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Showing TNFRSF21 — DR6 is a alias.

TNFRSF21

Tumor necrosis factor receptor superfamily member 21 · UniProt O75509

Length
655 aa
Mass
71.8 kDa
Annotated
2026-06-10
53 papers in source corpus 20 papers cited in narrative 21 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

TNFRSF21 (DR6) is a type I transmembrane death-domain receptor of the TNF receptor superfamily that acts as a context-dependent signaling hub coupling extracellular ligand engagement to apoptosis, inflammation, and developmental remodeling (PMID:9714541, PMID:19225519). Its ectodomain comprises four cysteine-rich domains arranged in a rod-like structure with receptor-specific surface patches for ligand recognition (PMID:21463639), and it is activated at the cell surface by ligand-induced dimerization: an N-terminal fragment of APP binds the DR6 ectodomain and drives dimerization (PMID:19225519, PMID:25838500), while RBP4 acts as an antagonistic ligand that forces a non-productive Ca2+-sensitive homodimer and blocks pro-degenerative heterointeractions. Engaged DR6 signals through a FADD-independent route to activate NF-κB and JNK and to trigger apoptosis (PMID:9714541, PMID:11753679); in developing neurons it executes trophic-deprivation degeneration by directing caspase-3-mediated cell-body death and caspase-6-mediated axon pruning, acting downstream of axonal spheroid rupture in a calpain-dependent manner (PMID:19225519, PMID:31628183). DR6 partners with p75NTR to mediate Aβ-induced cortical neuron death (PMID:23559013) and with TROY downstream of Wnt/β-catenin to drive VEGF-dependent JNK activation, CNS angiogenesis, and blood-brain-barrier formation (PMID:22340501, PMID:38609388). ADAM10 sheds the receptor to release a soluble ectodomain that acts non-cell-autonomously to restrain Schwann cell proliferation and myelination, independent of the cytoplasmic death domain (PMID:29459438). In the immune system DR6 is a negative regulator of CD4+ T cell activation, limiting proliferation and Th2 cytokine responses and constraining graft-versus-host disease (PMID:11485735, PMID:12244201). In pathological vascular and tumor settings it promotes endothelial necroptosis via RIPK3/p-MLKL and tumor angiogenesis through IL-6/STAT3/p38 MAPK signaling (PMID:34105277, PMID:42020785, PMID:26950598), and in carcinoma cells it activates an AKT/NF-κB pro-survival program (PMID:38478147).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1998 Medium

    Established DR6 as a death-domain TNFR superfamily receptor that couples to canonical inflammatory and stress signaling, answering what kind of receptor this orphan was.

    Evidence Co-IP, ectopic expression and reporter assays in mammalian cells

    PMID:9714541

    Open questions at the time
    • No physiological ligand identified
    • TRADD interaction not placed in a downstream effector pathway
  2. 2001 Medium

    Defined the apoptotic wiring of DR6 as FADD-independent and showed its expression is induced by TNF-α via NF-κB, clarifying both how it kills and how it is transcriptionally controlled.

    Evidence Dominant-negative FADD, Bcl-2/Bcl-xL rescue, NF-κB inhibitor and RT-PCR/western assays

    PMID:11753679

    Open questions at the time
    • Identity of the FADD-independent adaptor unresolved
    • Apoptotic mechanism studied only in overexpression
  3. 2001 High

    Revealed an unanticipated immunological role: DR6 negatively regulates CD4+ T cell activation, expanding its function beyond apoptosis.

    Evidence DR6 KO mouse, proliferation/cytokine/transcription-factor assays

    PMID:11485735

    Open questions at the time
    • Ligand mediating T cell suppression not defined
    • Intracellular signaling linking DR6 to NF-ATc not mapped
  4. 2002 Medium

    Confirmed the negative-regulatory role of DR6 in vivo, showing loss accelerates graft-versus-host disease.

    Evidence Adoptive transfer of DR6 KO T cells in parent-to-F1 GVHD model

    PMID:12244201

    Open questions at the time
    • Cell-intrinsic versus extrinsic basis of the phenotype not separated
    • No ligand identified
  5. 2009 High

    Identified N-APP as a DR6 ligand and assigned DR6 distinct caspase routes for cell-body death (caspase 3) versus axon pruning (caspase 6) during trophic deprivation, providing the first ligand and developmental mechanism.

    Evidence DR6 KO/siRNA, binding assays, caspase-specific assays, NMJ genetic epistasis with APP mutants

    PMID:19225519

    Open questions at the time
    • Mechanism segregating caspase-3 vs caspase-6 outputs unknown
    • Proximal cytoplasmic signaling adaptor undefined
  6. 2011 High

    Provided the structural framework for DR6 ligand recognition by resolving its four-CRD ectodomain.

    Evidence X-ray crystallography of recombinant DR6 ectodomain at 2.2 Å

    PMID:21463639

    Open questions at the time
    • No ligand bound in this structure
    • Activation-associated conformational changes not captured
  7. 2012 High

    Placed DR6 in a TROY-containing complex downstream of Wnt/β-catenin that drives CNS angiogenesis and BBB formation via VEGF-dependent JNK, defining a developmental vascular function.

    Evidence Co-IP, zebrafish and mouse knockouts, endothelial sprouting and JNK assays, expression profiling

    PMID:22340501

    Open questions at the time
    • Ligand triggering endothelial DR6/TROY signaling unknown
    • Stoichiometry of the DR6/TROY complex undefined
  8. 2013 High

    Showed DR6 forms a complex with p75NTR to mediate Aβ-induced cortical neuron death, linking it to amyloid neurotoxicity.

    Evidence Reciprocal Co-IP, DR6 and p75NTR null neurons, dominant-negative and blocking antibody, caspase 3 assays

    PMID:23559013

    Open questions at the time
    • Whether Aβ binds DR6 directly not established
    • Relationship between p75NTR and APP ligand pathways unclear
  9. 2013 Medium

    Extended DR6-driven death to motor neurons in ALS and showed antagonist antibody promotes survival via Akt/caspase-3, indicating therapeutic tractability.

    Evidence Antagonist antibody 5D10, caspase 3 and Akt assays, multiple stress models and SOD1(G93A) mice

    PMID:24113175

    Open questions at the time
    • Endogenous ligand in ALS models not identified
    • Antibody mechanism of action not structurally defined
  10. 2015 High

    Defined the structural basis of APP-induced activation by resolving the DR6 ectodomain/APP-E2 complex and supporting a dimerization model.

    Evidence X-ray crystallography of DR6 ectodomain/APP-E2 complex

    PMID:25838500

    Open questions at the time
    • Higher-order receptor clustering not visualized
    • Coupling of dimerization to cytoplasmic signaling not shown structurally
  11. 2015 Medium

    Identified miR-210 as a post-transcriptional repressor of DR6 that dampens NF-κB-driven inflammation, adding a regulatory input layer.

    Evidence Luciferase 3'-UTR reporter, miR-210 mimic/siDR6, NF-κB and cytokine assays in chondrocytes

    PMID:26244598

    Open questions at the time
    • Generality of miR-210 control beyond chondrocytes untested
    • In vivo relevance not demonstrated
  12. 2016 Medium

    Linked DR6 to tumor angiogenesis through IL-6/STAT3 and IL-6/p38 MAPK control of pro-angiogenic factors.

    Evidence DR6 knockdown in B16 cells, xenograft, cytokine profiling, pathway inhibitors

    PMID:26950598

    Open questions at the time
    • Receptor-proximal events upstream of IL-6 not defined
    • Single tumor model
  13. 2018 High

    Revealed a non-cell-autonomous mechanism: ADAM10 sheds DR6 to release a soluble ectodomain that restrains Schwann cell myelination independent of the death domain.

    Evidence DR6 KO mice, ADAM10 cleavage mapping, sDR6 rescue and death-domain deletion construct, myelination assays

    PMID:29459438

    Open questions at the time
    • Receptor/target of sDR6 on Schwann cells unknown
    • Regulation of ADAM10 cleavage not defined
  14. 2019 Medium

    Positioned DR6 at the catastrophic transition of axon degeneration, downstream of spheroid rupture and calpain-dependent, refining its temporal role.

    Evidence DR6 KO neurons, conditioned-media transfer, live imaging, calpain inhibitors

    PMID:31628183

    Open questions at the time
    • Diffusible factor in conditioned media not identified
    • Link between calpain and DR6 activation unresolved
  15. 2020 Medium

    Reinforced DR6/APP interaction and showed DR6 knockdown reduces APP expression, neuroinflammation, and apoptosis in AD model mice.

    Evidence Co-IP, knockdown, cytokine ELISA, apoptosis flow cytometry

    PMID:33075465

    Open questions at the time
    • Directionality of DR6-APP regulation not mechanistically resolved
    • Single AD model
  16. 2021 Medium

    Demonstrated tumor-cell APP engages endothelial DR6 to trigger necroptosis enabling metastasis, and that blocking the interaction is anti-metastatic.

    Evidence Peptidomimetic binding (KD 51 nM), in vitro necroptosis, multiple metastasis mouse models

    PMID:34105277

    Open questions at the time
    • Mechanism linking DR6 to RIPK3/MLKL necrosome not detailed here
    • Single lab
  17. 2024 Medium

    Showed endothelial DR6 maintains BBB integrity against Aβ oligomers through Wnt/β-catenin and JNK, connecting its vascular and amyloid roles.

    Evidence DR6 knockdown/overexpression in brain endothelial cells, Aβ treatment, pathway western blots, permeability assay

    PMID:38609388

    Open questions at the time
    • In vivo BBB confirmation absent
    • Ligand driving protective signaling unknown
  18. 2024 Medium

    Established DR6 as an upstream activator of AKT/NF-κB driving proliferation, invasion, and stemness in colorectal cancer.

    Evidence Knockdown/overexpression, SC79 rescue, functional assays, xenograft

    PMID:38478147

    Open questions at the time
    • Receptor-proximal coupling to AKT undefined
    • Ligand in CRC context unknown
  19. 2024 Medium

    Identified RBP4 as an antagonistic ligand that drives Ca2+-sensitive DR6 homodimerization via an extracellular disordered region to block pro-degenerative heterointeractions, reframing dimerization state as the activity switch.

    Evidence Single-molecule photobleaching, single-receptor tracking, domain mutation analysis (preprint)

    Open questions at the time
    • Preprint, single lab, not independently replicated
    • In vivo neuroprotection by RBP4 not shown
  20. 2025 Medium

    Showed TNFRSF21 promotes endothelial necroptosis in sepsis by upregulating the RIPK3/p-MLKL necrosome, extending its necroptotic role to systemic vascular injury.

    Evidence shTNFRSF21, RIPK3/p-MLKL western blots, CLP and LPS sepsis models, survival/leakage assays

    PMID:42020785

    Open questions at the time
    • Molecular link from DR6 to necrosome assembly not defined
    • Activating ligand in sepsis unknown
  21. 2026 Medium

    Revealed a non-neuronal epithelial function: TNFRSF21 interacts with APP and regulates keratinization genes and wound healing.

    Evidence Co-IP, knockdown/overexpression in keratinocytes, RNA-seq, wound-healing mouse model

    PMID:41914294

    Open questions at the time
    • Signaling pathway linking DR6 to keratin genes not mapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ligand-driven dimerization state (productive APP-induced vs antagonistic RBP4-induced) is decoded into divergent outputs—apoptosis, necroptosis, NF-κB/JNK, AKT survival—through a defined cytoplasmic adaptor remains unresolved.
  • FADD-independent proximal adaptor unidentified
  • Mechanism selecting caspase-3 vs caspase-6 vs RIPK3 outputs unknown
  • No unified model reconciling pro-death and pro-survival roles across cell types

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0038024 cargo receptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 2
Partners
ADAM10APPP75NTRRBP4TRADDTROY
Complex memberships
DR6/TROY complexDR6/p75NTR signaling complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 DR6 (TNFRSF21) is a type I transmembrane receptor with four extracellular cysteine-rich motifs and a cytoplasmic death domain. Ectopic expression induces apoptosis and activation of both NF-κB and JNK. DR6 interacts with TRADD (the adaptor previously shown to associate with TNFR1), identified by co-immunoprecipitation. Co-immunoprecipitation, ectopic expression in mammalian cells, apoptosis assays, NF-κB and JNK reporter assays FEBS letters Medium 9714541
2001 DR6-mediated apoptosis is inhibited by Bcl-2, Bcl-xL, and survivin, but a dominant-negative FADD mutant failed to protect against DR6-induced apoptosis, indicating DR6 induces apoptosis via a FADD-independent mechanism. TNF-alpha induces DR6 mRNA and protein expression through NF-κB activation. Dominant-negative FADD co-expression, Bcl-2/Bcl-xL overexpression rescue assays, TNF-alpha treatment with NF-κB inhibitors, RT-PCR and western blot Oncogene Medium 11753679
2001 DR6 is highly expressed in resting T cells and downregulated upon activation. DR6-deficient mice show hyperproliferation of CD4+ T cells in response to TCR stimulation and protein antigen challenge, enhanced IL-2 responsiveness, increased CD28 and decreased CTLA-4 expression, and enhanced Th2 cytokine production associated with increased nuclear NF-ATc. DR6 thus functions as a negative regulatory receptor for CD4+ T cell activation. DR6 knockout mouse generation, T cell proliferation assays, cytokine measurement, flow cytometry, transcription factor nuclear localization assays Immunity High 11485735
2009 DR6 is broadly expressed by developing neurons and is required for normal cell body death (via caspase 3) and axonal pruning (via caspase 6) after trophic-factor deprivation. Trophic-factor deprivation triggers BACE-dependent shedding of surface APP, releasing an N-terminal APP fragment (N-APP) that binds DR6 and triggers degeneration. Loss- and gain-of-function studies in vitro and in vivo, plus a common neuromuscular junction phenotype in APP and DR6 mutant mice, support this model. Loss-of-function (DR6 KO mice, siRNA), gain-of-function, binding assays (N-APP/DR6 interaction), caspase activity assays, in vivo axon pruning/neuron death assays, genetic epistasis (NMJ phenotype in double mutant mice) Nature High 19225519
2011 Crystal structure of the extracellular cysteine-rich region of DR6 resolved to 2.2 Å, showing four cysteine-rich domains (CRDs) arranged in a rod-like structure with DR6-specific surface patches responsible for ligand recognition. X-ray crystallography of recombinant DR6 extracellular domain Journal of molecular biology High 21463639
2012 DR6 and TROY (TNFRSF19) interact both genetically and physically, are required for VEGF-mediated JNK activation and human brain endothelial sprouting in vitro, and regulate CNS-specific angiogenesis and blood-brain barrier formation. DR6 and TROY are downstream target genes of Wnt/β-catenin signaling in brain endothelium. Co-immunoprecipitation (DR6/TROY physical interaction), zebrafish and mouse genetic knockouts, in vitro endothelial sprouting assays, JNK activity assays, gene expression profiling Developmental cell High 22340501
2013 DR6 binds p75NTR and forms a signaling complex responsible for Aβ-induced cortical neuron death. Cortical neurons from DR6 or p75NTR null mice are resistant to Aβ-induced neurotoxicity. Blocking DR6/p75NTR interaction with anti-DR6 antibodies or dominant-negative DR6 (lacking the cytoplasmic death domain) attenuates caspase 3 activation and cell death. Co-immunoprecipitation (DR6/p75NTR complex), DR6 and p75NTR null mouse neurons, dominant-negative DR6 construct, anti-DR6 blocking antibodies, caspase 3 activity assays Cell death & disease High 23559013
2015 Crystal structure of DR6 ectodomain in complex with the E2 domain of APP, showing the structural basis of APP binding to DR6 and supporting a model in which APP induces DR6 dimerization and activation at the cell surface. X-ray crystallography of DR6 ectodomain/APP-E2 complex Genes & development High 25838500
2015 miR-210 targets the 3'-UTR of DR6 to inhibit its expression (confirmed by luciferase assay), thereby inhibiting NF-κB pathway activation and reducing inflammatory cytokine production and apoptosis in chondrocytes. Luciferase reporter assay (miR-210 targeting DR6 3'-UTR), miR-210 mimic/siDR6 transfection, NF-κB pathway activation assays, cytokine ELISA Scientific reports Medium 26244598
2016 DR6 knockdown in mouse B16 melanoma cells suppresses tumor angiogenesis in vivo by inhibiting IL-6 secretion, which in turn reduces VEGF-A, PDGF-β, VEGF-D, and PDGFR-α expression. DR6-dependent angiogenesis proceeds through IL-6/P38 MAPK and IL-6/STAT3 pathways. DR6 knockdown in B16 cells, xenograft tumor model, cytokine profiling, pathway inhibitor assays (P38 MAPK, STAT3) Oncogenesis Medium 26950598
2018 Neuronal DR6 is cleaved by ADAM10, releasing a soluble DR6 ectodomain (sDR6) that acts in a non-cell-autonomous (paracrine) manner to reduce Schwann cell proliferation and myelination. This function is independent of DR6's cytoplasmic death domain. The sDR6 ectodomain alone was sufficient to rescue the precocious myelination phenotype observed in DR6 KO mice. DR6 KO mice, in vitro myelination assay, ADAM10 cleavage identification (proteomics/biochemistry), sDR6 rescue experiment, death domain deletion construct The EMBO journal High 29459438
2019 DR6, but not p75NTR, is required for transition into the catastrophic phase of axon degeneration in response to conditioned media from degenerating axons following trophic withdrawal. DR6 acts downstream of spheroid rupture and is calpain-dependent in this process, but is not required for intra-axonal calcium flux, spheroid formation, or spheroid rupture. DR6 KO mouse neurons, conditioned media transfer assay, live imaging of axon degeneration phases, calpain inhibitor assays The Journal of neuroscience Medium 31628183
2020 APP and TNFRSF21 interact at the protein level (confirmed by Co-IP) in AD model mice. TNFRSF21 knockdown reduces APP expression and decreases neuroinflammation (TNF-α, IL-5, IFN-γ levels) and neuronal apoptosis in transgenic AD mice. Co-immunoprecipitation, TNFRSF21 knockdown in vitro, ELISA for inflammatory cytokines, flow cytometry for apoptosis, immunofluorescence European journal of pharmaceutical sciences Medium 33075465
2021 APP expressed on tumor cells binds DR6 on vascular endothelial cells to initiate the necroptosis pathway, leading to endothelial cell death and tumor cell extravasation/metastasis. A peptidomimetic inhibitor of DR6/APP interaction (PEG-tAHP-DRI, KD = 51.12 nM) blocked TC-induced EC necroptosis in vitro and anti-hematogenous metastasis in multiple mouse models. Phage display-derived peptidomimetic binding assay (KD measurement), in vitro necroptosis assay, multiple in vivo metastatic mouse models (B16F10, 4T1, CT26) Advanced science Medium 34105277
2024 Suppression of endothelial DR6 results in blood-brain barrier malfunction in the presence of Aβ oligomers, while DR6 overexpression in brain endothelial cells increases BBB functional proteins through activation of Wnt/β-catenin and JNK pathways and rescues BBB dysfunction in vitro. DR6 knockdown/overexpression in cultured brain endothelial cells, Aβ25-35 oligomer treatment, western blot for BBB functional proteins and pathway activation (Wnt/β-catenin, JNK), in vitro BBB permeability assay Cell death & disease Medium 38609388
2024 DR6 knockdown in colorectal cancer cells reduces AKT and NF-κB phosphorylation, and treatment with AKT activator SC79 rescues the inhibitory effects of DR6 knockdown on proliferation, migration, invasion, and stemness, establishing DR6 as an upstream activator of the AKT/NF-κB pathway in CRC. DR6 knockdown/overexpression, CCK-8 proliferation assay, transwell assays, sphere-forming assays, western blot for p-AKT and p-NF-κB, AKT activator rescue experiment, nude mouse xenograft Biochemical genetics Medium 38478147
2024 RBP4 (retinol binding protein 4) was identified as an antagonistic ligand of DR6. RBP4 drives DR6 dimerization on the plasma membrane via an extracellular intrinsically disordered region, preventing DR6 pro-degenerative heterointeractions and neurodegenerative processes. DR6 homodimerization is Ca2+-sensitive and depends on the extracellular intrinsically disordered region. Single-molecule photobleaching, single-receptor tracking, RBP4-DR6 binding characterization, domain deletion/mutation analysis bioRxivpreprint Medium
2025 TNFRSF21 promotes necroptosis of vascular endothelial cells in sepsis by upregulating RIPK3 and phospho-MLKL (necrosome components). shTNFRSF21 inhibited necrosome (RIPK3/p-MLKL) formation in septic vascular endothelial cells, improved vascular leakage in septic rats, and prolonged survival. shTNFRSF21 knockdown, western blot for RIPK3/p-MLKL, CLP and LPS sepsis models in vivo, vascular leakage assays, necroptosis inhibitor treatment Journal of molecular medicine Medium 42020785
2026 TNFRSF21 interacts with APP (confirmed by immunoprecipitation) in keratinocytes and regulates epithelial keratinization: TNFRSF21 knockdown downregulates KRT8, KRT18, and Claudin-1, while overexpression upregulates them and accelerates wound healing in a mouse model. Co-immunoprecipitation (TNFRSF21/APP interaction), gene knockdown and overexpression in keratinocytes, bulk RNA-seq, PPI analysis, full-thickness dorsal skin wound mouse model, immunostaining Frontiers in bioscience Medium 41914294
2002 Transfer of DR6 KO T cells into allogeneic recipients accelerates onset and increases severity of acute graft-versus-host disease, demonstrating that DR6 serves as a negative regulatory molecule in T cell immune responses in vivo. Enhanced activation and expansion of DR6 KO CD4+ and CD8+ T cells was observed. Adoptive transfer of DR6 KO T cells in parent-to-F1 GVHD model, histopathological analysis, T cell expansion quantification Journal of immunology Medium 12244201
2013 DR6 promotes motor neuron death in ALS through activation of the caspase 3 signaling pathway. Blocking DR6 with antagonist antibody 5D10 promotes motor neuron survival via activation of Akt phosphorylation and inhibition of caspase 3, in growth factor withdrawal, arsenite treatment, and SOD1(G93A) astrocyte co-culture models. DR6 antagonist antibody treatment, caspase 3 activity assays, Akt phosphorylation western blot, in vitro motor neuron survival assays, SOD1(G93A) transgenic mouse treatment Cell death & disease Medium 24113175

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 817 19225519
1982 Long-term human cytolytic T-cell lines allospecific for HLA-DR6 antigen are OKT4+. Proceedings of the National Academy of Sciences of the United States of America 331 6980419
1998 Identification and functional characterization of DR6, a novel death domain-containing TNF receptor. FEBS letters 229 9714541
2012 Death receptors DR6 and TROY regulate brain vascular development. Developmental cell 108 22340501
2015 MiR-210 inhibits NF-κB signaling pathway by targeting DR6 in osteoarthritis. Scientific reports 97 26244598
1994 Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype. Human immunology 86 7860360
2001 Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB. Oncogene 80 11753679
2001 Increased frequency of HLA-DR6 allele in Italian patients with hepatitis C virus-associated oral lichen planus. The British journal of dermatology 79 11298540
2018 Role of SARM1 and DR6 in retinal ganglion cell axonal and somal degeneration following axonal injury. Experimental eye research 68 29526794
2001 Enhanced CD4+ T cell proliferation and Th2 cytokine production in DR6-deficient mice. Immunity 64 11485735
1994 Certain HLA-DR5 and -DR6 major histocompatibility complex class II alleles are associated with a CD8 lymphocytic host response to human immunodeficiency virus type 1 characterized by low lymphocyte viral strain heterogeneity and slow disease progression. Proceedings of the National Academy of Sciences of the United States of America 56 7972086
2009 Tumor necrosis factor receptor superfamily member 21: TNFR-related death receptor-6, DR6. Advances in experimental medicine and biology 54 19760075
1997 Cloning of the human phospholipase C-gamma1 promoter and identification of a DR6-type vitamin D-responsive element. The Journal of biological chemistry 50 9045685
2013 A DR6/p75(NTR) complex is responsible for β-amyloid-induced cortical neuron death. Cell death & disease 44 23559013
2007 Primary sclerosing cholangitis is associated with extended HLA-DR3 and HLA-DR6 haplotypes. Tissue antigens 34 17257319
2013 Death receptor 6 (DR6) antagonist antibody is neuroprotective in the mouse SOD1G93A model of amyotrophic lateral sclerosis. Cell death & disease 29 24113175
2011 The crystal structure of death receptor 6 (DR6): a potential receptor of the amyloid precursor protein (APP). Journal of molecular biology 24 21463639
1996 HLA-DR6 (possibly DRB1*1301) is associated with susceptibility to Takayasu arteritis in Mexicans. Heart and vessels 24 9248846
1996 Six new DR52-associated DRB1 alleles, three of DR8, two of DR11, and one of DR6, reflect a variety of mechanisms which generate polymorphism in the MHC. Tissue antigens 23 8883301
2019 TNFRSF21 mutations cause high myopia. Journal of medical genetics 21 31189563
2019 Three Novel Players: PTK2B, SYK, and TNFRSF21 Were Identified to Be Involved in the Regulation of Bovine Mastitis Susceptibility via GWAS and Post-transcriptional Analysis. Frontiers in immunology 21 31447828
2016 Death receptor 6 (DR6) is required for mouse B16 tumor angiogenesis via the NF-κB, P38 MAPK and STAT3 pathways. Oncogenesis 21 26950598
2015 The crystal structure of DR6 in complex with the amyloid precursor protein provides insight into death receptor activation. Genes & development 21 25838500
2018 Upregulated miR‑20a‑5p expression promotes proliferation and invasion of head and neck squamous cell carcinoma cells by targeting of TNFRSF21. Oncology reports 20 29901115
2020 Amyloid precursor protein binds with TNFRSF21 to induce neural inflammation in Alzheimer's Disease. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 18 33075465
2018 Non-cell-autonomous function of DR6 in Schwann cell proliferation. The EMBO journal 17 29459438
2006 Prediction of desmoglein-3 peptides reveals multiple shared T-cell epitopes in HLA DR4- and DR6-associated pemphigus vulgaris. BMC bioinformatics 17 17254312
2022 M2 macrophage facilitated angiogenesis in cutaneous squamous cell carcinoma via circ_TNFRSF21/miR-3619-5p/ROCK axis. The Kaohsiung journal of medical sciences 15 35593591
2021 Multi-Arm PEG/Peptidomimetic Conjugate Inhibitors of DR6/APP Interaction Block Hematogenous Tumor Cell Extravasation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 15 34105277
2019 p75NTR and DR6 Regulate Distinct Phases of Axon Degeneration Demarcated by Spheroid Rupture. The Journal of neuroscience : the official journal of the Society for Neuroscience 14 31628183
1993 DR6 in Koreans. DR11 frequently acts as a recipient gene to create DR13 alleles. Human immunology 14 8300408
2010 The DR1 and DR6 first exons of human herpesvirus 6A are not required for virus replication in culture and are deleted in virus stocks that replicate well in T-cell lines. Journal of virology 12 20053742
2024 Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease. Cell death & disease 11 38609388
2016 Association of Immunosuppression with DR6 Expression during the Development and Progression of Spontaneous Ovarian Cancer in Laying Hen Model. Journal of immunology research 10 27579331
2013 Developmental patterns of DR6 in normal human hippocampus and in Down syndrome. Journal of neurodevelopmental disorders 10 23618225
2012 DR6 as a diagnostic and predictive biomarker in adult sarcoma. PloS one 9 22567163
2023 Circ_TNFRSF21 promotes cSCC metastasis and M2 macrophage polarization via miR-214-3p/CHI3L1. Journal of dermatological science 8 37442735
2023 Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma. The Journal of allergy and clinical immunology 8 37944567
2021 Expression of cell proliferation regulatory factors bricd5, tnfrsf21, cdk1 correlates with expression of clock gene cry1 in testes of Hu rams during puberty. Molecular biology reports 8 34626314
2019 Death Receptor 6 (DR6) Is Overexpressed in Astrocytomas. Anticancer research 8 31092421
2014 The DR6 protein from human herpesvirus-6B induces p53-independent cell cycle arrest in G2/M. Virology 7 24606703
2011 Computational prediction and analysis of the DR6-NAPP interaction. Proteins 7 21337622
2002 Accelerated onset and increased severity of acute graft-versus-host disease following adoptive transfer of DR6-deficient T cells. Journal of immunology (Baltimore, Md. : 1950) 7 12244201
2016 Enhancement of Ovarian Tumor Detection by DR6-Targeted Ultrasound Imaging Agents in Laying Hen Model of Spontaneous Ovarian Cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 6 27465898
2017 Determination of normal expression patterns of CD86, CD210a, CD261, CD262, CD264, CD358, and CD361 in peripheral blood and bone marrow cells by flow cytometry. Immunology letters 5 29274771
2022 CCN1 suppresses cell proliferation of esophageal squamous cell carcinoma through amyloid precursor protein without DR6 participation. Cellular signalling 4 35654297
2024 LPA suppresses HLA-DR expression in human melanoma cells: a potential immune escape mechanism involving LPAR1 and DR6-mediated release of IL-10. Acta pharmacologica Sinica 3 39187677
2020 miR-106a mimics the nuclear factor-κB signalling pathway by targeting DR6 in rats with osteoarthritis. Archives of medical science : AMS 2 38414449
2025 Loss of TNFRSF21 induces cisplatin sensitivity in lung adenocarcinoma. Oncology research 1 40109864
2024 DR6 Augments Colorectal Cancer Cell Growth, Invasion, and Stemness by Activating AKT/NF-κB Pathway. Biochemical genetics 1 38478147
2026 TNFRSF21 Orchestrates Epithelial Keratinization and Tight Junction Integrity in Periodontitis-Associated Oral Mucosal Repair. Frontiers in bioscience (Landmark edition) 0 41914294
2026 The role and mechanism of TNFRSF21 in promoting necroptosis of vascular endothelial cells and inducing vascular leakage in sepsis. Journal of molecular medicine (Berlin, Germany) 0 42020785
2025 Unraveling the mechanism of alleviating hyperoxia-induced Bronchopulmonary dysplasia: miR-93-5p-mediated regulation of TNFRSF21. Pediatrics and neonatology 0 41469311

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