Affinage

TNFRSF10B

Tumor necrosis factor receptor superfamily member 10B · UniProt O14763

Length
440 aa
Mass
47.9 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF10B (DR5/TRAIL-R2) is a death receptor that transduces extrinsic apoptotic signals upon binding its ligand TRAIL or upon ligand-independent clustering when ectodomain autoinhibition is relieved. TRAIL binds DR5 with the highest affinity among TRAIL receptors (KD ≤ 2 nM at 37°C), triggering transmembrane helix-mediated higher-order oligomerization that recruits FADD and caspase-8 into a death-inducing signaling complex (DISC), preferentially assembled within lipid rafts; DISC composition is tuned by FLIP(L) stoichiometry—which can either accelerate or inhibit caspase-8 activation—and by SCFSkp2-dependent ubiquitination of processed FLIP(L) (PMID:10770955, PMID:30827683, PMID:19432816, PMID:32009295, PMID:32313199). DR5 transcription is activated by p53 via an intronic response element, by CHOP via a promoter-binding site, and by dephosphorylated p73 following CDK4/6 inhibition, while cell-surface DR5 levels are maintained by YIPF2-mediated competition with RAB8 vesicle trafficking and reduced by HBV HBx-directed autophagic degradation (PMID:15110170, PMID:19037087, PMID:35149588, PMID:32303681, PMID:27740879). Beyond canonical apoptosis in cancer cells and during anoikis, DR5 mediates tissue-specific cell death in spermatogonial stem cells after irradiation and in neurons following cerebral ischemia, and participates in dual pro-apoptotic/pro-survival signaling platforms formed with DR4 and DcR2 that activate NF-κB and MAPK pathways (PMID:25358794, PMID:20359534, PMID:29048428, PMID:16980609).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2000 High

    Establishing the quantitative ligand-receptor interaction hierarchy resolved which TRAIL receptor dominates signaling under physiological conditions: DR5 binds TRAIL with the highest affinity (KD ≤ 2 nM at 37°C) among all five receptors.

    Evidence Isothermal titration calorimetry and competitive ELISA at multiple temperatures

    PMID:10770955

    Open questions at the time
    • Affinity measurements do not address how receptor density or co-receptor expression modulates effective signaling in vivo
  2. 2001 Medium

    The identification of loss-of-function DR5 missense mutations in gastric cancers established that DR5 acts as an independent tumor suppressor whose inactivation provides an alternative to p53 loss for apoptosis evasion.

    Evidence Mutational analysis of 43 gastric cancers with transfection-based functional assays of mutant DR5

    PMID:11677215

    Open questions at the time
    • Mutations characterized in a single cancer type
    • No structural explanation for loss of function
    • Not independently replicated in a second cohort
  3. 2004 Medium

    Mapping the minimal promoter and intronic p53-response element resolved how DR5 is transcriptionally regulated and linked p53 status to DR5 expression, while the finding that SRP is dispensable for DR5 (but not DR4) surface delivery revealed distinct ER-trafficking routes for these homologous receptors.

    Evidence Promoter deletion/reporter assays for p53 element; siRNA library screen with flow cytometry for SRP requirement

    PMID:15110170 PMID:15356269

    Open questions at the time
    • Sp1 and p53 contributions not dissected under endogenous chromatin context
    • Alternative DR5 ER-targeting mechanism not identified
  4. 2006 High

    Delineation of decoy receptor mechanisms showed that DcR2 inhibits DR5 signaling by co-assembling into the DISC and blocking caspase activation, while DcR1 sequesters TRAIL in lipid rafts—two mechanistically distinct inhibitory strategies acting on the same receptor.

    Evidence DISC co-immunoprecipitation, lipid raft fractionation, and functional apoptosis assays

    PMID:16980609

    Open questions at the time
    • Stoichiometric requirements for DcR2 inhibition within the DISC not quantified
    • In vivo relevance of lipid raft compartmentalization not tested
  5. 2008 Medium

    DR5 was established as the primary mediator of anoikis in colorectal carcinoma cells and its transcription was shown to be induced by CHOP via a promoter-binding site, expanding DR5 function beyond ligand-dependent killing to detachment-induced and ER-stress-linked apoptosis.

    Evidence Suspension culture with antagonistic DR5 antibody/siRNA blockade; CHOP-site promoter mutagenesis with rottlerin-induced DR5 upregulation

    PMID:18245494 PMID:19037087

    Open questions at the time
    • Anoikis role shown in one cell type
    • Relative contributions of CHOP vs. p53 to DR5 induction under stress not compared
  6. 2009 High

    DISC biochemical analysis in glioblastoma demonstrated that DR5 homotrimerization and DISC assembly occur preferentially in lipid rafts, while TRAIL-resistant cells redirect the DISC to non-raft fractions enriched in c-FLIP, RIP, and PED/PEA-15, thereby switching output from caspase-8 activation to NF-κB signaling.

    Evidence DISC immunoprecipitation with lipid raft fractionation and siRNA rescue of caspase-8 cleavage

    PMID:19432816

    Open questions at the time
    • Mechanism governing raft vs. non-raft DISC partitioning not identified
    • Whether raft localization is a cause or consequence of resistance not fully resolved
  7. 2010 Medium

    DR5 was implicated in neuronal delayed apoptosis after cerebral ischemia (where neurons express DR5 and surrounding glia express TRAIL), and pancreatic cancer studies revealed DR4-DR5 heterocomplexes and PKC-dependent control of DR5 signaling competence, broadening DR5 biology to non-cancer contexts and heteromeric receptor assemblies.

    Evidence Soluble DR5 blockade in mouse ischemia model; DR4/DR5 receptor-specific Fab and DISC IP in pancreatic cancer cells

    PMID:20354842 PMID:20359534

    Open questions at the time
    • Molecular basis of PKC-mediated DR5 suppression unknown
    • DR4-DR5 heterocomplex stoichiometry not determined
  8. 2012 Medium

    p53 was shown to selectively control DR5 (but not DR4) expression and agonist sensitivity in myeloma, and the small molecule bioymifi was found to directly cluster DR5 extracellularly to trigger apoptosis without TRAIL, demonstrating that forced receptor clustering suffices for signaling.

    Evidence p53 siRNA/nutlin-3a with DR5 agonistic antibody in myeloma; high-throughput screen identifying bioymifi with DR5 clustering microscopy

    PMID:22738917 PMID:23292651

    Open questions at the time
    • Bioymifi binding site on DR5 not structurally resolved
    • In vivo efficacy of bioymifi not demonstrated
  9. 2013 High

    The 2.1 Å crystal structure of HCMV UL141 bound to DR5 revealed how a viral immunoevasin blocks DR5 surface expression: a UL141 homodimer engages two DR5 monomers at a site overlapping the TRAIL-binding surface, defining a non-canonical DR5 interaction mode exploited for immune evasion.

    Evidence X-ray crystallography at 2.1 Å resolution with binding affinity assays

    PMID:23555243

    Open questions at the time
    • Whether UL141 also affects intracellular DR5 trafficking not addressed
    • Relevance to in vivo HCMV pathogenesis not tested
  10. 2014 Medium

    Genetic epistasis in mouse spermatogonial stem cells established that the p53–Trp53inp1–Tnfrsf10b axis mediates extrinsic-pathway apoptosis after irradiation in SSCs, whereas Bbc3/PUMA governs intrinsic apoptosis in committed spermatogonia, revealing cell-type-specific death receptor pathway usage.

    Evidence Spermatogonial transplantation in Trp53/Bbc3/Tnfrsf10b single and compound KO mice with irradiation

    PMID:25358794

    Open questions at the time
    • Mechanism by which Trp53inp1 upregulates Tnfrsf10b not molecularly defined
    • Whether human SSCs show the same pathway dependence is unknown
  11. 2016 High

    HBV HBx was identified as an autophagy receptor-like molecule that directly binds DR5, recruits it to LC3B-positive autophagosomes, and targets it for lysosomal degradation—the first demonstration of selective autophagic degradation of a death receptor as a viral immune evasion strategy.

    Evidence Co-IP, GST pulldown, LC3B tandem-fluorescence microscopy, autophagy inhibition, and patient liver tissue validation

    PMID:27740879

    Open questions at the time
    • Autophagy receptor motif in HBx mediating DR5 recognition not mapped
    • Whether other death receptors are co-degraded not tested
  12. 2017 Medium

    DR5 was shown to participate in composite hetero-oligomeric signaling platforms with DR4 and DcR2 that simultaneously engage pro-apoptotic (FADD/caspase-8) and pro-survival (NF-κB, PI3K/Akt, MAPK) outputs, establishing that a single DR5 receptor can propagate both death and survival signals.

    Evidence DISC immunoprecipitation with receptor-specific siRNA and dominant-negative constructs

    PMID:29048428

    Open questions at the time
    • Structural basis of heteromeric receptor assembly unknown
    • Quantitative determinants of death vs. survival output balance not defined
  13. 2019 High

    NMR structure of the DR5 transmembrane helix revealed a dimer-of-trimers higher-order assembly that is necessary and sufficient for signaling; the unliganded ectodomain autoinhibits this clustering, and proteolytic ectodomain removal fully activates signaling without ligand—resolving the long-standing question of how TRAIL binding is transduced across the membrane.

    Evidence NMR in bicelles, site-directed TMH mutagenesis, ectodomain proteolytic removal functional assays

    PMID:30827683

    Open questions at the time
    • Full-length receptor structure in native membrane not available
    • How ectodomain conformational change is transmitted to the TMH not resolved at atomic level
  14. 2020 High

    The DISC assembly mechanism was refined: FLIP(L) acts as a stoichiometry-dependent modulator—promoting initial caspase-8 activation at low ratios but inhibiting at high ratios—and the SCFSkp2 E3 ligase was found to ubiquitinate processed FLIP(L) at the DISC, providing a built-in mechanism for shifting the apoptotic threshold. Cell-surface DR5 levels were shown to be maintained by YIPF2 competing with RAB8-mediated internalization.

    Evidence DISC IP with FLIP stoichiometry manipulation; Cullin-1 NEDDylation inhibitor and Skp2 siRNA with ubiquitination assays; YIPF2/RAB8/DR5 Co-IP with flow cytometry

    PMID:32009295 PMID:32303681 PMID:32313199

    Open questions at the time
    • Structural basis of FLIP(L) stoichiometric switching unknown
    • Whether SCFSkp2 modulation of FLIP occurs at all death receptor DISCs not tested
    • YIPF2-RAB8 competition validated in one cell type
  15. 2022 High

    DR5 was placed at the nexus of senescence-associated vulnerability and CDK4/6-p73 transcriptional control: senescent cancer cells upregulate DR5 via NF-κB but are protected by cFLIP, while CDK4/6 inhibition dephosphorylates p73 to transcriptionally activate DR5 and promote immunogenic cell death—establishing DR5 as a pharmacologically exploitable node in therapy-induced senescence and combination immunotherapy.

    Evidence CRISPR screens in senescent cells with DR5 agonist/BRD2 inhibitor in xenografts; CDK4/6 kinase assay, p73 phospho-mutagenesis, DR5 KO in vivo

    PMID:35149588 PMID:36414711

    Open questions at the time
    • Whether p73-mediated DR5 induction operates in non-cancer tissues unknown
    • Bystander killing mechanism via secreted cytokines not fully characterized
  16. 2023 High

    KIM1 was identified as a novel non-TRAIL ligand that binds the DR5 ectodomain, promotes DR5 multimerization, and activates caspase-dependent renal tubular apoptosis during acute kidney injury—extending DR5 function to a non-canonical ligand context in non-cancer tissue.

    Evidence Renal tubule-specific Kim1 KO mouse, Co-IP of KIM1-DR5, YY1 ChIP, blocking peptides in cisplatin and ischemia-reperfusion AKI models

    PMID:37460623

    Open questions at the time
    • Structural basis of KIM1-DR5 interaction not determined
    • Whether KIM1-DR5 interaction occurs in tissues other than kidney not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of DR5 in native membranes, the precise conformational mechanism by which ectodomain engagement releases TMH autoinhibition, the quantitative rules governing death-vs-survival signaling output from heteromeric DR4/DR5/DcR2 platforms, and whether non-canonical ligands such as KIM1 engage the same or distinct multimerization geometry as TRAIL.
  • No full-length DR5 structure in native membrane
  • Ectodomain-to-TMH allosteric mechanism unresolved at atomic level
  • Heteromeric receptor stoichiometry and signaling rules not quantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 6
Localization
GO:0005886 plasma membrane 5 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-5357801 Programmed Cell Death 6 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-9612973 Autophagy 1
Partners
CASP8CFLARFADDHAVCR1RAB8TNFRSF10DTNFSF10YIPF2
Complex memberships
DISC (death-inducing signaling complex)DR4-DR5-DcR2 hetero-oligomeric signaling platform

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 DcR2 (TRAIL-R4) is co-recruited with DR5 into the DISC upon TRAIL stimulation, where it inhibits initiator caspase activation; DcR2 also prevents DR4 recruitment within the DR5 DISC. In contrast, DcR1 inhibits DR5-mediated apoptosis by titrating TRAIL within lipid rafts rather than joining the DISC. Co-immunoprecipitation, DISC analysis, lipid raft fractionation, functional apoptosis assays Molecular and cellular biology High 16980609
2000 At physiological temperature (37°C), TRAIL binds DR5 with the highest affinity (KD ≤ 2 nM) among all its receptors (DR4, DcR1, DcR2, OPG), a temperature-dependent rank ordering not apparent at 4°C. Isothermal titration calorimetry, competitive ELISA, cell-surface binding assays The Journal of biological chemistry High 10770955
2019 The DR5 transmembrane helix (TMH) alone assembles a higher-order structure (dimer-trimer interaction network) that drives signaling; the unliganded ectodomain autoinhibits this clustering. Single TMH mutations disrupting either trimerization or dimerization abolish ligand-induced receptor activation. Proteolytic removal of the ectodomain fully activates downstream signaling in the absence of ligand. NMR structure of TMH in bicelles, site-directed mutagenesis of TMH, ectodomain proteolytic removal functional assays Cell High 30827683
2009 In glioblastoma, DR5 homotrimerizes upon TRAIL binding and recruits FADD and caspase-8 for DISC assembly in lipid rafts, initiating caspase-8 cleavage and apoptosis. In TRAIL-resistant cells, DISC is modified by RIP, c-FLIP, and PED/PEA-15 in non-raft fractions, inhibiting caspase-8 and activating NF-κB; siRNA knockdown of these modifiers redistributes DISC to lipid rafts and restores caspase-8 cleavage. DISC immunoprecipitation, lipid raft fractionation, siRNA knockdown, caspase activity assays Journal of cellular and molecular medicine High 19432816
2013 The HCMV UL141 glycoprotein forms a homodimer that engages two TRAIL-R2 monomers 90° apart in a heterotetrameric complex, using its Ig-domain to contact a surface on TRAIL-R2 that partially overlaps with the TRAIL binding site plus an additional distinct patch, enabling non-canonical death receptor interactions and blocking surface expression of DR5. X-ray crystal structure at 2.1 Å, binding affinity assays PLoS pathogens High 23555243
2006 Phage display-identified peptides and synthetic antibodies binding DR5 share a conserved tripeptide motif (within a disulfide-constrained loop or CDR-H3); X-ray crystal structure of an antibody:DR5 complex confirmed this motif is buried at the interface. Oligomeric presentation of DR5-binding peptides/antibodies induces potent proapoptotic signaling. Phage display, X-ray crystallography of antibody:DR5 complex, cell-based apoptosis assays Journal of molecular biology High 16859704
2016 Hepatitis B virus X protein (HBx) acts as an autophagy receptor-like molecule that directly binds TNFRSF10B/DR5 and recruits it to phagophores (LC3B-positive autophagosomes), leading to lysosomal (not proteasomal) degradation of DR5, thereby suppressing TRAIL-mediated apoptosis and aiding viral immune evasion. Co-immunoprecipitation, GST pulldown, LC3B tandem-fluorescence microscopy, pharmacological autophagy inhibition, LC3B siRNA knockdown, immunoblotting of patient liver tissues Autophagy High 27740879
2004 The signal recognition particle (SRP) complex is selectively required for DR4- but not DR5-mediated apoptosis: SRP siRNA knockdown dramatically reduces cell-surface DR4 and inhibits DR4-dependent cell death, while having little effect on cell-surface DR5 levels or DR5-mediated apoptosis. siRNA library screen, flow cytometry for cell-surface receptor levels, cell viability apoptosis assays, stable knockdown cell lines Molecular biology of the cell High 15356269
2020 FLIP(L) can both inhibit and promote caspase-8 at the TRAIL-R2 DISC in a stoichiometry-dependent manner. FLIP(L) recruitment to the DISC requires caspase-8 despite its ability to interact with FADD alone. In the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has slower kinetics but ultimately greater apoptosis. DISC immunoprecipitation, caspase activity assays, FLIP stoichiometry manipulation, FLIP/caspase-8 genetic manipulation EMBO reports High 32009295
2020 The SCFSkp2 E3 ubiquitin ligase complex (containing Cullin-1 in its active NEDDylated form) interacts with both the DR5 pre-ligand association complex (PLAC) and the activated DISC. Processing of FLIP(L) to its p43-form at the TRAIL-R2 DISC enhances its interaction with co-localized SCFSkp2, leading to FLIP(L) ubiquitination and degradation, thereby modulating DR5-mediated apoptosis. Co-immunoprecipitation, NEDDylation inhibitor (MLN4924), siRNA knockdown, ubiquitination assays Cell death and differentiation High 32313199
2022 Senescent cancer cells upregulate DR5 and its ligand TRAIL via NF-κB signaling but are protected from death by increased cFLIP expression. CRISPR screens identified cFLIP loss as a vulnerability of senescent cancer cells. DR5 agonistic antibody activation combined with BRD2 inhibitor-mediated cFLIP suppression efficiently kills senescent cancer cells; adjacent non-senescent cells are also killed via a bystander cytokine-secretion mechanism. CRISPR/Cas9 genetic screens, DR5 agonistic antibody treatment, BRD2 inhibition, animal xenograft models Nature cancer High 36414711
2022 CDK4/6 phosphorylate the p53 family member p73 at threonine 86, sequestering p73 in the cytoplasm. CDK4/6 inhibition causes p73 dephosphorylation and nuclear translocation, which transcriptionally activates DR5 (TNFRSF10B). DR5 induction then promotes immunogenic cancer cell death; DR5 deletion in cancer cells abrogates the sensitizing effects of CDK4/6 inhibitors on TRAIL, 5-FU, and anti-PD-1 therapy. CDK4/6 kinase assay, phospho-site mutagenesis, nuclear fractionation, transcription reporter assay, DR5 knockout in vitro and in vivo Cancer research High 35149588
2023 KIM1 (kidney injury molecule-1) binds directly to the extracellular domain (ECD) of DR5 (TNFRSF10B), promoting DR5 multimerization, activating the caspase cascade, and inducing renal tubular cell apoptosis during AKI. Upstream, transcription factor YY1 is downregulated upon injury and normally represses KIM1 transcription by binding its promoter. Blocking KIM1-DR5 interaction with designed peptides is reno-protective. Renal tubule-specific Kim1 knockout mouse, Co-immunoprecipitation of KIM1 with DR5, YY1 ChIP at KIM1 promoter, rationally designed blocking peptides, cisplatin and ischemia/reperfusion AKI models Nature communications High 37460623
2001 Missense mutations of KILLER/DR5 in gastric cancers are loss-of-function: mutant DR5 proteins inhibit apoptotic cell death in transfection assays and tumors harboring DR5 mutations lack p53 mutations, indicating an independent mechanism of apoptosis escape. Mutation analysis of 43 gastric cancers, allelic loss analysis, transfection-based apoptosis assays of mutant DR5 constructs Gastroenterology Medium 11677215
2004 The TRAIL-R2 (DR5) promoter lacks a canonical TATA-box but contains two functional Sp1-binding sites; a p53-binding site in intron 1 mediates p53-dependent transcriptional upregulation of DR5. The minimal promoter is within -198 to -116 upstream of the ATG. Promoter deletion analysis, reporter gene assays, identification of p53-response element in intron 1 Vitamins and hormones Medium 15110170
2012 Small-molecule bioymifi directly targets DR5 extracellularly to induce DR5 clustering and aggregation on the cell surface, leading to caspase-dependent apoptosis in human cancer cells, acting as a single agent without requiring TRAIL. High-throughput chemical screen, structure-activity relationship studies, cell-based apoptosis assays, DR5 clustering microscopy Nature chemical biology Medium 23292651
2008 DR5 mediates anoikis (detachment-induced apoptosis) in human colorectal carcinoma cells through the extrinsic apoptotic pathway: suspension culture increases DR5 and TRAIL expression, an antagonistic anti-DR5 antibody blocks caspase-8 activation, and DR5 or TRAIL siRNA knockdown inhibits anoikis. DR4 antibody or TRAIL-neutralizing antibody do not consistently reduce anoikis. Suspension culture anoikis model, antagonistic DR5 antibody treatment, siRNA knockdown of DR5 and TRAIL, caspase-8 cleavage assays Cancer research Medium 18245494
2017 DR5 assembles composite pro-apoptotic/pro-survival plasma membrane-proximal platforms within DR4-DR5-DcR2 hetero-oligomeric complexes; a single DR5 receptor suffices to propagate TRAIL signaling to both death and survival (NF-κB, PI3K/Akt, MAPK) pathways. FADD and procaspase-8 at these complexes also transduce non-apoptotic signaling, not exclusively pro-apoptotic signals. DISC immunoprecipitation, receptor-specific siRNA, dominant-negative constructs, signaling pathway assays Cell death & disease Medium 29048428
2014 In mouse spermatogonial stem cells (SSCs), the Trp53-Trp53inp1-Tnfrsf10b (DR5) pathway mediates radiation-induced apoptosis via the extrinsic pathway; Tnfrsf10b deficiency (but not Bbc3/PUMA deficiency) rescues SSCs after irradiation, whereas Bbc3 mediates apoptosis in committed spermatogonia. Trp53inp1 upregulates Tnfrsf10b upon irradiation. Spermatogonial transplantation, genetic KO of Trp53/Bbc3/Tnfrsf10b in mice, irradiation dose-response Stem cell reports Medium 25358794
2010 DR5 is upregulated in neurons following transient global cerebral ischemia (while TRAIL is upregulated in astrocytes/microglia); treatment with soluble DR5 protein blocks endogenous TRAIL-DR5 interaction and reduces ischemic neuronal death, demonstrating that the TRAIL-DR5 axis mediates delayed neuronal apoptosis after ischemia. RT-PCR, immunohistochemistry, dual immunofluorescence, soluble DR5 pharmacological blockade in mouse ischemia model Neurobiology of disease Medium 20359534
2008 Rottlerin upregulates DR5 expression (mRNA and protein) via a CHOP-dependent mechanism (CHOP-binding site in DR5 promoter is required) and independently of PKC-delta. DR5 upregulation is required for rottlerin-induced apoptosis, as DR5 siRNA attenuates cell death. siRNA knockdown of DR5, DR5 promoter reporter with CHOP-binding site mutation, PKC-delta siRNA and overexpression, Western blot and RT-PCR Carcinogenesis Medium 19037087
2015 An ERV9-LTR inserted upstream of TNFRSF10B drives a distinct proapoptotic DR5 transcript in male germline cells; HDAC inhibitors reactivate this ERV9-LTR-driven TNFRSF10B expression in testicular cancer cells, and cell death upon HDAC inhibitor + TRAIL treatment depends on TNFRSF10B expression. 3'RACE/next-generation sequencing, HDAC inhibitor treatment, siRNA/shRNA knockdown of TNFRSF10B, cell death assays Cell death and differentiation Medium 26024393
2020 YIPF2 physically interacts with both TNFRSF10B (DR5) and RAB8, and competes with RAB8 to prevent RAB8-mediated removal of DR5 from the plasma membrane to the cytoplasm, thereby maintaining high cell-surface DR5 levels and promoting chemotherapy-induced apoptosis in NSCLC cells. Co-immunoprecipitation of YIPF2/RAB8/DR5, flow cytometry of cell-surface DR5, siRNA knockdown, pemetrexed treatment Cell death & disease Medium 32303681
2012 p53 selectively controls myeloma cell sensitivity to DR5-mediated (but not DR4-mediated) apoptosis: TP53 wild-type cells overexpress DR5; p53 activation (by nutlin-3a or melphalan) increases DR5 expression and lexatumumab (DR5 agonist) efficacy; p53 silencing decreases DR5 expression and induces resistance to lexatumumab, without affecting DR4 expression or sensitivity to mapatumumab. p53 siRNA, nutlin-3a pharmacological activation, Western blot for DR4/DR5, DR5/DR4 agonistic antibody treatment (lexatumumab/mapatumumab), primary myeloma cells Cancer research Medium 22738917
2010 In pancreatic cancer cells, TRAIL signals predominantly through DR4 despite functional DR5 expression; TRAIL stimulates DR4-DR5 heterocomplexes in addition to DR4 and DR5 homocomplexes, but DR4-specific Fab fragment blockade abolishes most TRAIL-induced apoptosis. PKC inhibition enables DR5 to trigger apoptosis in response to TRAIL. DR4/DR5 receptor-specific Fab blockade, DISC immunoprecipitation, PKC inhibition, agonistic antibodies (mapatumumab/lexatumumab) Journal of molecular medicine Medium 20354842
2016 KPNB1 (importin β1) inhibition overcomes TRAIL resistance in glioblastoma cells by promoting ATF4-mediated DR5 upregulation (via UPR), enhancing DISC assembly, freeing Bax/Bak from Mcl-1, and downregulating FLIP through 4E-BP1-mediated translational suppression. KPNB1 also regulates nuclear import of DR5. KPNB1 siRNA and pharmacological inhibition, ATF4 siRNA, DISC immunoprecipitation, Western blot, caspase assays Cell death & disease Medium 30742128

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 PUMA, a potent killer with or without p53. Oncogene 465 19641508
2002 Mitochondria, the killer organelles and their weapons. Journal of cellular physiology 376 12115719
2003 What does it take to make a natural killer? Nature reviews. Immunology 343 12766763
2006 Differential inhibition of TRAIL-mediated DR5-DISC formation by decoy receptors 1 and 2. Molecular and cellular biology 250 16980609
2003 Granzyme B: a natural born killer. Immunological reviews 212 12752668
2000 Temperature-sensitive differential affinity of TRAIL for its receptors. DR5 is the highest affinity receptor. The Journal of biological chemistry 212 10770955
2020 SnapShot: Natural Killer Cells. Cell 169 32200803
2010 Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Current opinion in cell biology 121 20813513
2019 Higher-Order Clustering of the Transmembrane Anchor of DR5 Drives Signaling. Cell 116 30827683
2012 Small-molecule activation of the TRAIL receptor DR5 in human cancer cells. Nature chemical biology 94 23292651
2009 Apoptin, a tumor-selective killer. Biochimica et biophysica acta 90 19374922
2009 Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTbetaR. mAbs 89 20061822
2004 Differential regulation of the TRAIL death receptors DR4 and DR5 by the signal recognition particle. Molecular biology of the cell 89 15356269
2002 Natural killer and natural killer-T cells in psoriasis. Archives of dermatological research 89 12420105
2002 Biology of killer yeasts. International microbiology : the official journal of the Spanish Society for Microbiology 88 12180782
2016 Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5. Oncotarget 86 27129166
2014 Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells. Journal of experimental & clinical cancer research : CR 84 24387758
1986 Natural killer cells. Annual review of medicine 83 3518610
1990 Colicins: prokaryotic killer-pores. Experientia 74 1689257
2018 CART cells are prone to Fas- and DR5-mediated cell death. Journal for immunotherapy of cancer 73 30005714
2010 TRAIL signaling is mediated by DR4 in pancreatic tumor cells despite the expression of functional DR5. Journal of molecular medicine (Berlin, Germany) 73 20354842
2009 DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas. Journal of cellular and molecular medicine 73 19432816
2018 Genetic Villains: Killer Meiotic Drivers. Trends in genetics : TIG 71 29499907
2015 Parvovirus Family Conundrum: What Makes a Killer? Annual review of virology 68 26958923
2014 How to trigger a killer: modulation of natural killer cell reactivity on many levels. Advances in immunology 68 25175775
1997 Natural killer cell receptors. Current opinion in immunology 67 9203417
2017 Antibodies and Derivatives Targeting DR4 and DR5 for Cancer Therapy. Antibodies (Basel, Switzerland) 65 31548531
2015 Boosting vaccine efficacy the natural (killer) way. Trends in immunology 64 26272882
2017 GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction. European journal of preventive cardiology 62 28762762
2012 Cell death via DR5, but not DR4, is regulated by p53 in myeloma cells. Cancer research 61 22738917
2015 Revving up Natural Killer Cells and Cytokine-Induced Killer Cells Against Hematological Malignancies. Frontiers in immunology 58 26029215
2017 Natural Killer Cells: Angels and Devils for Immunotherapy. International journal of molecular sciences 57 28850071
2019 Granulysin: killer lymphocyte safeguard against microbes. Current opinion in immunology 56 31112765
2016 Hepatitis B virus-triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response. Autophagy 54 27740879
2008 Rottlerin induces apoptosis via death receptor 5 (DR5) upregulation through CHOP-dependent and PKC delta-independent mechanism in human malignant tumor cells. Carcinogenesis 54 19037087
2022 cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis. Nature cancer 53 36414711
2007 Zymocin, a composite chitinase and tRNase killer toxin from yeast. Biochemical Society transactions 53 18031261
2001 Inactivating mutations of KILLER/DR5 gene in gastric cancers. Gastroenterology 50 11677215
2019 BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5. Cancer research 48 30674532
2013 The Stat3 paradox: a killer and an oncogene. Molecular and cellular endocrinology 48 23827176
2023 A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury. Nature communications 47 37460623
2006 Activation of the proapoptotic death receptor DR5 by oligomeric peptide and antibody agonists. Journal of molecular biology 46 16859704
2020 A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis. EMBO reports 45 32009295
2006 Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells. Carcinogenesis 45 16571651
2017 Dual role of DR5 in death and survival signaling leads to TRAIL resistance in cancer cells. Cell death & disease 44 29048428
2015 A benzimidazole derivative exhibiting antitumor activity blocks EGFR and HER2 activity and upregulates DR5 in breast cancer cells. Cell death & disease 44 25766325
2020 Dual Epitope Targeting and Enhanced Hexamerization by DR5 Antibodies as a Novel Approach to Induce Potent Antitumor Activity Through DR5 Agonism. Molecular cancer therapeutics 43 32847982
2013 Structure of human cytomegalovirus UL141 binding to TRAIL-R2 reveals novel, non-canonical death receptor interactions. PLoS pathogens 43 23555243
1996 Converting cancer genes into killer genes. Proceedings of the National Academy of Sciences of the United States of America 41 8633039
2008 DR5 receptor mediates anoikis in human colorectal carcinoma cell lines. Cancer research 39 18245494
2007 The death receptor DR5 is involved in TRAIL-mediated human osteoclast apoptosis. Apoptosis : an international journal on programmed cell death 39 17558561
2008 Natural killer cell receptors. Advances in experimental medicine and biology 38 19065782
2018 miR-128 Targets the SIRT1/ROS/DR5 Pathway to Sensitize Colorectal Cancer to TRAIL-Induced Apoptosis. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 37 30257253
2010 Blocking TRAIL-DR5 signaling with soluble DR5 reduces delayed neuronal damage after transient global cerebral ischemia. Neurobiology of disease 37 20359534
2015 Comprehensive identification of genes driven by ERV9-LTRs reveals TNFRSF10B as a re-activatable mediator of testicular cancer cell death. Cell death and differentiation 36 26024393
2016 Intracellular localization of DR5 and related regulatory pathways as a mechanism of resistance to TRAIL in cancer. Cellular and molecular life sciences : CMLS 34 27510421
2013 Salirasib sensitizes hepatocarcinoma cells to TRAIL-induced apoptosis through DR5 and survivin-dependent mechanisms. Cell death & disease 34 23348585
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