Affinage

ADAM8

Disintegrin and metalloproteinase domain-containing protein 8 · UniProt P78325

Length
824 aa
Mass
88.8 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADAM8 (CD156) is a membrane-anchored metalloprotease-disintegrin that couples regulated ectodomain shedding to adhesion-dependent signaling, controlling leukocyte migration, osteoclast-mediated bone resorption, angiogenesis, and tumor invasion (PMID:20194813, PMID:20683884, PMID:24375628, PMID:9126482). Its protease domain is activated by an obligatory autocatalytic mechanism: a pre-processing cleavage at Glu158 that requires the disintegrin and cysteine-rich/EGF domains fractures the prodomain before final cysteine-switch removal at Cys167, and active-site mutation (E330Q) of the HExxH motif abolishes activity (PMID:12372841, PMID:18811590). Correct maturation also depends on site-specific N-glycosylation, with Asn-91 required for ER exit and Asn-612 for Golgi exit and cell-surface display (PMID:25336660). Unusually among ADAMs, ADAM8 is resistant to all four TIMPs but inhibited by hydroxamate-based compounds, a selectivity traced to an S1-pocket threonine (T300) (PMID:12135759, PMID:30738011). Once active, ADAM8 sheds a broad substrate set including CD23, L-selectin, CHL1, APP, VCAM-1, PSGL-1, periostin, and pro-angiogenic receptors, generating products with distinct downstream consequences (PMID:12777399, PMID:14761956, PMID:17548643, PMID:16154205, PMID:28378503, PMID:20119708). Beyond catalysis, the disintegrin domain mediates cell adhesion and, through multimerization, associates with β1 integrin to drive ERK1/2, Akt/PI3K, and downstream invasion programs, while the cytoplasmic domain is required for pERK/pCREB-dependent MMP-9 transcription (PMID:12372841, PMID:25629724, PMID:24375628, PMID:28986926). In disease contexts ADAM8 promotes pancreatic, breast, and glioblastoma tumor invasion, angiogenesis, and chemoresistance (PMID:25629724, PMID:24375628, PMID:25825051), and is genetically required for allergic airway inflammation, arthritis, and inflammatory osteoclastogenesis, though it can also exert anti-inflammatory effects by promoting intrinsic apoptosis of myeloid leukocytes and, in macrophages, by binding ANXA2 to regulate mTOR-autophagy (PMID:20194813, PMID:19737139, PMID:20683884, PMID:23670189, PMID:39097092).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 Medium

    Establishing ADAM8's domain architecture and expression pattern defined it as a candidate metalloprotease-disintegrin of myeloid lineage, framing all later mechanistic work.

    Evidence cDNA cloning/sequencing, Northern blot, and chromosomal mapping in human; genomic exon mapping and promoter reporter assays in mouse

    PMID:9126482 PMID:9218457

    Open questions at the time
    • Did not demonstrate catalytic activity or identify substrates
    • Promoter elements mapped only in monocytic cells
  2. 2001 Medium

    Mapping osteoclast-stimulatory activity to the disintegrin/cysteine-rich domain showed ADAM8 has non-proteolytic adhesion/signaling functions in bone biology.

    Evidence Antisense knockdown, secretable-form conditioned media, and truncation constructs in mouse bone marrow cultures with pit formation assay

    PMID:11341326

    Open questions at the time
    • Receptor/ligand partner for the disintegrin domain not identified
    • Single-lab loss-of-function
  3. 2002 High

    Reconstitution with active-site mutants established ADAM8 as a genuine autocatalytically activated metalloprotease distinct from TIMP-regulated ADAMs/MMPs.

    Evidence E330Q active-site mutagenesis, co-transfection trans-cleavage rescue, in vitro protease assays with purified enzyme, and TIMP/hydroxamate inhibition tests

    PMID:12135759 PMID:12372841

    Open questions at the time
    • Physiological substrates not yet defined
    • Structural basis of TIMP resistance unresolved at this stage
  4. 2003 High

    Identification of CD23 as a shed substrate connected ADAM8 catalysis to a defined immune-relevant cleavage event.

    Evidence Soluble CD23 release with active vs. E330Q ADAM8, co-IP of ADAM8 with membrane CD23, and peptide library specificity profiling

    PMID:12777399

    Open questions at the time
    • In vivo CD23 shedding by ADAM8 not demonstrated
    • Recognition determinants only partially mapped
  5. 2004 High

    CHL1 was established as a specific ADAM8 substrate with a functional neural readout, distinguishing ADAM8 from ADAM10/17.

    Evidence In vitro CHL1-Fc cleavage, WT vs. E330Q transfection, Adam8-/- brain extracts, and co-culture neurite/apoptosis assays

    PMID:14761956

    Open questions at the time
    • Physiological neural phenotype of impaired CHL1 processing not characterized in vivo
    • Receptor mediating processed-CHL1 effects unknown
  6. 2006 Medium

    Profiling substrate peptides and APP cleavage broadened the substrate repertoire and defined sequence criteria for ADAM8 cleavage.

    Evidence ProteaseSpot peptide cleavage with recombinant ADAM8, APP cleavage in HEK293 with WT vs. inactive enzyme, and cleavage-site mutagenesis

    PMID:16542157

    Open questions at the time
    • Many peptide hits not validated as full-length substrates in vivo
    • Single-lab study
  7. 2007 Medium

    Neutrophil studies showed ADAM8 is granule-stored, activation-mobilized to the surface, and itself shed, linking its trafficking to leukocyte function.

    Evidence Subcellular fractionation, confocal imaging of granule mobilization, and L-selectin shedding assay

    PMID:17548643

    Open questions at the time
    • Mechanism triggering granule mobilization not defined
    • L-selectin shedding shown in heterologous cells
  8. 2009 High

    Defining a DIS/CR-EGF-dependent pre-processing step at Glu158 prior to Cys167 removal explained how ADAM8 escapes prodomain auto-inhibition.

    Evidence N-terminal sequencing of intermediates, enterokinase-bypass constructs, and domain-deletion specific-activity measurements

    PMID:18811590

    Open questions at the time
    • Whether pre-processing is intra- or intermolecular not fully resolved
    • Trafficking compartment of each step not localized
  9. 2005 Medium

    Knockout and transgenic mouse models established ADAM8 as dispensable for development but functionally required and substrate-directed (VCAM-1) in inflammatory contexts.

    Evidence Adam8-/- phenotyping with developmental expression mapping; ADAM8-transgenic mice in OVA asthma with VCAM-1 shedding assays

    PMID:15580619 PMID:16154205

    Open questions at the time
    • Functional redundancy masking developmental roles not excluded
    • VCAM-1 shedding study single-lab and transgenic-driven
  10. 2010 High

    Genetic and chimera experiments placed ADAM8 as required for allergic airway inflammation through promigratory roles in both hematopoietic and non-hematopoietic compartments, while also limiting pathological angiogenesis.

    Evidence Adam8-/- mice in OVA asthma with bone marrow chimeras; ADAM8 overexpression shedding assays plus Adam8-/- OIR and tumor models

    PMID:20119708 PMID:20194813

    Open questions at the time
    • Causal substrate(s) mediating the migration defect not pinpointed
    • Pro- vs anti-angiogenic balance context-dependence unresolved
  11. 2011 High

    Complementary gain- and loss-of-function osteoclast models linked ADAM8 to TRAF6/NF-κB/Erk/Akt signaling and inflammatory bone resorption.

    Evidence TRAP-ADAM8 transgenic and Adam8-/- mice with TNF-α calvarial model and pathway immunoblots

    PMID:20683884

    Open questions at the time
    • Direct molecular link from ADAM8 to TRAF6 induction not defined
    • Catalytic vs. adhesion contribution to osteoclast phenotype not dissected
  12. 2009 High

    A catalytically inactive E330Q knock-in established that ADAM8 proteolytic activity is required for experimental arthritis.

    Evidence E330Q knock-in DBA/1J mice in collagen-induced arthritis with histological scoring

    PMID:19737139

    Open questions at the time
    • Relevant arthritic substrates not identified
    • Single-lab disease model
  13. 2013 High

    Studies in TNBC and AAI revealed a dual role: ADAM8 drives β1-integrin-dependent angiogenesis and metastasis in cancer yet limits airway inflammation by promoting intrinsic apoptosis of myeloid leukocytes.

    Evidence shRNA knockdown, orthotopic and resection mouse models, anti-ADAM8 antibody therapy, VEGF-A/transendothelial assays; Adam8-/- mice with chimeras and intrinsic vs extrinsic apoptosis assays

    PMID:23670189 PMID:24375628

    Open questions at the time
    • Molecular basis of cell-type-dependent pro- vs anti-inflammatory switch unresolved
    • Apoptosis-promoting mechanism downstream of ADAM8 not defined
  14. 2014 High

    Site-specific N-glycosylation was shown to control ADAM8 ER/Golgi trafficking, stability, and surface dimerization, with dimerization selective to ERα-negative breast cancer cells.

    Evidence Mutagenesis of four Asn sites, glycosidase treatment, fractionation, flow cytometry, and glycan analysis

    PMID:25336660

    Open questions at the time
    • Why dimerization is restricted to ERα-negative cells not mechanistically explained
    • Glycan-dependent partner interactions not mapped
  15. 2015 High

    Multimerization-dependent association with β1 integrin was shown to drive cancer invasion and was therapeutically targetable, while ADAM8 was implicated in glioblastoma chemoresistance via pAkt/pERK signaling.

    Evidence Co-IP with β1 integrin, structure-guided peptidomimetic BK-1361, invasion/ERK/MMP assays and PDAC mouse models; GBM knockdown/overexpression/inhibition with proteomic substrate ID (c-met, CD44)

    PMID:25629724 PMID:25825051

    Open questions at the time
    • Whether β1-integrin signaling requires catalytic activity not fully separated
    • GBM substrate-to-resistance causal chain partly correlative
  16. 2017 High

    Cytoplasmic-domain and leukocyte-migration studies dissected adhesion/signaling functions: the cytoplasmic tail drives pERK/pCREB-dependent MMP-9 transcription and PSGL-1 shedding, and leukocytic ADAM8 is intrinsically required for chemotaxis and transmigration.

    Evidence WT vs. cytoplasmic-deletion rescue, qPCR/immunoblot, anti-PSGL-1 blocking; THP-1 knockdown, Adam8-/- LPS lung model, BMDM transfer, and αL-integrin/migration assays; eosinophil migration on periostin with ADAM8/protease blocking

    PMID:28378503 PMID:28596294 PMID:28986926

    Open questions at the time
    • Direct effectors binding the cytoplasmic tail to drive ERK/CREB not all identified
    • Relative weight of shedding vs. integrin signaling in migration unresolved
  17. 2022 Medium

    Tumor microenvironment and vesicle studies extended ADAM8's reach: it forms an HB-EGF/EGFR–CCL2–TAM feedback loop in glioblastoma and is packaged with LCN2/MMP-9 into extracellular vesicles via a TSG101-independent route.

    Evidence Co-culture qPCR screen, RNA-seq, CCL2/EGFR analyses, TAM recruitment models; CRISPR KO PDAC cells with EV proteomics and macrophage co-culture

    PMID:35216088 PMID:36230833

    Open questions at the time
    • EV sorting mechanism replacing ESCRT-I not identified
    • In vivo relevance of EV-borne ADAM8 not established
  18. 2024 High

    A non-proteolytic intracellular function emerged: macrophage ADAM8 binds and phosphorylates ANXA2 to sustain mTOR signaling and suppress autophagy, impairing post-infarct cardiac repair.

    Evidence Macrophage-specific ADAM8 KO, bone marrow transplantation, Co-IP/MS, RNA-seq, and phospho-specific immunoblots (p-ANXA2, p-mTOR)

    PMID:39097092

    Open questions at the time
    • How a membrane sheddase accesses cytoplasmic ANXA2 to drive its phosphorylation not mechanistically explained
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ADAM8 selects between its proteolytic (sheddase), adhesive (disintegrin/β1-integrin), and intracellular (cytoplasmic-tail/ANXA2) modes in a cell-type-specific manner — and how this dictates its opposing pro- versus anti-inflammatory and pro- versus anti-angiogenic outcomes — remains unresolved.
  • No high-resolution structure of full-length or multimerized ADAM8
  • Unifying model integrating catalysis, integrin signaling, and intracellular partners absent
  • Determinants of context-dependent functional polarity unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016787 hydrolase activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
ANXA2CD23CHL1ITGB1LCN2MMP9PSGL1

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ADAM8 undergoes autocatalytic prodomain removal: mutation of Glu330 to Gln in the Zn2+-binding motif (HExxH) completely blocks propeptide cleavage. The ectodomain (but not the isolated MP domain) can trans-cleave the propeptide from catalytically inactive ADAM8. Active soluble ADAM8 cleaves myelin basic protein and a fluorogenic peptide substrate, inhibited by batimastat (IC50 ~50 nM) but not by TIMPs 1–4. A remnant form lacking the MP domain mediates cell adhesion via the disintegrin/Cys-rich domain, blocked by anti-disintegrin antibody. Site-directed mutagenesis (E330Q), co-transfection rescue assay, in vitro protease assay with purified enzyme, cell adhesion assay with substrate-bound recombinant protein The Journal of biological chemistry High 12372841
2002 Soluble recombinant ADAM8 is an active metalloprotease in vitro that hydrolyzes myelin basic protein and peptide substrates derived from known metalloprotease cleavage sites of membrane-bound cytokines/receptors. Unlike ADAM10, 12, 17 and MT-MMPs, ADAM8 activity is not inhibited by any of the four TIMPs (TIMP-1 to -4), but is inhibited by hydroxamate-based inhibitors. In vitro protease assay with purified recombinant ADAM8; TIMP inhibition assay FEBS letters High 12135759
2003 ADAM8 catalyzes ectodomain shedding of CD23 (the low-affinity IgE receptor FcεRII): proteolytically inactive ADAM8 (E330Q mutant) does not release soluble CD23, and a physical association between ADAM8 and membrane-bound CD23 was detected. ADAM8 also has distinct substrate specificity from ADAM17 on synthetic peptide libraries. Soluble CD23 release assay with active vs. inactive (E330Q) ADAM8; co-immunoprecipitation of ADAM8 with membrane CD23; peptide substrate library screening The Journal of biological chemistry High 12777399
2004 ADAM8 cleaves the neural cell adhesion molecule CHL1 at two sites in its extracellular fibronectin domains (releasing 125 kDa and 165 kDa fragments), inhibited by batimastat. The inactive E330Q-ADAM8 mutant does not cleave CHL1, while active ADAM10 and ADAM17 also fail to cleave CHL1, establishing ADAM8 substrate specificity. In ADAM8-deficient mice, CHL1 processing in brain extracts is almost undetectable. Processed CHL1 promotes neurite outgrowth and suppresses neuronal cell death in co-culture assays; these effects are absent with the inactive E330Q mutant. In vitro cleavage of CHL1-Fc fusion protein; transfection with WT vs. E330Q ADAM8; brain extracts from Adam8-/- mice; co-culture neurite outgrowth and apoptosis assays The Journal of biological chemistry High 14761956
2006 Soluble ADAM8 (pro- + metalloprotease domain, autoactivated by autocatalytic prodomain removal) cleaves peptides representing extracellular domain sequences of 14 membrane proteins involved in inflammation and neurodegeneration (including amyloid precursor protein APP) out of 34 tested. Full-length APP is cleaved by active ADAM8 in HEK293 cells with similar efficiency to ADAM10; inactive ADAM8 does not cleave APP. Amino acid substitution analysis of the MBP cleavage sequence defined sequence criteria for ADAM8 cleavage. ProteaseSpot peptide cleavage assay with E. coli-expressed recombinant ADAM8; APP cleavage in HEK293 cells with WT vs. inactive ADAM8; mutagenesis of cleavage sequence Biological chemistry Medium 16542157
2007 ADAM8 is constitutively present on the cell surface and in intracellular granules of human neutrophils. Upon activation, ADAM8 is mobilized from granules to the plasma membrane and then shed through a metalloproteinase-dependent mechanism. Cell-surface and soluble ADAM8 increase ectodomain shedding of membrane-bound L-selectin in mammalian cells. Subcellular fractionation, immunofluorescence, confocal imaging of granule mobilization; L-selectin shedding assay in ADAM8-expressing cells Journal of immunology Medium 17548643
2001 The cysteine-rich/disintegrin domain of ADAM8 is responsible for stimulating osteoclast (OCL) formation and bone-resorbing activity. Conditioned media from cells expressing a secretable form of ADAM8 increased OCL formation dose-dependently; antisense oligonucleotides to ADAM8 inhibited OCL formation; truncation analysis mapped the OCL-stimulatory activity to the disintegrin/Cys-rich domain. Antisense oligonucleotide knockdown in mouse bone marrow cultures; conditioned media from ADAM8-transfected cells; truncation/domain mapping constructs; pit formation assay Journal of bone and mineral research Medium 11341326
2009 ADAM8 activation requires a novel pre-processing step: before terminal autocatalytic prodomain removal, the prodomain is first cleaved at Glu158 (N-terminal sequencing data), fracturing the pro-segment prior to removal of the cysteine switch (Cys167). This pre-processing requires the disintegrin (DIS) and cysteine-rich/EGF (CR/EGF) domains — ADAM8 constructs lacking these domains cannot complete pre-processing. Without pre-processing, the pro-segment re-associates with the catalytic domain and strongly inhibits activity. N-terminal sequencing of activation intermediates; enterokinase-cleavable construct engineering to bypass pre-processing; domain-deletion constructs; specific activity measurements Bioscience reports High 18811590
2014 N-glycosylation at four sites (Asn-67, Asn-91, Asn-436, Asn-612) is required for correct ADAM8 processing, localization, stability, and activity. Asn-91 glycosylation (high mannose, prodomain) is essential for exit from the ER; Asn-612 (complex type, remnant form) for exit from the Golgi and cell-surface localization; Asn-436 mutation leads to enhanced lysosomal degradation. ADAM8 dimerization on the cell surface was detected specifically in ERα-negative (but not ERα-positive) breast cancer cells and required N-glycosylation. Site-directed mutagenesis of four Asn sites; glycosidase treatment; subcellular fractionation; Western blot for processing; flow cytometry for surface localization; glycan analysis The Journal of biological chemistry High 25336660
2015 ADAM8 requires multimerization for biological function and associates with β1 integrin on the cell surface of pancreatic cancer (PDAC) cells. A peptidomimetic inhibitor (BK-1361), designed by structural modelling of the disintegrin domain, prevents ADAM8 multimerization and reduces PDAC cell invasiveness, ERK1/2 activation, and MMP activity. In vivo, BK-1361 decreased tumor burden and metastasis in mouse models of PDAC. Co-immunoprecipitation (ADAM8 with β1 integrin); structural modelling of disintegrin domain for inhibitor design; invasion assays; ERK1/2 and MMP activity assays; mouse xenograft and Kras(G12D) PDAC model Nature communications High 25629724
2013 In triple-negative breast cancer (TNBC), ADAM8 promotes angiogenesis through release of VEGF-A and transendothelial cell migration via β1-integrin activation. ADAM8 knockdown tumors in an orthotopic mouse model failed to grow beyond palpable size and showed poor vascularization, reduced circulating tumor cells, and reduced brain metastases. Anti-ADAM8 antibody treatment reduced primary tumor burden and metastases in a resection model. shRNA knockdown; orthotopic mouse model; antibody treatment in vivo; VEGF-A release assay; β1-integrin activation assay; transendothelial migration assay EMBO molecular medicine High 24375628
2015 ADAM8 mediates temozolomide (TMZ) chemoresistance in glioblastoma (GBM) cells by enhancing pAkt/PI3K and pERK1/2 signaling. Soluble HGF receptor/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells by proteomics; blocking HGF R/c-met prevented TMZ-induced invasiveness. ADAM8 knockdown or pharmacological inhibition (with BB-94 but not the ADAM8-sparing BB-2516) increased TMZ sensitivity. ADAM8 shRNA knockdown, overexpression, and pharmacological inhibition; proteomics substrate identification; blocking antibodies for c-met; pAkt/pERK immunoblotting; Matrigel invasion assay Neuro-oncology Medium 25825051
2017 ADAM8 cytoplasmic domain is required for MMP-9 upregulation: re-expression of WT ADAM8 (but not ADAM8 lacking the cytoplasmic domain) in ADAM8-knockdown breast cancer cells restored elevated pERK1/2, pCREB(S133), and MMP-9 transcription. ADAM8 also sheds PSGL-1 from breast cancer cells, and antibodies against PSGL-1 reduced transendothelial migration, linking ADAM8-mediated PSGL-1 shedding to transendothelial migration. Re-expression of WT vs. cytoplasmic-domain-deleted ADAM8; pERK/pCREB immunoblotting; qPCR for MMP-9; anti-PSGL-1 antibody blocking in transendothelial migration assay International journal of cancer Medium 28986926
2010 ADAM8 deficiency in mice completely prevents development of ovalbumin-induced airway inflammation and hyperresponsiveness. ADAM8 expression is required in both hematopoietic cells (including T cells) and non-hematopoietic cells for full asthma manifestation, demonstrated by bone marrow chimera experiments. Loss of ADAM8 impaired migration of T cells, eosinophils, and myeloid cells from blood vessels to the lung. Adam8-/- knockout mice; OVA-induced asthma model; bone marrow chimera experiments; bronchoalveolar lavage analysis; histology; airway hyperresponsiveness measurement American journal of respiratory and critical care medicine High 20194813
2013 ADAM8 limits allergic airway inflammation (AAI) by activating the intrinsic apoptosis pathway in myeloid leukocytes (eosinophils and macrophages): Adam8-/- mice have fewer apoptotic eosinophils and macrophages in airways during AAI, and Adam8-/- macrophages and eosinophils show reduced apoptosis when the intrinsic (but not the extrinsic) apoptosis pathway is triggered in vitro. Leukocyte-derived ADAM8 predominantly mediates this anti-inflammatory activity, confirmed by bone marrow chimeras. Adam8-/- knockout mice; bone marrow chimera; OVA and house dust mite AAI models; apoptosis assays (intrinsic vs. extrinsic pathway activation) in isolated cells; airway leukocyte counting Journal of immunology High 23670189
2005 ADAM8-deficient (Adam8-/-) mice develop normally without major defects in any tissue or organ, indicating ADAM8 is dispensable for normal development and homeostasis. Expression analysis showed ADAM8 is prominently expressed during mouse development in decidua, trophoblast derivatives, gonadal ridge, thymus, cartilage/bone, brain, spinal cord, and perivenous mesenchyme. Targeted gene deletion (Adam8-/- mice); developmental expression analysis by in situ hybridization/immunostaining; histological phenotyping Developmental dynamics Medium 15580619
2005 ADAM8-mediated shedding of VCAM-1 from endothelial cells reduces eosinophil adhesion (via α4β1 integrin) and suppresses experimental asthma: ADAM8-transgenic mice (expressing ectodomain of CD156/ADAM8) show markedly reduced cellular infiltrates in peribronchovascular lesions compared to controls, associated with increased VCAM-1 shedding. ADAM8 transgenic mice; OVA-induced asthma model; VCAM-1 shedding assay in human umbilical vein endothelial cells stimulated with ADAM8-transgenic cells Immunology letters Medium 16154205
2011 ADAM8 overexpression in osteoclast (OCL) precursors (TRAP-ADAM8 transgenic mice) produces osteopenia, hypermultinucleated OCLs with increased bone resorption capacity, enhanced OCL precursor fusion, increased TRAF6 expression, and elevated NF-κB, Erk, and Akt signaling, as well as increased p-Pyk2 and p-Src activation. ADAM8 knockout mice do not display a basal bone phenotype but fail to increase RANKL production, OCL formation, or calvarial fibrosis in response to TNF-α. TRAP-ADAM8 transgenic overexpression mice; Adam8-/- knockout mice; TNF-α calvarial injection model; osteoclast formation and bone resorption assays; Western blot for TRAF6, NF-κB, Erk, Akt, p-Pyk2, p-Src Journal of bone and mineral research High 20683884
2009 Catalytically inactive ADAM8 (E330Q knock-in transgenic DBA/1J mice) shows decreased incidence and severity of collagen-induced arthritis with reduced synovial inflammation, cartilage degradation, and bone resorption, demonstrating that ADAM8 proteolytic activity is required for experimental arthritis development. Transgenic mice expressing E330Q catalytically inactive ADAM8; LPS-synchronized collagen-induced arthritis model; histological scoring of joints; expression profiling Clinical and experimental immunology High 19737139
2010 ADAM8 overexpression in endothelial cells increases ectodomain shedding of multiple pro-angiogenic membrane proteins including CD31, Tie-2, Flk-1, Flt-1, EphrinB2, EphB4, VE-cadherin, KL-1, E-selectin, and neuregulin-1β2. In Adam8-/- mice, the oxygen-induced retinopathy model shows more retinal re-vascularization but fewer neovascular tufts, and heterotopically injected tumor cells grow faster, suggesting ADAM8 limits pathological angiogenesis. ADAM8 overexpression in endothelial cells with ectodomain shedding assays; Adam8-/- mice in OIR model; tumor cell heterotopic injection model Journal of molecular medicine Medium 20119708
2017 ADAM8 promotes migration of IL-5-stimulated eosinophils on periostin-rich extracellular matrix: ADAM8 on eosinophils degrades (sheds the Stiny-1 epitope of) periostin in the extracellular matrix and is required for migration. Shed ADAM8 proteoforms lacking the cytoplasmic tail were detected in supernatants. ADAM8 antibodies and metalloproteinase inhibitors both blocked eosinophil migration and periostin epitope clearance. Fluorescence microscopy of eosinophil migration on periostin; anti-ADAM8 and metalloprotease inhibitor blocking; Western blot of ADAM8 proteoforms in supernatants Clinical and experimental allergy Medium 28378503
2017 Leukocytic ADAM8 is required for chemokine-induced chemotaxis and transendothelial and transepithelial migration of monocytic THP-1 cells, as well as αL-integrin upregulation and THP-1 adhesion to endothelial cells. On endothelial cells, ADAM8 enhances transendothelial migration and cytokine-induced permeability. In Adam8-/- mice, intranasal LPS-induced acute lung inflammation shows reduced leukocyte infiltration. Bone marrow macrophage transfer experiments confirmed a predominantly leukocyte-intrinsic promigratory function. shRNA knockdown in THP-1 cells; Adam8-/- knockout mice; LPS-induced acute lung inflammation model; BMDM transfer experiments; transendothelial/transepithelial migration assays; αL-integrin flow cytometry American journal of physiology. Lung cellular and molecular physiology High 28596294
2020 ADAM8 regulates angiogenesis in glioblastoma via the JAK/STAT3 pathway controlling osteopontin (OPN) expression: ADAM8 knockdown in U87 glioma cells decreased angiogenesis and tumor volumes in vivo. In vitro, ADAM8 regulates OPN through JAK/STAT3 signaling in both glioma cells and primary macrophages. ADAM8 shRNA knockdown; stereotactic mouse brain injection model; in vitro angiogenesis assays; JAK/STAT3 pathway inhibition; OPN measurement Biological chemistry Medium 33544472
2022 ADAM8 is present as an active protease in extracellular vesicles (EVs) from PDAC cells and is associated with lipocalin 2 (LCN2) and MMP-9 in an ADAM8-dependent manner (ADAM8 KO cells show reduced LCN2 and MMP-9 in EVs). ADAM8 sorting into EVs is independent of the TSG101 ESCRT-I pathway despite the presence of a PTAP recognition motif in ADAM8's cytoplasmic domain. ADAM8 CRISPR KO in PDAC cells; EV isolation and proteomics; Western blot for LCN2, MMP-9, TSG101 in EVs; co-culture with macrophages International journal of molecular sciences Medium 35216088
2024 In macrophages after myocardial infarction, ADAM8 binds to ANXA2 and promotes phosphorylation of ANXA2 at Ser26. ADAM8 knockout impedes ANXA2 phosphorylation, inhibits mTOR Ser2448 phosphorylation, and activates autophagy, leading to enhanced angiogenesis and suppressed inflammation. Macrophage-specific ADAM8 KO mice show improved cardiac repair, confirmed by bone marrow transplantation; these effects are reversed by ADAM8 overexpression. Macrophage-specific ADAM8 KO (CRISPR/Cas9, Lyz2-Cre); bone marrow transplantation; Co-IP/mass spectrometry (ADAM8-ANXA2 interaction); RNA sequencing; phospho-specific Western blots (p-mTOR, p-ANXA2); ANXA2 phosphorylation activation/inactivation experiments Journal of advanced research High 39097092
1997 Human CD156 (ADAM8) cDNA encodes a transmembrane glycoprotein with an extracellular region containing metalloprotease, disintegrin, cysteine-rich, and EGF-like domains homologous to hemorrhagic snake venom proteins. mRNA is expressed in macrophage cell lines, granulocytes, monocytes, and B cells but not T cell lines. The gene maps to human chromosome 10q26.3. cDNA cloning and sequencing from THP-1 macrophage and granulocyte libraries; Northern blot expression analysis; chromosomal mapping Genomics Medium 9126482
1997 The murine CD156/ADAM8 gene spans ~14 kb, is composed of 24 exons, and encodes a protein with metalloprotease domain (exons 7–12), disintegrin domain (exons 12–15), and transmembrane region (single exon 19). The promoter contains cis-acting elements at positions −183, −334, and −623 and LPS-inducible elements at −183 and −390, and interferon-γ-inducible regions at −202, −507, and −659, defined by CAT reporter assays in monocytic cells. Genomic cloning, sequencing and exon mapping; chloramphenicol acetyltransferase (CAT) reporter assays with promoter deletion constructs in monocytic cell line; LPS and IFN-γ stimulation The Journal of biological chemistry Medium 9218457
2019 ADAM8 inhibition by hydroxamate-based inhibitors: BB-94 (batimastat), GW280264, FC387, and FC143 inhibit ADAM8 in vitro and in cell-based CD23 shedding assays; GM6001, TAPI2, and BB-2516 (marimastat) weakly inhibit ADAM8; GI254023 (ADAM10-specific) does not inhibit ADAM8. Structural modelling of the S1 position reveals T300 in ADAM8 (and T347 in ADAM17) vs. V327 in ADAM10 explains differential inhibitor selectivity. In vitro recombinant ADAM8 protease assay; cell-based CD23 shedding assay in HEK293 cells; structural modelling of inhibitor binding Biological chemistry Medium 30738011
2022 In glioblastoma, ADAM8 activates HB-EGF/EGFR signaling to upregulate CCL2 expression in tumor cells, which recruits tumor-associated macrophages (TAMs). TAMs in turn induce ADAM8 expression in GBM cells, forming a positive feedback loop that mediates TMZ chemoresistance. Only ADAM8 (and not other ADAM or MMP family members screened) was upregulated in GBM cells by macrophages under TMZ treatment. qPCR screen of ADAM/MMP family in co-culture; RNA-seq; ELISA and Western blot for CCL2; EGFR signaling analysis; in vitro and in vivo TAM recruitment assays; TCGA data analysis with IHC validation Cancers Medium 36230833

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Cell-specific delivery of diverse cargos by bacteriophage MS2 virus-like particles. ACS nano 273 21615170
2017 An improved MS2 system for accurate reporting of the mRNA life cycle. Nature methods 268 29131164
1993 The RNA binding site of bacteriophage MS2 coat protein. The EMBO journal 183 8440248
2003 Catalytic activity of ADAM8, ADAM15, and MDC-L (ADAM28) on synthetic peptide substrates and in ectodomain cleavage of CD23. The Journal of biological chemistry 149 12777399
2002 The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion. The Journal of biological chemistry 145 12372841
2020 RNA-protein interaction mapping via MS2- or Cas13-based APEX targeting. Proceedings of the National Academy of Sciences of the United States of America 141 32839320
2007 Increased expression of ADAM33 and ADAM8 with disease progression in asthma. The Journal of allergy and clinical immunology 123 17339047
2004 ADAM8 as a novel serological and histochemical marker for lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 123 15623614
2002 The enzymatic activity of ADAM8 and ADAM9 is not regulated by TIMPs. FEBS letters 121 12135759
2012 MS2-TRAP (MS2-tagged RNA affinity purification): tagging RNA to identify associated miRNAs. Methods (San Diego, Calif.) 117 22813890
2016 Asymmetric cryo-EM reconstruction of phage MS2 reveals genome structure in situ. Nature communications 116 27561669
2004 Ectodomain shedding of the neural recognition molecule CHL1 by the metalloprotease-disintegrin ADAM8 promotes neurite outgrowth and suppresses neuronal cell death. The Journal of biological chemistry 107 14761956
2007 Expression and regulation of the metalloproteinase ADAM-8 during human neutrophil pathophysiological activation and its catalytic activity on L-selectin shedding. Journal of immunology (Baltimore, Md. : 1950) 100 17548643
2015 ADAM8 as a drug target in pancreatic cancer. Nature communications 97 25629724
2005 Metalloprotease-disintegrin ADAM8: expression analysis and targeted deletion in mice. Developmental dynamics : an official publication of the American Association of Anatomists 96 15580619
1997 CD156 (human ADAM8): expression, primary amino acid sequence, and gene location. Genomics 94 9126482
2013 ADAM8 expression in invasive breast cancer promotes tumor dissemination and metastasis. EMBO molecular medicine 92 24375628
1998 A thermodynamic analysis of the sequence-specific binding of RNA by bacteriophage MS2 coat protein. Proceedings of the National Academy of Sciences of the United States of America 90 9689065
2001 ADAM8: a novel osteoclast stimulating factor. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 85 11341326
2015 Direct Evidence for Packaging Signal-Mediated Assembly of Bacteriophage MS2. Journal of molecular biology 80 26608810
2007 ADAM8 expression is associated with increased invasiveness and reduced patient survival in pancreatic cancer. Journal of cellular and molecular medicine 80 17979891
2017 Wheat Ms2 encodes for an orphan protein that confers male sterility in grass species. Nature communications 75 28452349
2006 Identification of candidate substrates for ectodomain shedding by the metalloprotease-disintegrin ADAM8. Biological chemistry 75 16542157
2019 ADAM8 in invasive cancers: links to tumor progression, metastasis, and chemoresistance. Clinical science (London, England : 1979) 72 30635388
2013 Messenger RNA vaccine based on recombinant MS2 virus-like particles against prostate cancer. International journal of cancer 72 24105486
2017 A TRIM insertion in the promoter of Ms2 causes male sterility in wheat. Nature communications 64 28497807
1996 Complementation of RNA binding site mutations in MS2 coat protein heterodimers. Nucleic acids research 64 8710507
1995 Probing sequence-specific RNA recognition by the bacteriophage MS2 coat protein. Nucleic acids research 62 7543200
1979 Secondary structure of MS2 phage RNA and bias in code word usage. Nucleic acids research 58 537920
2015 A novel delivery platform based on Bacteriophage MS2 virus-like particles. Virus research 56 26415756
2010 The metalloprotease-disintegrin ADAM8 is essential for the development of experimental asthma. American journal of respiratory and critical care medicine 55 20194813
2015 The metalloprotease-disintegrin ADAM8 contributes to temozolomide chemoresistance and enhanced invasiveness of human glioblastoma cells. Neuro-oncology 52 25825051
2017 ADAM8 expression in breast cancer derived brain metastases: Functional implications on MMP-9 expression and transendothelial migration in breast cancer cells. International journal of cancer 49 28986926
2010 ADAM8 is a negative regulator of retinal neovascularization and of the growth of heterotopically injected tumor cells in mice. Journal of molecular medicine (Berlin, Germany) 46 20119708
1998 Crystal structures of MS2 coat protein mutants in complex with wild-type RNA operator fragments. Nucleic acids research 45 9469847
2009 ADAM8 is selectively up-regulated in endothelial cells and is associated with angiogenesis after spinal cord injury in adult mice. The Journal of comparative neurology 44 19003792
2016 Identification of mRNA-Interacting Factors by MS2-TRAP (MS2-Tagged RNA Affinity Purification). Methods in molecular biology (Clifton, N.J.) 43 26965253
2005 Role of ADAM8 in experimental asthma. Immunology letters 42 16154205
2022 An improved imaging system that corrects MS2-induced RNA destabilization. Nature methods 40 36357695
2016 Bacteriophage MS2 genomic RNA encodes an assembly instruction manual for its capsid. Bacteriophage 40 27144089
1997 Role of the coat protein-RNA interaction in the life cycle of bacteriophage MS2. Molecular & general genetics : MGG 40 9180688
2019 Propofol inhibits pancreatic cancer proliferation and metastasis by up-regulating miR-328 and down-regulating ADAM8. Basic & clinical pharmacology & toxicology 39 30861616
2009 ADAM8/MS2/CD156, an emerging drug target in the treatment of inflammatory and invasive pathologies. Current pharmaceutical design 39 19601829
2010 Novel alternatively spliced ADAM8 isoforms contribute to the aggressive bone metastatic phenotype of lung cancer. Oncogene 38 20453887
1997 Structure of the murine CD156 gene, characterization of its promoter, and chromosomal location. The Journal of biological chemistry 38 9218457
2017 The metalloproteinase ADAM8 promotes leukocyte recruitment in vitro and in acute lung inflammation. American journal of physiology. Lung cellular and molecular physiology 34 28596294
2011 ADAM8 enhances osteoclast precursor fusion and osteoclast formation in vitro and in vivo. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 20683884
2008 Involvement of a disintegrin and a metalloproteinase 8 (ADAM8) in osteoclastogenesis and pathological bone destruction. Annals of the rheumatic diseases 34 18397961
2004 Reduced intragraft mRNA expression of matrix metalloproteinases Mmp3, Mmp12, Mmp13 and Adam8, and diminished transplant arteriosclerosis in Ccr5-deficient mice. European journal of immunology 34 15307189
2002 CD156 transgenic mice. Different responses between inflammatory types. Pathobiology : journal of immunopathology, molecular and cellular biology 34 12415192
2019 Propofol inhibits pancreatic cancer progress under hypoxia via ADAM8. Journal of hepato-biliary-pancreatic sciences 33 30945470
2014 Adsorption of Rotavirus, MS2 Bacteriophage and Surface-Modified Silica Nanoparticles to Hydrophobic Matter. Food and environmental virology 33 25342436
2014 Anti-inflammatory macrophages activate invasion in pancreatic adenocarcinoma by increasing the MMP9 and ADAM8 expression. Medical oncology (Northwood, London, England) 32 24526468
2006 Elevated soluble ADAM8 in bronchoalveolar lavage fluid in patients with eosinophilic pneumonia. International archives of allergy and immunology 32 17124430
2003 Purification of functional RNA-protein complexes using MS2-MBP. Current protocols in molecular biology 32 18265330
2013 Adam8 limits the development of allergic airway inflammation in mice. Journal of immunology (Baltimore, Md. : 1950) 31 23670189
2009 ADAM8: a new therapeutic target for asthma. Expert opinion on therapeutic targets 31 19397475
2003 Increased expression of a novel osteoclast-stimulating factor, ADAM8, in interface tissue around loosened hip prostheses. The Journal of rheumatology 31 12966612
2015 Promising MS2 mediated virus-like particle vaccine against foot-and-mouth disease. Antiviral research 29 25676866
2014 Sputum ADAM8 expression is increased in severe asthma and COPD. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 29 24147597
2023 The versatile roles of ADAM8 in cancer cell migration, mechanics, and extracellular matrix remodeling. Frontiers in cell and developmental biology 27 36910158
2019 Bacteriophage MS2 displays unreported capsid variability assembling T = 4 and mixed capsids. Molecular microbiology 27 31618483
2016 A novel peptide ADAM8 inhibitor attenuates bronchial hyperresponsiveness and Th2 cytokine mediated inflammation of murine asthmatic models. Scientific reports 27 27458083
2021 Quantitative Consequences of Protein Carriers in Immunopeptidomics and Tyrosine Phosphorylation MS2 Analyses. Molecular & cellular proteomics : MCP 24 34052394
2020 MS2-TRIBE Evaluates Both Protein-RNA Interactions and Nuclear Organization of Transcription by RNA Editing. iScience 24 32674054
2020 New Generations of MS2 Variants and MCP Fusions to Detect Single mRNAs in Living Eukaryotic Cells. Methods in molecular biology (Clifton, N.J.) 24 32710406
2015 Identification of lncRNA MEG3 Binding Protein Using MS2-Tagged RNA Affinity Purification and Mass Spectrometry. Applied biochemistry and biotechnology 24 26155902
2020 ADAM8 affects glioblastoma progression by regulating osteopontin-mediated angiogenesis. Biological chemistry 23 33544472
2019 Imaging Single mRNA Molecules in Mammalian Cells Using an Optimized MS2-MCP System. Methods in molecular biology (Clifton, N.J.) 23 31407274
2017 IL-5-stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8-dependent migration. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 23 28378503
2019 Propofol affects the growth and metastasis of pancreatic cancer via ADAM8. Pharmacological reports : PR 22 32048249
2018 A CRISPR/Cas9 platform for MS2-labelling of single mRNA in live stem cells. Methods (San Diego, Calif.) 22 30217531
2014 N-glycosylation regulates ADAM8 processing and activation. The Journal of biological chemistry 22 25336660
2018 Single-mRNA detection in living S. cerevisiae using a re-engineered MS2 system. Nature protocols 21 30218101
1997 MS2 coat protein mutants which bind Qbeta RNA. Nucleic acids research 21 9207028
2017 MS2 Lysis of Escherichia coli Depends on Host Chaperone DnaJ. Journal of bacteriology 20 28396351
2011 Common variation in the ADAM8 gene affects serum sADAM8 concentrations and the risk of myocardial infarction in two independent cohorts. Atherosclerosis 20 21640993
2009 Upregulation of ADAM8 in the airways of mice with allergic bronchial asthma. Lung 20 19373511
2009 ADAM8 and its single nucleotide polymorphism 2662 T/G are associated with advanced atherosclerosis and fatal myocardial infarction: Tampere vascular study. Annals of medicine 20 19575316
2021 Optimizing the synthesis and purification of MS2 virus like particles. Scientific reports 19 34615923
2012 Protective effects of ADAM8 against cisplatin-mediated apoptosis in non-small-cell lung cancer. Cell biology international 19 23319321
2009 Autoactivation of human ADAM8: a novel pre-processing step is required for catalytic activity. Bioscience reports 19 18811590
2022 Improved alpharetrovirus-based Gag.MS2 particles for efficient and transient delivery of CRISPR-Cas9 into target cells. Molecular therapy. Nucleic acids 18 35141043
2021 Live imaging and quantitation of nascent transcription using the MS2/MCP system in the Drosophila embryo. STAR protocols 18 33778778
2017 Mutational analysis of the MS2 lysis protein L. Microbiology (Reading, England) 18 28691656
2012 Selection and evaluation of single domain antibodies toward MS2 phage and coat protein. Molecular immunology 18 22898187
2011 Myocardial infarction induces early increased remote ADAM8 expression of rat hearts after cardiac arrest. Scandinavian journal of clinical and laboratory investigation 18 21728900
2022 The GBM Tumor Microenvironment as a Modulator of Therapy Response: ADAM8 Causes Tumor Infiltration of Tams through HB-EGF/EGFR-Mediated CCL2 Expression and Overcomes TMZ Chemosensitization in Glioblastoma. Cancers 17 36230833
2019 Elevated expression of the metalloproteinase ADAM8 associates with vascular diseases in mice and humans. Atherosclerosis 17 30910225
2019 Virulence Factor Identification in the Banana Pathogen Dickeya zeae MS2. Applied and environmental microbiology 17 31540986
2009 Increased serum ADAM8 concentration in patients with drug-induced eosinophilic pneumonia-ADAM8 expression depends on a the allergen route of entry. Respiratory medicine 17 19625177
2009 Reduced incidence and severity of experimental autoimmune arthritis in mice expressing catalytically inactive A disintegrin and metalloproteinase 8 (ADAM8). Clinical and experimental immunology 17 19737139
2024 Virus-like particles derived from bacteriophage MS2 as antigen scaffolds and RNA protective shells. Nanomedicine (London, England) 16 38629576
2023 MS2 Virus-like Particles as a Versatile Peptide Presentation Platform: Insights into the Deterministic Abilities for Accommodating Heterologous Peptide Lengths. ACS synthetic biology 16 37946498
2022 ADAM8-Dependent Extracellular Signaling in the Tumor Microenvironment Involves Regulated Release of Lipocalin 2 and MMP-9. International journal of molecular sciences 16 35216088
2020 Structural Organizations of Qβ and MS2 Phages Affect Capsid Protein Modifications by Oxidants Hypochlorous Acid and Peroxynitrite. Frontiers in microbiology 16 32582098
2019 Metalloprotease inhibitor profiles of human ADAM8 in vitro and in cell-based assays. Biological chemistry 16 30738011
2014 MS2 bacteriophage reduction and microbial communities in biosand filters. Environmental science & technology 16 24857308
2024 ADAM8 deficiency in macrophages promotes cardiac repair after myocardial infarction via ANXA2-mTOR-autophagy pathway. Journal of advanced research 15 39097092
2008 ADAM8 in allergy. Inflammation & allergy drug targets 15 18691140

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