Tumor necrosis factor receptor 21, N-terminal (IPR034034)

Short name: TNFRSF21_N

Overlapping homologous superfamilies


Domain relationships



Tumor necrosis factor receptor superfamily member 21 (TNFRSF21), also known as death receptor 6 (DR6), CD358, or BM-018, is highly expressed in differentiating neurons as well as in the adult brain, and is upregulated in injured neurons [PMID: 19225519]. DR6 negatively regulates neuron, axon, and oligodendrocyte survival, hinders axondendrocyte and oligodendrocyte regeneration and its inhibition has a neuro-protective effect in nerve injury [PMID: 23084432]. It activates nuclear factor kappa-B (NFkB) and mitogen-activated protein kinase 8 (MAPK8, also called c-Jun N-terminal kinase 1), and induces cell apoptosis by associating with TNFRSF1A-associated via death domain (TRADD), which is known to mediate signal transduction of tumor necrosis factor receptors [PMID: 9714541]. TNFRSF21 plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation [PMID: 11714751]. It binds alpha-amyloid precursor protein (APP); when released, APP binds in an autocrine/paracrine manner to activate a caspase-dependent self-destruction program that removes unnecessary or connectionless axons [PMID: 19225519]. Increasing beta-catenin levels in brain endothelium upregulates TNFRSF21 and TNFRSF19, indicating that these death receptors are downstream target genes of Wnt/beta-catenin signaling, which has been shown to be required for blood-brain barrier development [PMID: 22340501]. DR6 is up-regulated in numerous solid tumors as well as in tumor vascular cells, including ovarian cancer and may be a clinically useful diagnostic and predictive serum biomarker for some adult sarcoma subtypes [PMID: 22567163].

This entry represents the N-terminal domain of TNFRSF21. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [PMID: 9538693, PMID: 8387891, PMID: 11796220].

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.