Affinage

CD63

CD63 antigen · UniProt P08962

Length
238 aa
Mass
25.6 kDa
Annotated
2026-06-09
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CD63 is a tetraspanin membrane protein that organizes endocytic and secretory trafficking and acts as a membrane scaffold linking transmembrane partners to the endo-lysosomal machinery (PMID:18930046, PMID:14660791). It traffics from the ER to late endosomes/multivesicular bodies, where it is enriched on intraluminal vesicles and from which it can be released as exosomes, while a pool also cycles to the plasma membrane and back; comparison with plasma-membrane-stabilized mutants shows that CD63's residence on internal membranes is a key determinant of whether it is sorted into endosome-derived versus plasma-membrane-derived vesicles (PMID:18930046, PMID:34282141). CD63 promotes internalization of partner membrane proteins through its capacity to engage the clathrin adaptor complexes AP-2 and AP-3, redirecting cargo such as the H,K-ATPase β-subunit from the surface to CD63+ intracellular compartments (PMID:18930046, PMID:14660791), and it likewise governs basolateral membrane insertion and recycling of the organic cation transporter OCT2 via Rab4-positive sorting endosomes (PMID:28031320) and endosomal recruitment of CXCR4 in activated B cells (PMID:21270405). In secretory and granule-bearing cells CD63 is a constituent of platelet dense granules and lysosomes, Weibel-Palade bodies, and crystalloid/secretory granules, relocating to the plasma membrane upon stimulated exocytosis (PMID:10793155, PMID:7682577, PMID:8353283, PMID:12010805); it is required for ER/Golgi export and granule targeting of neutrophil elastase through its large extracellular loop (PMID:18669870) and for FcεRI-mediated mast cell degranulation acting via the Gab2-PI3K pathway (PMID:23945142, PMID:15684326). CD63 nucleates signaling complexes at the cell surface, associating with integrins α3β1 and α6β1 together with a type II PI 4-kinase in peripheral focal complexes (PMID:9006891, PMID:7629079), and serving as the cell-surface receptor for TIMP-1, which it couples to β1 integrin to drive PI3K/FAK-dependent survival, migration, and granulopoiesis (PMID:16917503, PMID:26001794, PMID:24635319). It further modulates Src-family kinase activity in complexes with RPTPα to regulate ROMK channels (PMID:18211905). CD63 controls extracellular vesicle cargo sorting, being required for exosomal packaging of the EBV oncoprotein LMP1 (PMID:27974566) and for iron-loading-induced secretion of ferritin-containing EVs through the IRE-IRP system and NCOA4 (PMID:34265052), and it is exploited by multiple pathogens including human papillomavirus (via a CD63-syntenin-1-ALIX complex) (PMID:27578500), Lujo virus (facilitating pH-activated membrane fusion) (PMID:29120745), and HIV-1 (PMID:18682304, PMID:24507450). At the organismal level CD63 sustains TGFβ receptor signaling to maintain hematopoietic stem cell quiescence and repopulating capacity (PMID:34363017), and its loss in mice produces a selective renal water-balance defect with lamellar inclusions in collecting-duct principal cells, indicating tetraspanin redundancy in most tissues (PMID:19075008). CD63 expression is N-glycosylated by the RPN2/oligosaccharyltransferase complex, which controls its localization (PMID:24884960), and is transcriptionally repressed by BCL6 (PMID:21270405) from a TATA-less, AP-1-responsive promoter (PMID:1599482).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1993 High

    Establishing where CD63 resides defined it as a regulated-secretory and granule membrane protein rather than a static surface antigen, linking it to a human bleeding disorder.

    Evidence Immunoblotting, FACS, N-terminal sequencing and HPS platelet analysis identifying CD63/granulophysin in dense granules, lysosomes and Weibel-Palade bodies with thrombin-induced surface exposure

    PMID:7682577 PMID:8353283

    Open questions at the time
    • Did not define the trafficking machinery routing CD63 to these granules
    • Molecular basis of the HPS deficiency not resolved
  2. 1997 High

    Showing CD63 forms integrin-α3β1/α6β1 complexes containing a PI 4-kinase established it as a scaffold nucleating a peripheral signaling pathway distinct from FAK/focal-adhesion signaling.

    Evidence Co-immunoprecipitation, PI 4-K enzymatic assays in CD63 immunoprecipitates, and localization to focal complexes across cell lines (building on 1995 integrin association mapping)

    PMID:7629079 PMID:9006891

    Open questions at the time
    • Direct versus indirect nature of the CD63-PI4K interaction unresolved
    • Physiological output of the integrin-PI4K complex not defined
  3. 2003 High

    Demonstrating CD63 drives internalization of the H,K-ATPase β-subunit via AP-2/AP-3 explained mechanistically how CD63 sorts partner membrane proteins into the endocytic pathway.

    Evidence Co-IP, biochemical endocytosis assays and CD63 adaptor-binding mutants in parietal and COS-7 cells

    PMID:14660791

    Open questions at the time
    • Whether all CD63 cargo use the same AP-dependent route untested
    • Stoichiometry of CD63-cargo-adaptor assembly unknown
  4. 2006 High

    Identifying CD63 as a direct TIMP-1 receptor coupling to β1 integrin connected an extracellular ligand to intracellular survival signaling.

    Evidence Yeast two-hybrid, reciprocal Co-IP, shRNA knockdown and 3D matrigel survival assays

    PMID:16917503

    Open questions at the time
    • Direct binding interface on CD63 not mapped
    • Whether TIMP-1 signaling is protease-independent unresolved at this stage
  5. 2008 High

    Defining CD63's clathrin-dependent endocytosis and its loss-of-function phenotype in mice clarified the trafficking itinerary and revealed tetraspanin redundancy in vivo.

    Evidence Subcellular fractionation, live imaging and EM of trafficking, alongside CD63 knockout mice showing a selective collecting-duct water-balance defect

    PMID:18930046 PMID:19075008

    Open questions at the time
    • Identity of compensating tetraspanins not established
    • Mechanistic basis of the renal lamellar inclusions undefined
  6. 2008 High

    CD63 was shown to act in two distinct signaling and biosynthetic contexts: a renal RPTPα/c-Src complex regulating ROMK channels, and granule targeting of neutrophil elastase via its large extracellular loop.

    Evidence Co-IP in native tissue and transfected cells with oocyte voltage-clamp electrophysiology; Co-IP, domain mutants, RNAi and EM in HL-60 cells

    PMID:18211905 PMID:18669870

    Open questions at the time
    • How CD63 modulates Src catalytic activity structurally unknown
    • Whether elastase targeting generalizes to other granule proteases untested
  7. 2013 High

    Genetic CD63 loss established a non-redundant requirement for FcεRI-triggered mast cell degranulation, refining earlier antibody-based observations to a defined Gab2-PI3K axis.

    Evidence CD63 knockout mast cells and mice with β-hexosaminidase/TNF-α release assays and passive cutaneous anaphylaxis, complementing earlier anti-CD63 Gab2-PI3K pathway studies

    PMID:15684326 PMID:23945142

    Open questions at the time
    • How CD63 selectively couples to the FcεRI but not PMA/ionomycin pathway unresolved
    • Direct molecular link between CD63 and Gab2 not shown
  8. 2017 High

    CRISPR knockout showing CD63 is required for exosomal LMP1 packaging established a causal role in selecting cargo into MVB-derived vesicles and in restraining intracellular oncogenic signaling.

    Evidence CRISPR/Cas9 knockout, nanoparticle tracking, exosome immunoisolation and signaling pathway dissection

    PMID:27974566 PMID:29212935

    Open questions at the time
    • Direct CD63-LMP1 contact not demonstrated
    • Generalizability of CD63-dependent cargo selection to endogenous proteins unclear
  9. 2021 High

    Distinguishing endosome- from plasma-membrane-derived vesicles and identifying an IRE-controlled, ferritin-loaded EV pathway refined how CD63's subcellular residence dictates vesicle origin and cargo.

    Evidence Live intracellular tracking, comparative proteomics and PM-stabilized mutants; IRE identification in CD63 5'UTR with iron-loading and NCOA4 EV analyses

    PMID:34265052 PMID:34282141

    Open questions at the time
    • Sorting signals routing CD63 to exosomes versus ectosomes incompletely defined
    • Mechanism by which NCOA4-bound ferritin reaches CD63+ EVs unresolved
  10. 2021 High

    Demonstrating CD63 sustains TGFβ receptor signaling to enforce HSC quiescence linked its receptor-scaffolding activity to a stem-cell maintenance function.

    Evidence CD63 knockout mice, HSC transplantation, TGFβ signaling assays and Co-IP with TGFβRI/II

    PMID:34363017

    Open questions at the time
    • Whether CD63 stabilizes receptors at the surface or in endosomes unresolved
    • Direct versus indirect CD63-TGFβ receptor binding not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CD63 selects specific cargo and partners for distinct destinations (exosome versus ectosome, degranulation versus surface signaling) and what structural features of its extracellular loop and adaptor-binding motifs determine these choices remains unresolved.
  • No unifying structural model of CD63-cargo-adaptor assembly
  • Determinants partitioning CD63 between competing trafficking fates undefined
  • Extent of functional redundancy with other tetraspanins across tissues unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 4 GO:0001618 virus receptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005768 endosome 6 GO:0005764 lysosome 4 GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 4 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1643685 Disease 5 R-HSA-5653656 Vesicle-mediated transport 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-9609507 Protein localization 3
Partners
ITGA3ITGB1PDCD6IPRPTPASDCBPSLC22A2TGFBR1TIMP1
Complex memberships
CD63-RPTPα-c-Src complexCD63-integrin α3β1/α6β1-PI4K type II complexCD63-syntenin-1-ALIX complexTIMP-1-CD63-integrin β1 complex

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 CD63 is endocytosed via a clathrin-dependent pathway at the cell surface and is enriched on intraluminal vesicles of late endosomes/multivesicular bodies, from which it can be secreted as exosomes through fusion of endosomes with the plasma membrane. Evidence was also presented for a role of caveolae in CD63 endocytosis. Subcellular fractionation, live-cell imaging, electron microscopy, review of trafficking studies Experimental cell research High 18930046
2021 CD63 traffics from the endoplasmic reticulum to late endosomes where it resides, distinct from CD9 which localizes predominantly at the plasma membrane. A PM-stabilized mutant CD63 is more abundantly released in EVs than wild-type CD63, indicating that in HeLa cells ectosomes (PM-derived) are more prominent than exosomes (endosome-derived). Proteomic comparison identified LAMP1 as likely specific to exosomes and BSG/SLC3A2 as likely ectosome-specific. Live intracellular tracking, comparative proteomics, pH neutralization experiments, mutant CD63 stabilized at plasma membrane Nature communications High 34282141
2006 CD63 was identified as a direct cell-surface binding partner for TIMP-1 by yeast two-hybrid screening, confirmed by co-immunoprecipitation. CD63 forms a complex with TIMP-1 and integrin β1 on the cell surface. shRNA-mediated CD63 knockdown reduced TIMP-1 binding, TIMP-1/integrin β1 co-localization, integrin β1 activation, cell survival signaling, and apoptosis inhibition in 3D matrigel cultures. Yeast two-hybrid, co-immunoprecipitation, confocal microscopy, shRNA knockdown, 3D matrigel assay The EMBO journal High 16917503
2000 In human endothelial cells, CD63 distributes predominantly to internal membranes of multivesicular-multilamellar late endosomes containing lysobisphosphatidic acid, and is also present in Weibel-Palade bodies. CD63 cycles between late endosomes and Weibel-Palade bodies; treatment with U18666A (mimicking Niemann-Pick C) blocked this cycling and caused accumulation in late endosomes. Immunofluorescence, subcellular fractionation, drug treatment (U18666A), electron microscopy Molecular biology of the cell High 10793155
1997 CD63 and CD81 form specific complexes with integrin α3β1 that also contain a phosphatidylinositol 4-kinase (PI 4-K, consistent with type II, ~55 kDa). PI 4-K co-purified with CD63 independently of α3β1. These complexes localize to focal complexes at the cell periphery rather than focal adhesions, providing a signaling pathway distinct from conventional integrin/FAK signaling. Enzymatic assays (PI 4-K activity), co-immunoprecipitation, immunochemical assays, subcellular localization The Journal of biological chemistry High 9006891
1995 CD63 specifically associates with VLA-3 (α3β1) and VLA-6 (α6β1) integrins but not α2β1 or α5β1, as demonstrated by co-immunoprecipitation from Brij 96 lysates. The cytoplasmic domain of α3 was neither required nor sufficient for CD63 association, indicating interaction elsewhere in the complex. Monoclonal antibody screening, co-immunoprecipitation, immunofluorescence colocalization, large-scale purification and N-terminal sequencing The Journal of biological chemistry High 7629079
1993 CD63 (granulophysin) is a component of platelet dense granules and lysosomes; it is deficient in Hermansky-Pudlak syndrome platelets. Anti-CD63 antibodies cross-block anti-granulophysin antibodies, and N-terminal sequencing confirmed identity between granulophysin, CD63, ME491, and pltgp40. FACS revealed biphasic CD63 surface expression after thrombin stimulation in control but not HPS platelets, indicating exocytosis-coupled surface exposure. Immunofluorescence, immunoblotting, FACS, ELISA, N-terminal amino acid sequencing, sequential immunodepletion The Journal of clinical investigation High 7682577
1993 CD63 is a component of Weibel-Palade bodies in human endothelial cells, co-localizing with von Willebrand factor and P-selectin. CD63 biosynthesis and glycosylation pattern in endothelial cells were confirmed by Western blotting of subcellular fractions enriched in Weibel-Palade bodies. Monoclonal antibody generation, immunofluorescence, Western blotting of subcellular fractions, immunopurification Blood High 8353283
2003 CD63 enhances internalization of the H,K-ATPase β-subunit. CD63 co-localizes with and co-precipitates the β-subunit in parietal cells and COS-7 cells. Co-expression with CD63 redistributes the β-subunit from the cell surface to CD63+ intracellular compartments via enhanced endocytosis. This depends on CD63's ability to interact with adaptor protein complexes AP-2 and AP-3. Co-immunoprecipitation, immunofluorescence, biochemical endocytosis assays, CD63 mutant analysis, COS-7 overexpression Proceedings of the National Academy of Sciences of the United States of America High 14660791
2017 CD63 is required for efficient exosomal packaging of EBV oncoprotein LMP1 into MVB-derived vesicles. CRISPR/Cas9 knockout of CD63 reduced LMP1-induced particle secretion and severely impaired LMP1 packaging. CD63 KO was associated with disrupted perinuclear localization of LMP1 and increased noncanonical NF-κB and MAPK/ERK activation, while LMP1 trafficking to lipid rafts and canonical NF-κB/PI3K-Akt pathways were unaffected. CRISPR/Cas9 knockout, nanoparticle tracking analysis, gradient purification, immunoisolation of CD63+ exosomes, western blotting Journal of virology High 27974566
2018 CD63 regulates the intersection of endosomal and autophagic pathways. CD63-dependent vesicle protein secretion opposes LMP1-mediated intracellular signaling including mTOR-associated proteins. CD63 KO resulted in mTOR activation coincident with development of serum-dependent autophagic vacuoles that are acidified in the presence of high LMP1 levels. Disruption of autolysosomal processes increased LMP1 secretion and dampened signal transduction. CD63 knockout cells, mTOR pathway analysis, autophagy assays, acidification measurements, vesicle secretion quantification Journal of virology Medium 29212935
2021 CD63 expression is regulated by the IRE-IRP system via a canonical IRE in the 5' UTR of CD63 mRNA. Iron loading increases CD63 expression and secretion of CD63+ EVs containing ferritin-H and ferritin-L. Under iron loading, intracellular ferritin is transferred via NCOA4 to CD63+ EVs for secretion. IRE identification in CD63 5'UTR, iron loading experiments, EV isolation, western blotting for ferritin subunits, NCOA4 functional studies Blood High 34265052
2014 RPN2 (ribophorin II, part of N-oligosaccharyltransferase complex) mediates N-glycosylation of CD63. RPN2 knockdown reduces CD63 glycosylation and deregulates its localization. CD63 silencing displaced MDR1 from the cell surface, reducing chemoresistance and invasion ability of breast cancer cells. RPN2 knockdown, glycosylation analysis, subcellular localization studies, invasion assays, MDR1 localization by immunofluorescence Molecular cancer Medium 24884960
2016 CD63 forms a complex with syntenin-1 and ALIX in early CD63-positive endosomes after HPV internalization. This CD63-syntenin-1-ALIX complex controls delivery of internalised HPV particles to multivesicular endosomes; depletion of CD63 or syntenin-1 markedly suppressed infectivity of HPV types 16, 18 and 31 and impaired capsid disassembly. Co-immunoprecipitation, electron microscopy, immunofluorescence, shRNA depletion, infectivity assays Scientific reports High 27578500
2017 A genome-wide haploid genetic screen identified CD63 as a host factor required for Lujo virus (LUJV) GP-mediated infection. CD63 stimulates pH-activated LUJV GP-mediated membrane fusion (distinct from its role as a cell-surface receptor). Genome-wide haploid genetic screen, recombinant VSV-LUJV infection assay, functional complementation Cell host & microbe High 29120745
1996 CD63 associates with CD11/CD18 (Mac-1) and with tyrosine kinase activity (predominantly Src family kinases Lyn and Hck) in neutrophils. CD63 antibody cross-linking triggers a transient activation signal requiring extracellular calcium, upregulates CD11/CD18, and enhances neutrophil adhesion. Co-immunoprecipitation, protein kinase activity assays, flow cytometry, adhesion assays, calcium depletion experiments Journal of immunology Medium 8871662
2004 CD63 in immature dendritic cells is internalized via the endocytic pathway through early endosomes, lysosomes, and MHC class II-enriched compartments (MIICs) within one hour of stimulation. CD63 is internalized during Saccharomyces cerevisiae phagocytosis and associates with dectin-1. CD63 was found to associate with integrins CD11b and CD18 by immunoprecipitation. CD63 antibodies enhanced DC migration and decreased surface expression of CD29, CD11b, CD18, and α5 integrins. Confocal immunofluorescence, flow cytometry, immunoprecipitation, phagocytosis assays, migration assays Blood Medium 15130945
2008 CD63 is involved in granule targeting of neutrophil elastase (NE). CD63 associates with proNE upon co-expression, requiring intact large extracellular loop of CD63. CD63 depletion in HL-60 cells reduced NE processing (proNE to mature NE), reduced constitutive secretion, and caused lack of morphologically normal granules with absence of proNE/NE. CD63 thus participates in ER/Golgi export, cellular retention, and granule targeting of proNE. Co-immunoprecipitation (COS cells), RNAi in HL-60 cells, CD63 mutant expression, electron microscopy, secretion assays Blood High 18669870
2013 CD63 is required for efficient FcεRI-mediated mast cell degranulation. CD63-deficient mast cells showed significant decrease in FcεRI-mediated β-hexosaminidase and TNF-α release, but normal PMA/ionomycin-induced degranulation, IL-6 secretion, and leukotriene C4 production. CD63-deficient mice showed attenuated cutaneous anaphylactic reactions upon local mast cell reconstitution. No ultrastructural differences in granule morphology or FcεRI-induced global tyrosine phosphorylation/Akt phosphorylation were observed. CD63 knockout mouse model, bone marrow-derived mast cell development, β-hexosaminidase release assay, passive cutaneous anaphylaxis, Kit(w/w-v) reconstitution Journal of immunology High 23945142
2005 Anti-CD63 antibodies inhibit FcεRI-mediated mast cell degranulation but not leukotriene synthesis. This inhibition correlates with CD63-mediated inhibition of mast cell adhesion to fibronectin and vitronectin. Anti-CD63 impairs the Gab2-PI3K pathway essential for both degranulation and adhesion, without affecting global tyrosine phosphorylation or calcium mobilization. Anti-CD63 also inhibited FcεRI-mediated allergic reactions in vivo. Monoclonal antibody functional assays, adhesion assays, PI3K pathway analysis, calcium mobilization, in vivo allergy model The Journal of experimental medicine High 15684326
2005 Upon platelet activation and exocytosis, CD63 relocates from dense granule/lysosome membranes to the plasma membrane where it associates with αIIbβ3-CD9 complex and the actin cytoskeleton in an αIIbβ3-dependent manner. Anti-CD63 antibody (D545) inhibited platelet spreading, F-actin reorganization, vinculin redistribution, tyrosine phosphorylation, and FAK phosphorylation on immobilized fibrinogen. CD63 co-immunoprecipitated with a PI 4-kinase type II activity regardless of activation state. Immunofluorescence, confocal imaging, co-immunoprecipitation, lipid kinase assays, flow cytometry Thrombosis and haemostasis Medium 15711748
2008 CD63 deficiency in mice results in altered water balance: increased urinary flow, water intake, reduced urine osmolality, and abnormal intracellular lamellar inclusions in principal cells of the collecting duct. Despite CD63 abundance in late endosomes/lysosomes, loss of CD63 does not cause obvious endosomal/lysosomal abnormalities, suggesting functional compensation by other tetraspanins in most tissues. CD63 knockout mouse generation and analysis, histology, electron microscopy, water balance measurements, immune cell profiling Molecular and cellular biology High 19075008
2008 CD63 associates with receptor-linked tyrosine phosphatase alpha (RPTPα) and c-Src in renal cortex and transfected 293T cells. CD63 expression stimulates c-Src activity (increased pY416, decreased pY527). The CD63-RPTPα-c-Src complex enhances c-Src-induced inhibition of ROMK1 potassium channels and increases ROMK1 tyrosine phosphorylation. Co-immunoprecipitation (native tissue and transfected cells), two-electrode voltage clamp in Xenopus oocytes, phosphorylation analysis, herbimycin A inhibition The Journal of biological chemistry High 18211905
2016 CD63 interacts with human organic cation transporter 2 (hOCT2) as demonstrated by split-ubiquitin yeast 2-hybrid, pull-down, TIRF microscopy, FRET, and biotinylation assays. CD63 overexpression affects hOCT2 localization in HEK293 cells, and CD63-KO mice show impaired insertion of the mouse OCT2 ortholog into the proper basolateral membrane domain. CD63 and hOCT2 co-localize with Rab4, implicating CD63 in recycling from sorting endosomes to the basolateral membrane in polarized epithelia. Split-ubiquitin yeast 2-hybrid, pull-down, TIRF microscopy, FRET, biotinylation assay, CD63 KO mouse analysis, MDCK polarized cell studies FASEB journal High 28031320
2006 CD63 recruitment to Cryptococcus neoformans-containing phagosomes (but not polystyrene bead phagosomes) requires phagosomal acidification and occurs independently of MHC class II and LAMP-1. This selective recruitment was demonstrated by live-cell imaging with mRFP-tagged CD63 in primary bone marrow-derived macrophages. Live-cell imaging with fluorescent-tagged CD63, acidification inhibitors, MyD88-deficient macrophages, primary bone marrow-derived cultures Proceedings of the National Academy of Sciences of the United States of America High 17043215
2011 CD63 knockdown in EBV-transformed B cells (LCL) increased CD4+ T cell recognition of EBV antigens. This was not due to enhanced antigen processing or changes in MHC II expression. Exosome production significantly increased following CD63 knockdown, suggesting that CD63 negatively regulates exosome secretion and thereby MHC II-dependent T cell stimulation. shRNA knockdown, CD4+ T cell activation assays, exosome purification and quantification, MHC II expression analysis European journal of immunology Medium 21660937
2010 TIMP-1 signaling via CD63 and integrin β1 mediates anoikis resistance in melanoma cells through PI3-K signaling independently of Akt phosphorylation. Differential association of the TIMP1-CD63-β1-integrin complex was observed along melanoma progression steps, demonstrated by co-immunoprecipitation. Co-immunoprecipitation, flow cytometry, PI3-K inhibitors (Wortmannin, LY294002), anchorage impediment model Molecular cancer Medium 23522389
2015 TIMP-1 induces neutrophilia and granulopoiesis through CD63 signaling. The CD63-binding domain of TIMP-1 (distinct from its protease-inhibitory domain) was necessary and sufficient to augment granulopoiesis. Ablation of CD63 abolished both TIMP-1-induced neutrophilia and enhanced granulopoiesis in the bone marrow. TIMP-1 domain variants, CD63 knockout mice, BrdU pulse-labeling, bone marrow progenitor analysis, gene expression profiling Haematologica High 26001794
2014 TIMP-1 binding to CD63 activates β1 integrin-mediated signaling through Akt and FAK phosphorylation, enhancing focal adhesion formation, cytoskeletal reorganization, and migration of human neural stem cells. shRNA ablation of CD63 attenuated TIMP-1-induced migration and spreading; blocking β1 integrin or PI3K also blocked migration. shRNA knockdown, microarray/proteomics, migration/adhesion assays, Akt/FAK phosphorylation analysis, antibody blocking The Biochemical journal Medium 24635319
2019 TIMP-1/CD63/ITGB1/FAK signaling axis drives hypermotility in Toxoplasma gondii-infected dendritic cells. shRNA silencing of TIMP-1, CD63, or ITGB1 inhibited DC hypermotility; FAK inhibition (and inhibitors of SRC and PI3K) also abrogated hypermotility. This signaling cascade is hijacked by T. gondii for systemic dissemination. shRNA knockdown, antibody blockade, migration assays, kinase inhibitors Journal of cell science Medium 30635444
2008 CD63 is required for HIV-1 replication in macrophages and cell lines. CD63-specific siRNA inhibited HIV replication in macrophages (>90% knockdown) and in U373-MAGI cells, suggesting roles in both early infection events and later post-integration replication steps. siRNA knockdown, HIV replication assay, macrophage and cell line models Virology Medium 18682304
2014 CD63 plays a dual role in HIV-1 replication: supports Env-mediated (CD4/CCR5-dependent) entry or fusion (VSV/MLV pseudotype entry unaffected by CD63 silencing) and a post-integration step. CD63 co-localizes and co-immunoprecipitates with CD4 in macrophages, and CD63 silencing reduced expression of early HIV protein Tat and interaction with Gag, as well as late protein p24. siRNA knockdown, pseudotyped virus infectivity assays, co-immunoprecipitation, confocal microscopy, primary CD4+ T cells and dendritic cells Virology journal Medium 24507450
2010 Ameloblastin binds CD63 and promotes CD63 binding to integrin β1. The CD63-integrin β1 interaction induces Src kinase inactivation via CD63 binding to Src. This mechanism promotes osteogenic differentiation, and anti-CD63 antibody or constitutively active Src reversed these effects. Co-immunoprecipitation, anti-CD63 antibody blockade, constitutively active Src overexpression, osteogenic differentiation assays Molecular and cellular biology Medium 21149578
2011 CD63 mediates downregulation of CXCR4 in activated B cells by recruiting CXCR4 to late endosomes. BCL6 was found on the chromatin of the CD63 gene in resting B cells (functioning as a transcriptional repressor). siRNA knockdown of CD63 mRNA in Bcl6-deficient B cells upregulated CXCR4 expression, confirming CD63-dependent CXCR4 endosomal recruitment. siRNA knockdown, flow cytometry, chromatin immunoprecipitation (Bcl6 on CD63 gene), Bcl6 inhibitor experiments Journal of immunology Medium 21270405
2021 CD63 is required to sustain TGFβ signaling in hematopoietic stem cells through its interaction with TGFβ receptors I and II. CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity. CD63-high HSCs are more quiescent with greater self-renewal and myeloid differentiation than CD63-low/negative HSCs. CD63 knockout mice, HSC transplantation, TGFβ signaling assays, co-immunoprecipitation (CD63 with TGFβRI/II), irradiation and 5-FU stress models Cell death and differentiation High 34363017
2014 CD63 knockdown induces epithelial-like phenotype in melanoma cells with increased E-cadherin, downregulation of N-cadherin and Snail, and reduced β-catenin protein. β-catenin inhibitors mimicked this phenotype. CD63 overexpression reduces motility, invasiveness, protease activities, and tumor growth. CD63 regulates cell plasticity via PI3K/AKT-GSK3β-β-catenin pathway. siRNA knockdown, stable overexpression, β-catenin inhibitors, PI3K/AKT and GSK3β inhibitors, invasion assays, in vivo tumor xenograft International journal of cancer Medium 25354204
1992 The CD63 gene (ME491) consists of eight exons spanning 4 kb. The 5'-flanking region lacks a TATA box but contains GC-rich sequences with SP1 and ETF binding sites, and a functional AP-1 binding site that positively regulates gene expression, as demonstrated by deletion mutant analysis. Genomic cloning, primer extension, reporter gene assays, 5'-deletion mutant analysis Biochemical and biophysical research communications Medium 1599482
2007 Amelogenin interacts with CD63 via specific binding regions: the amelogenin PLSPILPELPLEAW region binds CD63 residues 165-205 (within the large extracellular loop EC2). This interaction mediates rapid endocytic uptake of amelogenin into CD63/LAMP1-positive vesicles in cells. In vitro binding assays, deletion/mutation mapping of binding regions, cell uptake experiments, confocal microscopy The Biochemical journal Medium 17708745
2020 CD63 induces STAT3 activation to maintain the phenotype and function of CD63+ cancer-associated fibroblasts (CAFs). CD63+ CAFs secrete exosomes enriched in miR-22 (packaged via SFRS1) that confer tamoxifen resistance to breast cancer cells. Single-cell RNA sequencing, exosome isolation, SFRS1 functional studies, CD63-neutralizing antibody, STAT3 activation assays, xenograft models Advanced science Medium 33173749
2002 CD63 mobilization from crystalloid granule membranes to the cell periphery and plasma membrane is associated with eosinophil mediator release (β-hexosaminidase, eosinophil peroxidase, RANTES). IFN-γ-induced CD63 mobilization preceded RANTES release, consistent with piecemeal degranulation. Both CD63 mobilization and mediator release were inhibited by dexamethasone and the tyrosine kinase inhibitor genistein. Confocal immunofluorescence, flow cytometry, secretion assays, pharmacological inhibition Blood Medium 12010805
2020 CD63 negatively regulates hepatocellular carcinoma by suppressing IL-6/IL-27-induced STAT3 activation. CD63 overexpression inhibited HCC cell proliferation and migration, while knockdown promoted these; STAT3 blockade impaired the promotive effects of CD63 knockdown. Overexpression, knockdown, RNA-sequencing, dual-luciferase reporter, STAT3 inhibition, xenograft model Journal of cellular and molecular medicine Medium 33277798

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9. Nature communications 693 34282141
2008 Trafficking and function of the tetraspanin CD63. Experimental cell research 610 18930046
2006 Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. The EMBO journal 278 16917503
2000 The tetraspanin CD63/lamp3 cycles between endocytic and secretory compartments in human endothelial cells. Molecular biology of the cell 258 10793155
1997 A novel link between integrins, transmembrane-4 superfamily proteins (CD63 and CD81), and phosphatidylinositol 4-kinase. The Journal of biological chemistry 222 9006891
2006 P-selectin- and CD63-exposing platelet microparticles reflect platelet activation in peripheral arterial disease and myocardial infarction. Clinical chemistry 174 16439610
2017 CD63 Regulates Epstein-Barr Virus LMP1 Exosomal Packaging, Enhancement of Vesicle Production, and Noncanonical NF-κB Signaling. Journal of virology 173 27974566
1995 Specific association of CD63 with the VLA-3 and VLA-6 integrins. The Journal of biological chemistry 166 7629079
2010 Expression of CD203c and CD63 in human basophils: relationship to differential regulation of piecemeal and anaphylactic degranulation processes. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 161 20633031
2001 Cell-autonomous expression of barley Mla1 confers race-specific resistance to the powdery mildew fungus via a Rar1-independent signaling pathway. The Plant cell 141 11226189
2020 CD63+ Cancer-Associated Fibroblasts Confer Tamoxifen Resistance to Breast Cancer Cells through Exosomal miR-22. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 135 33173749
1993 The protein CD63 is in platelet dense granules, is deficient in a patient with Hermansky-Pudlak syndrome, and appears identical to granulophysin. The Journal of clinical investigation 131 7682577
1993 CD63 is a component of Weibel-Palade bodies of human endothelial cells. Blood 131 8353283
2021 CD63 is regulated by iron via the IRE-IRP system and is important for ferritin secretion by extracellular vesicles. Blood 114 34265052
2018 Tetraspanin CD63 Bridges Autophagic and Endosomal Processes To Regulate Exosomal Secretion and Intracellular Signaling of Epstein-Barr Virus LMP1. Journal of virology 114 29212935
2003 STRO-1, HOP-26 (CD63), CD49a and SB-10 (CD166) as markers of primitive human marrow stromal cells and their more differentiated progeny: a comparative investigation in vitro. Cell and tissue research 113 12883998
2017 NRP2 and CD63 Are Host Factors for Lujo Virus Cell Entry. Cell host & microbe 110 29120745
2013 Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-K signaling pathway independently of Akt phosphorylation. Molecular cancer 109 23522389
2004 CD63 tetraspanin slows down cell migration and translocates to the endosomal-lysosomal-MIICs route after extracellular stimuli in human immature dendritic cells. Blood 109 15130945
2023 Differential proteomics argues against a general role for CD9, CD81 or CD63 in the sorting of proteins into extracellular vesicles. Journal of extracellular vesicles 105 37525398
2014 RPN2-mediated glycosylation of tetraspanin CD63 regulates breast cancer cell malignancy. Molecular cancer 104 24884960
2016 Efficient Payload Delivery by a Bispecific Antibody-Drug Conjugate Targeting HER2 and CD63. Molecular cancer therapeutics 103 27559142
1999 Human basophil activation measured by CD63 expression and LTC4 release in IgE-mediated food allergy. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 102 9988204
2003 The tetraspanin CD63 enhances the internalization of the H,K-ATPase beta-subunit. Proceedings of the National Academy of Sciences of the United States of America 100 14660791
1996 CD63 associates with tyrosine kinase activity and CD11/CD18, and transmits an activation signal in neutrophils. Journal of immunology (Baltimore, Md. : 1950) 94 8871662
1995 Suppression of human melanoma cell growth and metastasis by the melanoma-associated antigen CD63 (ME491). International journal of cancer 92 7665237
2020 Development of a CD63 Aptamer for Efficient Cancer Immunochemistry and Immunoaffinity-Based Exosome Isolation. Molecules (Basel, Switzerland) 86 33261145
2017 Exosomal Markers (CD63 and CD9) Expression Pattern Using Immunohistochemistry in Resected Malignant and Nonmalignant Pancreatic Specimens. Pancreas 84 28609367
2008 Deficiency of the tetraspanin CD63 associated with kidney pathology but normal lysosomal function. Molecular and cellular biology 84 19075008
1997 Regulation of tumor cell motility and migration by CD63 in a human melanoma cell line. Journal of immunology (Baltimore, Md. : 1950) 81 9120293
2016 The CD63-Syntenin-1 Complex Controls Post-Endocytic Trafficking of Oncogenic Human Papillomaviruses. Scientific reports 79 27578500
2002 Translocation of the tetraspanin CD63 in association with human eosinophil mediator release. Blood 78 12010805
1991 CD63/Pltgp40: a platelet activation antigen identical to the stage-specific, melanoma-associated antigen ME491. Blood 77 2070066
2020 Spatial and temporal tracking of cardiac exosomes in mouse using a nano-luciferase-CD63 fusion protein. Communications biology 74 32157172
1991 A cell surface glycoprotein of rat basophilic leukemia cells close to the high affinity IgE receptor (Fc epsilon RI). Similarity to human melanoma differentiation antigen ME491. The Journal of biological chemistry 74 1703158
2004 CD63 as an activation-linked T cell costimulatory element. Journal of immunology (Baltimore, Md. : 1950) 73 15528334
2024 VEGF-FGF Signaling Activates Quiescent CD63+ Liver Stem Cells to Proliferate and Differentiate. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 72 38881531
2003 CD63 expression on basophils as a tool for the diagnosis of pollen-associated food allergy: sensitivity and specificity. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 71 12752589
2021 Characteristics of TIMP1, CD63, and β1-Integrin and the Functional Impact of Their Interaction in Cancer. International journal of molecular sciences 70 34502227
2011 The role of tetraspanin CD63 in antigen presentation via MHC class II. European journal of immunology 70 21660937
2007 Cellular uptake of amelogenin, and its localization to CD63, and Lamp1-positive vesicles. Cellular and molecular life sciences : CMLS 60 17187173
2006 Comparison of basophil activation tests using CD63 or CD203c expression in patients with insect venom allergy. Allergy 59 16918511
2016 Altered expression of CD63 and exosomes in scleroderma dermal fibroblasts. Journal of dermatological science 58 27443953
2017 CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+ T Cell Responses. Journal of immunology (Baltimore, Md. : 1950) 57 28507029
2006 Recruitment of CD63 to Cryptococcus neoformans phagosomes requires acidification. Proceedings of the National Academy of Sciences of the United States of America 55 17043215
2023 Lack of involvement of CD63 and CD9 tetraspanins in the extracellular vesicle content delivery process. Communications biology 53 37198427
2019 A cell-based assay for CD63-containing extracellular vesicles. PloS one 53 31339911
2013 The tetraspanin CD63 is required for efficient IgE-mediated mast cell degranulation and anaphylaxis. Journal of immunology (Baltimore, Md. : 1950) 53 23945142
2005 Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo. The Journal of experimental medicine 51 15684326
2005 CD63 modulates spreading and tyrosine phosphorylation of platelets on immobilized fibrinogen. Thrombosis and haemostasis 49 15711748
2015 TIMP-1 signaling via CD63 triggers granulopoiesis and neutrophilia in mice. Haematologica 47 26001794
2008 The tetraspanin CD63 is involved in granule targeting of neutrophil elastase. Blood 46 18669870
1992 The rat mast cell antigen AD1 (homologue to human CD63 or melanoma antigen ME491) is expressed in other cells in culture. Journal of immunology (Baltimore, Md. : 1950) 46 1634775
2014 TIMP-1 modulates chemotaxis of human neural stem cells through CD63 and integrin signalling. The Biochemical journal 44 24635319
2013 Characterization of tetraspanins CD9, CD53, CD63, and CD81 in monocytes and macrophages in HIV-1 infection. Journal of leukocyte biology 44 23570947
2018 Clinico-pathological significance of exosome marker CD63 expression on cancer cells and stromal cells in gastric cancer. PloS one 42 30222750
2002 The protein tyrosine kinase Hck is located on lysosomal vesicles that are physically and functionally distinct from CD63-positive lysosomes in human macrophages. Journal of cell science 42 11801726
2010 Ameloblastin regulates osteogenic differentiation by inhibiting Src kinase via cross talk between integrin beta1 and CD63. Molecular and cellular biology 40 21149578
2003 Aspirin inhibits surface glycoprotein IIb/IIIa, P-selectin, CD63, and CD107a receptor expression on human platelets. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis 40 12695747
2018 CD63, MHC class 1, and CD47 identify subsets of extracellular vesicles containing distinct populations of noncoding RNAs. Scientific reports 38 29416092
2002 Complementary DNA arrays identify CD63 tetraspanin and alpha3 integrin chain as differentially expressed in low and high metastatic human colon carcinoma cells. Laboratory investigation; a journal of technical methods and pathology 38 12480921
2022 Aberrant TIMP-1 overexpression in tumor-associated fibroblasts drives tumor progression through CD63 in lung adenocarcinoma. Matrix biology : journal of the International Society for Matrix Biology 37 35787446
2014 CD63 tetraspanin is a negative driver of epithelial-to-mesenchymal transition in human melanoma cells. The Journal of investigative dermatology 36 24940653
2006 In vitro basophil activation using CD63 expression in patients with bee and wasp venom allergy. Journal of investigational allergology & clinical immunology 36 16599242
2019 TIMP-1 promotes hypermigration of Toxoplasma-infected primary dendritic cells via CD63-ITGB1-FAK signaling. Journal of cell science 35 30635444
2000 Increased expression of the tetraspanins CD53 and CD63 on apoptotic human neutrophils. Journal of leukocyte biology 35 10733097
2014 The dual role of tetraspanin CD63 in HIV-1 replication. Virology journal 34 24507450
2008 A critical role for CD63 in HIV replication and infection of macrophages and cell lines. Virology 34 18682304
2003 Molecular cloning of the cell surface antigen identified by the osteoprogenitor-specific monoclonal antibody, HOP-26. Journal of cellular biochemistry 34 12682908
1993 Decreased expression of human melanoma-associated antigen ME491 along the progression of melanoma pre-canceroses to invasive and metastatic melanomas. Melanoma research 34 8219756
1992 Genomic structure of the ME491/CD63 antigen gene and functional analysis of the 5'-flanking regulatory sequences. Biochemical and biophysical research communications 34 1599482
2018 Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63. Cancer medicine 33 30367559
2007 Determination of protein regions responsible for interactions of amelogenin with CD63 and LAMP1. The Biochemical journal 33 17708745
1991 Biochemical and immunohistochemical characteristics of CD62 and CD63 monoclonal antibodies. Expression of GMP-140 and LIMP-CD63 (CD63 antigen) in human lymphoid tissues. Virchows Archiv. B, Cell pathology including molecular pathology 33 1723556
2022 CD63-positive extracellular vesicles are potential diagnostic biomarkers of pancreatic ductal adenocarcinoma. BMC gastroenterology 32 35350978
2012 Marked differences in the signaling requirements for expression of CD203c and CD11b versus CD63 expression and histamine release in human basophils. International archives of allergy and immunology 32 22722613
2021 Resistance Training Diminishes the Expression of Exosome CD63 Protein without Modification of Plasma miR-146a-5p and cfDNA in the Elderly. Nutrients 31 33669497
2021 CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFβ signaling in mice. Cell death and differentiation 31 34363017
2004 CD82, and CD63 in thyroid cancer. International journal of molecular medicine 31 15375577
2018 Co-expression of TIMP-1 and its cell surface binding partner CD63 in glioblastomas. BMC cancer 30 29523123
2014 Tetraspanin CD63 acts as a pro-metastatic factor via β-catenin stabilization. International journal of cancer 30 25354204
1993 Isolation of a novel cDNA clone showing marked similarity to ME491/CD63 superfamily. Immunogenetics 29 8420826
2023 Parallel SPR and QCM-D Quantitative Analysis of CD9, CD63, and CD81 Tetraspanins: A Simple and Sensitive Way to Determine the Concentration of Extracellular Vesicles Isolated from Human Lung Cancer Cells. Analytical chemistry 27 37307147
2011 CXCR4 expression on activated B cells is downregulated by CD63 and IL-21. Journal of immunology (Baltimore, Md. : 1950) 26 21270405
2004 Peptide YY and neuropeptide Y induce villin expression, reduce adhesion, and enhance migration in small intestinal cells through the regulation of CD63, matrix metalloproteinase-3, and Cdc42 activity. The Journal of biological chemistry 26 15504731
2024 CD63+ cancer-associated fibroblasts confer CDK4/6 inhibitor resistance to breast cancer cells by exosomal miR-20. Cancer letters 25 38403110
2008 Simultaneous flow cytometric detection of basophil activation marker CD63 and intracellular phosphorylated p38 mitogen-activated protein kinase in birch pollen allergy. Cytometry. Part B, Clinical cytometry 25 18727065
2016 Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 28031320
2021 Exosomal CD63 in critically ill patients with sepsis. Scientific reports 21 34645935
2020 CD63 negatively regulates hepatocellular carcinoma development through suppression of inflammatory cytokine-induced STAT3 activation. Journal of cellular and molecular medicine 21 33277798
2015 Tetraspanin CD63 is a regulator of HIV-1 replication. International journal of clinical and experimental pathology 21 25973004
2008 Expression of tetraspan protein CD63 activates protein-tyrosine kinase (PTK) and enhances the PTK-induced inhibition of ROMK channels. The Journal of biological chemistry 21 18211905
2024 Myeloid-Mas Signaling Modulates Pathogenic Crosstalk among MYC+CD63+ Endothelial Cells, MMP12+ Macrophages, and Monocytes in Acetaminophen-Induced Liver Injury. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20 38350725
2023 Revisiting the Role of CD63 as Pro-Tumorigenic or Anti-Tumorigenic Tetraspanin in Cancers and its Theragnostic Implications. Advanced biology 20 37142558
1995 Cell surface expression of lysosome-associated membrane protein-2 (lamp2) and CD63 as markers of in vivo platelet activation in malignancy. European journal of haematology 20 7672086
2022 A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells. Cancers 18 36291767
2020 Cellular Evidence of CD63-Enriched Exosomes and Multivesicular Bodies within the Seminiferous Tubule during the Spermatogenesis of Turtles. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada 18 31753050
2016 Basophil CD63 expression in chronic spontaneous urticaria: correlation with allergic sensitization, serum autoreactivity and basophil reactivity. Journal of the European Academy of Dermatology and Venereology : JEADV 17 27518369
2009 Stimulus-specific regulation of CD63 and CD203c membrane expression in human basophils by the flavonoid quercetin. International immunopharmacology 17 19887118
1994 Molecular cloning of the murine homologue of CD63/ME491 and detection of its strong expression in the kidney and activated macrophages. Biochimica et biophysica acta 17 8148377

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