Promotes apoptosis, possibly via a pathway that involves the activation of NF-kappa-B. Can also promote apoptosis mediated by BAX and by the release of cytochrome c from the mitochondria into the cytoplasm. Plays a role in neuronal apoptosis, including apoptosis in response to amyloid peptides derived from APP, and is required for both normal cell body death and axonal pruning. Trophic-factor deprivation triggers the cleavage of surface APP by beta-secretase to release sAPP-beta which is further cleaved to release an N-terminal fragment of APP (N-APP). N-APP binds TNFRSF21; this triggers caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6). Negatively regulates oligodendrocyte survival, maturation and myelination. Plays a role in signaling cascades triggered by stimulation of T-cell receptors, in the adaptive immune response and in the regulation of T-cell differentiation and proliferation. Negatively regulates T-cell responses and the release of cytokines such as IL4, IL5, IL10, IL13 and IFNG by Th2 cells. Negatively regulates the production of IgG, IgM and IgM in response to antigens. May inhibit the activation of JNK in response to T-cell stimulation.

1. MiR20a5p functioned as an oncogene in HNSCC by downregulating TNFRSF21. PMID: 29901115
2. Knockdown death receptor 6 by shRNA in human pDCs cell line GEN2.2 significantly diminished the CpG-ODN induced IFN-regulatory factor 7 nuclear localization and IFN-I production. PMID: 26906057
3. data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies PMID: 27487218
4. Increase in the expression levels of mRNA and protein for the death receptor 6 is associated with various types of gynaecological malignancy. PMID: 25113253
5. Circulating levels of DR6 and Gpm6B correlate with breast cancer tumor grade. PMID: 24696529
6. The present findings suggested that DR6 is involved in the pathogenesis of endometriosis by creating the proliferative and anti-apoptotic characteristics of endometriosis. PMID: 24028773
7. Our results support the view that DR6 functions with APP to modulate synaptic density in the adult CNS PMID: 24806669
8. These results provide direct support for the model that APP and DR6 function cell autonomously and in the same pathway to control pruning PMID: 24806670
9. our findings provide new insight into a novel mechanism by which DR6 induces downstream signaling in response to an agonist antibody. PMID: 24374337
10. DR6 knockout mice are viable and fertile, and show hyperproliferation of T cells when stimulated. PMID: 11714751
11. DR6 mediates T cell proliferation and differentiation in mice. PMID: 11485735
12. DR6-induced apoptosis occurs through a new pathway that is different from the type I and type II pathways through interacting with Bax. PMID: 22761420
13. DR6 serum protein may be a tool to aid in the diagnosis of some sarcomatous tumors to improve treatment planning. PMID: 22567163
14. SAXS measurements on the ectodomain suggested that a dimer defines the minimal physical unit of an unliganded DR6 molecule in solution. PMID: 22525750
15. findings show that DR6 expression is significantly but transiently upregulated only in activated both CD4+ and CD8+ T cells in NF-kappaB and NF-AT dependent manner with a contribution of PI3K-dependent signaling PMID: 21501873
16. The model is used to provide a satisfying structural and energetic interpretation of DR6-growth factor-like domain of NAPP binding and to suggest the possibility of and a mechanism for spontaneous apoptosis. PMID: 21337622
17. androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between ARA267-alpha and DR6 PMID: 15623156
18. MMP-14 and DR6 are part of a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells PMID: 17962943
19. N-glycosylation of the extracellular part might participate in directing DR6 into lipid raft membrane microdomains. PMID: 19654028

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Cell membrane; Single-pass type I membrane protein.

Detected in fetal spinal cord and in brain neurons, with higher levels in brain from Alzheimer disease patients (at protein level). Highly expressed in heart, brain, placenta, pancreas, lymph node, thymus and prostate. Detected at lower levels in lung, sk

HGNC: 13469

OMIM: 605732

KEGG: hsa:27242

STRING: 9606.ENSP00000296861

UniGene: Hs.443577