosis regulation undefined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a strain-induced ADAM15/N-cadherin/PAK2/Nck mechanosignaling complex driving invasive gene expression in synovial fibroblasts.\",\n      \"evidence\": \"ADAM15 knockdown in RASFs, complex co-IP, phospho-PAK2 blots, and lncRNA/miRNA/CDH11 readouts\",\n      \"pmids\": [\"40118917\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ADAM15 catalytic activity contributes to this complex untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADAM15 isoform-specific cytoplasmic scaffolding, catalytic shedding, and integrin adhesion are integrated and prioritized within a single cell, and which functions dominate in each tissue context, remains unresolved.\",\n      \"evidence\": \"No single study integrates the catalytic, adhesive, and scaffold functions in a unified physiological model\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of the full-length protein in its membrane context\", \"Endogenous substrate repertoire incompletely defined\", \"Relative in vivo contribution of catalytic vs scaffold activity unresolved across tissues\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [7, 10, 11, 14, 22, 24]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [10, 14, 24]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [4, 20, 26]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 20, 27]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5, 6, 21]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [21, 33]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [33]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 17, 20, 26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 10, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [22, 33]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [19, 20, 23, 26, 33]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [9, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ITGAV\", \"ITGB3\", \"ITGB1\", \"SRC\", \"PTK2\", \"GRB2\", \"CALM1\", \"PABPC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}