Affinage

Showing TNFRSF10B — DR5 is a alias.

TNFRSF10B

Tumor necrosis factor receptor superfamily member 10B · UniProt O14763

Length
440 aa
Mass
47.9 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF10B (DR5/TRAIL-R2) is a cell-surface death receptor that transduces TRAIL signaling into apoptosis: it was identified by ligand affinity purification as a TRAIL receptor bearing two extracellular cysteine-rich repeats and a cytoplasmic death domain that recruits the adaptor FADD to drive caspase-dependent death (PMID:9311998, PMID:9430228). Receptor activation does not require ligand per se but rather higher-order clustering of its transmembrane helix (TMH), which possesses distinct trimerization and dimerization faces; the unliganded ectodomain autoinhibits this TMH clustering, and either ectodomain removal or agonistic antibody-driven superoligomerization is sufficient to fire downstream signaling (PMID:30827683, PMID:26672965). Receptor engagement nucleates a death-inducing signaling complex (DISC) whose output is set by the stoichiometry of FADD, procaspase-8, and FLIP isoforms—FLIP(L) acting as inhibitor or promoter of caspase-8 depending on its ratio to caspase-8—and is further tuned by decoy receptor co-recruitment and by the DISC-resident SCF^Skp2 ubiquitin ligase that limits FLIP(L) levels (PMID:16980609, PMID:32009295, PMID:32313199). The same platform also propagates non-apoptotic NF-κB and survival signaling and can drive pro-metastatic CXCR4 upregulation, so DISC composition determines a death-versus-survival balance (PMID:9430228, PMID:29048428, PMID:25909161). DR5 transcription is a convergence point for stress and tumor-suppressor pathways: p53 directly transactivates the gene through an intronic binding site, specifically in apoptosis-committed cells via the ATM–p53 axis (PMID:10777207, PMID:10597242), while STAT1 downstream of IFN-γ, DDIT3/KAT2A during ER stress, and p73 released by CDK4/6 inhibition provide p53-independent routes to induction (PMID:11139340, PMID:25770212, PMID:35149588). Surface and total receptor levels are post-transcriptionally controlled by YIPF2/RAB8-dependent recycling and by HBx-driven autophagic-lysosomal degradation (PMID:27740879, PMID:32303681). Loss-of-function DR5 mutations occur in gastric cancer, establishing it as a tumor suppressor (PMID:11677215).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    Establishing that TRAIL acts through a dedicated death-domain receptor answered how this cytokine triggers apoptosis and placed DR5 at the head of a FADD/caspase-8 extrinsic pathway.

    Evidence Ligand-based affinity purification, molecular cloning, and dominant-negative FADD inhibition across cell lines

    PMID:9311998 PMID:9430228

    Open questions at the time
    • Did not resolve the structural basis of receptor activation
    • Functional consequence of DR4/DR5 heteroassociation left undefined
  2. 2000 High

    Identifying an intronic p53-binding site answered how genotoxic stress and the ATM-p53 axis induce DR5, linking the death receptor to the DNA-damage response.

    Evidence EMSA, luciferase reporters with site-directed mutagenesis of BS2, adenoviral p53, and ATM-deficient lymphoblastoid cells

    PMID:10597242 PMID:10777207

    Open questions at the time
    • Why p53 induces DR5 only in apoptosis-committed and not arrest-committed cells is unexplained
    • Does not address p53-independent induction
  3. 2001 Medium

    Discovery of glucocorticoid-, IFN-γ/STAT1-, and bile-acid-driven DR5 induction in p53-mutant cells established that multiple stress inputs converge on DR5 transcription independently of p53.

    Evidence RT-PCR with actinomycin D, STAT1-mutant cells, and dominant-negative FADD/caspase-8 inhibitor epistasis

    PMID:11139340 PMID:11507096

    Open questions at the time
    • Direct STAT1 occupancy of the DR5 promoter not demonstrated
    • Mechanism of bile-acid-induced receptor aggregation undefined
  4. 2001 Medium

    Finding inactivating DR5 mutations with allelic loss in gastric cancer established DR5 as a tumor suppressor whose disruption disables death signaling.

    Evidence Tumor DNA sequencing, LOH analysis, and apoptosis assays of transfected mutants

    PMID:11677215

    Open questions at the time
    • Limited to gastric cancer cohort
    • Mechanism by which mutants block apoptosis not structurally defined
  5. 2006 High

    Dissecting how decoy receptors block DR5 clarified that DcR1 sequesters TRAIL in lipid rafts while DcR2 co-assembles within the DISC to inhibit caspase activation—two distinct regulatory layers on receptor output.

    Evidence DISC immunoprecipitation, lipid raft fractionation, and caspase activity assays

    PMID:16980609

    Open questions at the time
    • Stoichiometry of decoy co-recruitment in vivo unquantified
    • Did not address survival signaling outputs
  6. 2015 Medium

    Mapping the DDIT3/KAT2A complex and KDM4A silencing at the DR5/CHOP loci, plus ERV9-LTR-driven transcription, defined epigenetic and ER-stress transcriptional control of DR5 exploitable by HDAC and KDM4A inhibitors.

    Evidence Co-IP, ChIP, luciferase reporters, siRNA/small-molecule inhibition, and 3'RACE

    PMID:25770212 PMID:26024393 PMID:27612013

    Open questions at the time
    • Relative contribution of each transcriptional route in normal physiology unclear
    • Cell-type specificity of ERV9-LTR usage not generalized
  7. 2015 High

    Showing that an agonistic antibody (KMTR2) drives DR5 superoligomerization, with a single interface mutation abolishing apoptosis, established that receptor higher-order clustering—not mere occupancy—is the activating event.

    Evidence 2.1 Å crystal structure of the TRAIL-R2 ECD–KMTR2-Fab complex plus mutagenesis and apoptosis assays

    PMID:26672965

    Open questions at the time
    • Structure of the full receptor oligomer in membrane not resolved
    • Link from ECD clustering to intracellular DISC geometry inferred, not visualized
  8. 2017 High

    Genetic dissection resolved that DR5/caspase-8 is dispensable for ER-stress apoptosis (which uses BIM/PUMA-mitochondrial signaling), correcting a prior model, while DR5 simultaneously routes signals to both death and NF-κB/PI3K/MAPK survival pathways.

    Evidence Knockout mice and RNAi under ER stress; signaling-complex IP with siRNA epistasis

    PMID:28409774 PMID:29048428

    Open questions at the time
    • What molecular switch biases the DR5 platform toward death versus survival is unresolved
    • Context-dependence across tissues not mapped
  9. 2019 High

    The NMR structure of the DR5 TMH revealed dimerization and trimerization faces and that ectodomain removal alone activates signaling, establishing TMH self-assembly as the core mechanistic switch under ectodomain autoinhibition.

    Evidence NMR in bicelles, interface mutagenesis, ectodomain proteolysis, and cell-based signaling

    PMID:30827683

    Open questions at the time
    • How ligand binding releases ectodomain autoinhibition mechanically is not detailed
    • Higher-order network stoichiometry in cells not quantified
  10. 2020 High

    Quantitative DISC analyses showed FLIP(L) flips between anti- and pro-apoptotic roles by stoichiometry and that DISC-resident SCF^Skp2 degrades FLIP(L), defining the biochemical logic that sets apoptotic threshold and kinetics.

    Evidence DISC IP with FLIP/caspase-8 knockout and overexpression, ubiquitination assays, and NEDDylation inhibition (MLN4924)

    PMID:32009295 PMID:32313199

    Open questions at the time
    • In vivo relevance of SCF^Skp2-FLIP(L) regulation untested
    • Trigger that processes FLIP(L) to its p43 form at the DISC undefined
  11. 2020 High

    Identifying YIPF2/RAB8 recycling control and HBx-driven autophagic degradation of DR5 established post-translational regulation of receptor surface abundance as a determinant of apoptotic sensitivity and viral immune evasion.

    Evidence Co-IP, surface flow cytometry, recycling assays; LC3B knockdown and tandem-fluorescence imaging

    PMID:27740879 PMID:32303681

    Open questions at the time
    • YIPF2 finding rests on co-IP from a single lab without structural detail
    • Whether these trafficking routes operate in normal physiology vs. disease is unclear
  12. 2022 High

    Demonstrating that CDK4/6 sequester p73 (phospho-T86) and that their inhibition releases p73 to transactivate DR5, plus NF-κB-driven DR5 priming of senescent cells, established new transcriptional routes that sensitize tumors to DR5 agonism and immunotherapy.

    Evidence CDK4/6 kinase assay, nuclear fractionation, DR5-knockout epistasis in vivo; CRISPR screens and agonist/BRD2-inhibitor combinations

    PMID:35149588 PMID:36414711

    Open questions at the time
    • Whether p73-DR5 and NF-κB-DR5 routes act in the same tumors is unaddressed
    • cFLIP-imposed resistance threshold not quantitatively defined
  13. 2023 High

    Identifying KIM1 as an endogenous ECD ligand that promotes DR5 multimerization in acute kidney injury extended DR5 biology beyond TRAIL and revealed a peptide-blockable disease axis.

    Evidence KIM1-ECD binding and multimerization assays, tubule-specific Kim1 knockout mice, and peptide blocking in vivo

    PMID:37460623

    Open questions at the time
    • Whether KIM1 engages the same TMH-clustering mechanism as TRAIL is not shown
    • Generality beyond renal tubular cells untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what molecular determinant biases the assembled DR5 platform toward apoptosis versus NF-κB/survival/pro-metastatic output in a given cell, and how ectodomain autoinhibition is mechanically released by physiological ligands.
  • No unified model linking TMH clustering geometry to DISC composition and signaling outcome
  • Physiological ligand repertoire beyond TRAIL and KIM1 incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0060090 molecular adaptor activity 3 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-168256 Immune System 2
Partners
CASP8CFLAR (FLIP)CUL1FADDKIM1/HAVCR1RAB8TRAIL/TNFSF10YIPF2
Complex memberships
DISC (death-inducing signaling complex)SCF^Skp2 ubiquitin ligase (at the DISC)

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TRAIL-R2 (DR5/TNFRSF10B) was identified as a receptor for TRAIL by ligand-based affinity purification and molecular cloning. It contains two extracellular cysteine-rich repeats and a cytoplasmic death domain. TRAIL binds to recombinant cell-surface-expressed TRAIL-R2, and TRAIL-R2 mediates apoptosis via the intracellular adaptor molecule FADD/MORT1 through a caspase-dependent apoptotic pathway. Ligand-based affinity purification, molecular cloning, TRAIL-R2-Fc fusion protein inhibition assay, dominant-negative FADD inhibition The EMBO journal High 9311998
1997 TRAIL-R2 (DR5) signals FADD-dependent apoptosis. Both DR4 and DR5 bind the adaptor molecules FADD and TRADD. DR5 can associate with DR4, suggesting heteroreceptor signaling complexes. Death signals from DR5 are interrupted by dominant-negative FADD and by FLIP. DR5 also potently activates NF-κB, analogous to TNFR1. Co-immunoprecipitation, dominant-negative FADD overexpression, NF-κB reporter assay Immunity High 9430228
2000 Wild-type p53 directly transactivates the KILLER/DR5 (TNFRSF10B) gene through an intronic p53 DNA-binding site (BS2, located +0.25 kb downstream of the ATG within Intron 1). Mutation of BS2 abrogated both p53 binding and p53-dependent induction of the KILLER/DR5 promoter-reporter gene. Doxorubicin treatment increased p53 binding to BS2 in p53-wild-type cells. Modified p53-binding immunoselection protocol, EMSA, luciferase reporter assay, site-directed mutagenesis, adenoviral p53 overexpression Oncogene High 10777207
1999 KILLER/DR5 (TNFRSF10B) induction by p53 is restricted specifically to cells undergoing apoptosis and not to cells undergoing p53-dependent G1 arrest. In cells where p53 drives cell cycle arrest, KILLER/DR5 is not upregulated, whereas p21WAF1/CIP1 is. The ATM-p53 pathway is required for DR5 upregulation after DNA damage, as cells from ataxia-telangiectasia patients fail to upregulate KILLER/DR5 after irradiation. Induction is transcription-dependent (blocked by actinomycin D). Northern blot/mRNA analysis, inducible p53 expression system, actinomycin D inhibition, irradiated ATM-deficient lymphoblastoid cell lines Oncogene Medium 10597242
2001 p53-independent upregulation of KILLER/DR5 mRNA can be induced by dexamethasone (synthetic glucocorticoid) and interferon-gamma (IFN-γ) in cells with mutant p53. IFN-γ-mediated induction of KILLER/DR5 mRNA is delayed in cells lacking wild-type STAT1, implicating STAT1 as a mediator of IFN-γ-driven DR5 transcription. Similarly, TNF-α-induced DR5 upregulation is also delayed in STAT1-mutant cells. RT-PCR, actinomycin D inhibition, STAT1-mutant cell lines Experimental cell research Medium 11139340
2001 The toxic bile acid glycochenodeoxycholate (GCDC) induces apoptosis via a death receptor-mediated pathway that specifically involves TRAIL-R2/DR5. GCDC treatment increased TRAIL-R2/DR5 mRNA and protein expression 10-fold and caused aggregation of TRAIL-R2/DR5 on the cell surface. Apoptosis was inhibited by dominant-negative FADD and caspase-8 inhibitor, placing DR5 upstream of FADD and caspase-8. RT-PCR, protein expression (immunoblot), dominant-negative FADD transfection, caspase-8 inhibitor treatment, receptor aggregation assay The Journal of biological chemistry Medium 11507096
2001 Inactivating missense mutations in KILLER/DR5 (TNFRSF10B) were identified in gastric cancers, with two showing allelic loss in the remaining allele. All detected KILLER/DR5 mutants inhibited apoptotic cell death in transfection studies, demonstrating that these are loss-of-function mutations that can contribute to tumor development. Direct sequencing of tumor DNA, transfection of mutant constructs with apoptosis assays, loss-of-heterozygosity analysis Gastroenterology Medium 11677215
2006 DcR1 inhibits DR5-mediated TRAIL-induced apoptosis by titrating TRAIL within lipid rafts, preventing DISC assembly. In contrast, DcR2 is co-recruited with DR5 within the DISC, where it inhibits initiator caspase activation. DcR2 also prevents DR4 recruitment within the DR5 DISC. These distinct mechanisms reveal differential regulation of the DR5 DISC by the two decoy receptors. DISC immunoprecipitation, lipid raft fractionation, caspase activity assays, dominant-negative constructs Molecular and cellular biology High 16980609
2015 DDIT3 (CHOP) and KAT2A (GCN5) cooperatively regulate TNFRSF10B (DR5) expression during ER stress-mediated apoptosis. KAT2A physically interacts with the N-terminal region (amino acids 1-26) of DDIT3. KAT2A knockdown downregulated TNFRSF10B and decreased promoter activity of a luciferase reporter containing the DDIT3-binding site (-276/-264) of the TNFRSF10B promoter. ChIP results indicate KAT2A participates in a complex with DDIT3 and acetylates H3K9/K14 at the TNFRSF10B promoter. Co-immunoprecipitation, siRNA knockdown, luciferase reporter assay, chromatin immunoprecipitation (ChIP), Western blot The Journal of biological chemistry Medium 25770212
2019 The transmembrane helix (TMH) of DR5 alone can directly assemble a higher-order structure (dimer-trimer interaction networks) that drives signaling. NMR structure of the TMH in bicelles shows distinct trimerization and dimerization faces. Single-TMH mutations that disrupt either trimerization or dimerization abolish ligand-induced receptor activation. Proteolytic removal of the DR5 ectodomain can fully activate downstream signaling in the absence of ligand, indicating the unliganded ectodomain autoinhibits TMH clustering. NMR structure determination in bicelles, site-directed mutagenesis, ectodomain proteolytic removal, cell-based signaling assays Cell High 30827683
2016 Hepatitis B virus X protein (HBx) promotes lysosomal (autophagic) degradation of TNFRSF10B/DR5, thereby reducing DR5 protein levels and protecting virus-infected cells from TRAIL-mediated apoptosis. HBx directly interacts with TNFRSF10B and recruits it to phagophores (autophagosome precursors) by acting as an autophagy receptor-like molecule that promotes TNFRSF10B association with LC3B. HBx also induces autophagy itself. Immunoprecipitation, GST affinity isolation, LC3B knockdown, pharmacological autophagy inhibition, tandem-fluorescence LC3B microscopy, immunoblotting Autophagy High 27740879
2015 The chromatin demethylase KDM4A (JMJD2A), but not KDM4B, epigenetically silences DR5 (TNFRSF10B) expression in tumor cells. KDM4A inhibition switches histone-modifying enzyme complexes at the DR5 transcriptional activator CHOP gene promoter, dissociating KDM4A and the NCoR-HDAC corepressor complex and recruiting the histone acetyltransferase CBP, thereby inducing DR5 expression and TRAIL-dependent apoptosis. siRNA gene silencing, small-molecule KDM4A inhibitor, ChIP, gene expression analysis, apoptosis assays, tumor xenograft models Cell death and differentiation Medium 27612013
2017 DR5 alone can assemble composite plasma membrane-proximal pro-apoptotic and pro-survival signaling platforms in the context of DR4-DR5-DcR2 hetero-oligomeric complexes. Key apoptotic proteins FADD and procaspase-8 also participate in transducing non-apoptotic (survival) signaling downstream of DR5. DR5 thus simultaneously propagates TRAIL signaling to both death (caspase) and survival (NF-κB, PI3K/Akt, MAPK, JNK) pathways. Immunoprecipitation of signaling complexes, siRNA knockdown, protein overexpression, flow cytometry Cell death & disease Medium 29048428
2020 A revised DISC assembly model for TRAIL-R2 explains how FLIP(L) can act as both an inhibitor and promoter of caspase-8. FLIP(L) converts from anti-apoptotic to pro-apoptotic depending on its stoichiometry relative to caspase-8 at the DISC. In the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has significantly slower kinetics but ultimately greater extent of apoptosis. FLIP(L) recruitment to the TRAIL-R2 DISC is impaired in the absence of caspase-8, despite being able to interact with FADD. FLIP(S) is the more potent inhibitor of DISC-mediated apoptosis. DISC immunoprecipitation, FLIP(L)/FLIP(S)/caspase-8 knockout/overexpression systems, quantitative kinetic apoptosis assays EMBO reports High 32009295
2020 The SCFSkp2 ubiquitin ligase complex (containing Cullin-1 and Skp2) interacts with TRAIL-R2 (DR5) at both its pre-ligand association complex (PLAC) and the ligand-activated DISC. Cullin-1 interacts with TRAIL-R2 in its active NEDDylated form. Inhibiting Cullin-1 DISC recruitment via NEDDylation inhibitor (MLN4924) or siRNA increased TRAIL-induced apoptosis by enhancing FLIP(L) levels at the DISC. FLIP(L), but not FLIP(S), caspase-8, or FADD, directly interacts with Cullin-1 and Skp2. Processing of FLIP(L) to its p43 form at the DISC enhances its interaction with SCFSkp2, promoting its ubiquitination and degradation. Co-immunoprecipitation, siRNA knockdown, NEDDylation inhibitor MLN4924, ubiquitination assay, DISC immunoprecipitation Cell death and differentiation High 32313199
2008 DR5 mediates anoikis (detachment-induced apoptosis) in human colorectal carcinoma (CRC) cells via the extrinsic apoptotic pathway (caspase-8). DR5 expression increased at the mRNA and protein levels upon suspension culture. An antagonistic anti-DR5 antibody inhibited caspase-8 activation and anoikis in four human CRC lines. Knockdown of DR5 or its ligand TRAIL also inhibited anoikis. Neither anti-DR4 antibody nor anti-TRAIL neutralizing antibody consistently reduced anoikis. Antagonistic antibody treatment, siRNA knockdown, caspase inhibitor assays, protein expression analysis, suspension culture model Cancer research Medium 18245494
2015 A transcript encoding DR5 (TNFRSF10B) originates from an ERV9-LTR inserted upstream of the protein-coding regions of the TNFRSF10B gene. HDAC inhibitors induce this ERV9-LTR-driven DR5 transcript in testicular cancer cells. When testicular cancer cells are treated with HDAC inhibitors and TRAIL, rapid cell death occurs that depends on TNFRSF10B expression (demonstrated by siRNA knockdown). 3'RACE, next-generation sequencing, HDAC inhibitor treatment, siRNA knockdown, apoptosis assays Cell death and differentiation Medium 26024393
2015 TRAIL-R2 (DR5) knockdown in osteotropic breast cancer cells reduces CXCR4 expression and migration toward SDF-1, and strongly impairs bone metastasis formation in vivo. Conversely, overexpression of TRAIL-R2 upregulates CXCR4 and enhances SDF-1-directed migration, demonstrating a non-apoptotic, pro-metastatic signaling role for TRAIL-R2. siRNA knockdown, TRAIL-R2 overexpression, migration assay toward SDF-1, intracardiac injection xenograft model, CXCR4 protein quantification Oncotarget Medium 25909161
2023 KIM1 (kidney injury molecule-1) binds to the extracellular domain (ECD) of DR5/TNFRSF10B, promotes DR5 multimerization, and activates the downstream caspase cascade to induce renal tubular cell apoptosis during acute kidney injury. Transcription factor YY1, downregulated upon AKI, normally represses KIM1 expression by binding to its promoter. Blocking the KIM1-DR5 interaction with rationally designed peptides provides reno-protection against AKI. Binding assay (KIM1-ECD domain interaction), DR5 multimerization assay, renal tubular-specific Kim1 knockout mice, caspase activation assays, peptide blocking in vivo Nature communications High 37460623
2022 Senescent cancer cells are primed for apoptosis through NF-κB-mediated upregulation of DR5 and its ligand TRAIL, but are protected by increased cFLIP expression. Activation of DR5 signaling by an agonistic antibody, especially when combined with BRD2 inhibition to suppress cFLIP, efficiently kills senescent cancer cells. Senescent cells also sensitize adjacent non-senescent cells to DR5 agonist killing through a bystander effect mediated by cytokine secretion. CRISPR/Cas9 genetic screens, agonistic antibody treatment, BRD2 inhibition, NF-κB pathway analysis, in vivo animal models Nature cancer High 36414711
2022 CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, sequestering p73 in the cytoplasm. CDK4/6 inhibition causes dephosphorylation and nuclear translocation of p73, which transcriptionally activates DR5 (TNFRSF10B). p73-mediated DR5 induction by CDK4/6 inhibitors promotes immunogenic cell death, and deletion of DR5 abrogates the potentiating effects of CDK4/6 inhibitors on TRAIL, 5-fluorouracil chemotherapy, and anti-PD-1 immunotherapy. CDK4/6 kinase assay (phosphorylation of p73 at T86), nuclear fractionation, transcriptional reporter assay, DR5 knockout by CRISPR, in vitro and in vivo tumor models Cancer research High 35149588
2017 DR5 and caspase-8 are dispensable for ER stress-induced apoptotic cell death. Using knockout mouse models and RNAi-mediated gene silencing, the mitochondrial apoptotic pathway (activated by BH3-only BCL-2 family members BIM and PUMA), not the DR5/caspase-8 extrinsic pathway, is essential for ER stress-induced cell death. This is a negative finding that contradicts a prior report of DR5 being required for ER stress apoptosis. Knockout mouse models, RNAi gene silencing, apoptosis assays under ER stress conditions Cell death and differentiation High 28409774
2015 The fully human monoclonal antibody KMTR2 induces strong DR5 agonism by promoting TRAIL-R2 superoligomerization. The crystal structure of the extracellular region of TRAIL-R2 with KMTR2-Fab (resolved to 2.1 Å) shows two KMTR2-Fabs assembled via the CDR2 of the light chain, suggesting enhanced TRAIL-R2 oligomerization. A single mutation at Asn53 to Arg at the two-fold interface of KMTR2 abolishes apoptotic activity while retaining antigen-binding, confirming that superoligomerization drives agonistic activity. X-ray crystallography (2.1 Å resolution), site-directed mutagenesis, apoptosis assays, tumor regression models Scientific reports High 26672965
2020 YIPF2 promotes recycling of TNFRSF10B to the plasma membrane. YIPF2, RAB8, and TNFRSF10B physically interact with each other. YIPF2 inhibits the physical interaction between TNFRSF10B and RAB8, thereby suppressing RAB8-mediated removal of TNFRSF10B from the plasma membrane, maintaining high cell-surface levels of DR5, and enhancing chemotherapy-induced apoptosis. Co-immunoprecipitation, siRNA knockdown, cell surface flow cytometry, protein recycling assay Cell death & disease Medium 32303681
2014 The Trp53-Trp53inp1-Tnfrsf10b pathway regulates radiation-induced apoptosis in mouse spermatogonial stem cells (SSCs). Tnfrsf10b deficiency, but not Bbc3 (PUMA) deficiency, protected SSCs (not committed spermatogonia) after irradiation. Tnfrsf10b was upregulated by Trp53inp1 upon irradiation. This reveals tissue-specific pathway selection: SSCs use the extrinsic (Tnfrsf10b) pathway while progenitor cells use the intrinsic (Bbc3) pathway. Spermatogonial transplantation assay (functional stem cell readout), Trp53/Tnfrsf10b/Bbc3 knockout mice, irradiation, mRNA expression analysis Stem cell reports Medium 25358794
2012 p53 specifically modulates DR5 (but not DR4) expression in myeloma cells. TP53 wild-type myeloma cells overexpress DR5 in correlation with sensitivity to lexatumumab (anti-DR5 antibody). Both non-genotoxic (nutlin-3a) and genotoxic (melphalan) p53-inducing stresses increase DR5 expression and synergistically increase sensitivity to lexatumumab only in TP53 wild-type cells. Silencing of p53 decreases DR5 expression and induces resistance to lexatumumab, without affecting DR4 expression. p53 siRNA knockdown, nutlin-3a and melphalan treatment, DR5/DR4 protein quantification, apoptosis assays with DR5/DR4-specific antibodies Cancer research Medium 22738917
2016 Karyopherin β1 (KPNB1) inhibition drives nuclear import-independent upregulation of DR5 through the unfolded protein response (UPR): KPNB1 inhibition activates ATF4-mediated DR5 expression and promotes DISC assembly. In addition, KPNB1 inhibition-induced autophagy degrades cleaved caspase-8, limiting apoptosis. Inhibition of autophagic flux combined with KPNB1 inhibition and TRAIL further enhances apoptosis in a caspase-8-dependent manner. siRNA knockdown, pharmacological KPNB1 inhibition, UPR pathway analysis, DISC immunoprecipitation, autophagy flux assay, caspase-8 inhibitor rescue Cell death & disease Medium 30742128

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Caspases: killer proteases. Trends in biochemical sciences 2030 9270303
1997 TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. The EMBO journal 969 9311998
1997 TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB. Immunity 598 9430228
2008 PUMA, a potent killer with or without p53. Oncogene 467 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 344 12766763
2000 Wild-type p53 transactivates the KILLER/DR5 gene through an intronic sequence-specific DNA-binding site. Oncogene 302 10777207
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 214 12752668
2020 SnapShot: Natural Killer Cells. Cell 172 32200803
2001 The bile acid glycochenodeoxycholate induces trail-receptor 2/DR5 expression and apoptosis. The Journal of biological chemistry 155 11507096
2019 Higher-Order Clustering of the Transmembrane Anchor of DR5 Drives Signaling. Cell 121 30827683
2010 Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Current opinion in cell biology 121 20813513
1992 Modulation of natural killer and lymphokine-activated killer cell cytotoxicity by lactoferrin. Journal of leukocyte biology 119 1564398
2001 p53-independent upregulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma. Experimental cell research 110 11139340
1999 Induction of the TRAIL receptor KILLER/DR5 in p53-dependent apoptosis but not growth arrest. Oncogene 101 10597242
2015 DDIT3 and KAT2A Proteins Regulate TNFRSF10A and TNFRSF10B Expression in Endoplasmic Reticulum Stress-mediated Apoptosis in Human Lung Cancer Cells. The Journal of biological chemistry 96 25770212
2012 Small-molecule activation of the TRAIL receptor DR5 in human cancer cells. Nature chemical biology 95 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
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
2014 Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells. Journal of experimental & clinical cancer research : CR 87 24387758
2016 Extracellular miR-1246 promotes lung cancer cell proliferation and enhances radioresistance by directly targeting DR5. Oncotarget 86 27129166
2010 Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. Cancer research 85 20103630
2003 TRAIL-R2 (DR5) mediates apoptosis of synovial fibroblasts in rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950) 85 12847280
1986 Natural killer cells. Annual review of medicine 83 3518610
2010 Once a killer, always a killer: from cytotoxic T cell to memory cell. Immunological reviews 76 20536565
2018 CART cells are prone to Fas- and DR5-mediated cell death. Journal for immunotherapy of cancer 74 30005714
1990 Colicins: prokaryotic killer-pores. Experientia 74 1689257
2018 Genetic Villains: Killer Meiotic Drivers. Trends in genetics : TIG 73 29499907
2020 The role of natural killer cell in gastrointestinal cancer: killer or helper. Oncogene 69 33262461
2015 Parvovirus Family Conundrum: What Makes a Killer? Annual review of virology 69 26958923
2014 How to trigger a killer: modulation of natural killer cell reactivity on many levels. Advances in immunology 68 25175775
2017 DR5 and caspase-8 are dispensable in ER stress-induced apoptosis. Cell death and differentiation 67 28409774
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) 66 31548531
2015 Boosting vaccine efficacy the natural (killer) way. Trends in immunology 64 26272882
2014 TRAIL-R2-specific antibodies and recombinant TRAIL can synergise to kill cancer cells. Oncogene 64 24909167
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
2022 cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis. Nature cancer 58 36414711
2000 KILLER/DR5, a novel DNA-damage inducible death receptor gene, links the p53-tumor suppressor to caspase activation and apoptotic death. Advances in experimental medicine and biology 58 10810622
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
1985 The killer molecule of complement. The Journal of investigative dermatology 55 3891882
2016 Hepatitis B virus-triggered autophagy targets TNFRSF10B/death receptor 5 for degradation to limit TNFSF10/TRAIL response. Autophagy 54 27740879
2001 Inactivating mutations of KILLER/DR5 gene in gastric cancers. Gastroenterology 50 11677215
2023 A renal YY1-KIM1-DR5 axis regulates the progression of acute kidney injury. Nature communications 49 37460623
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