TNFRSF21 Gene

HGNC Family	Tumor necrosis factor receptor superfamily (TNFRSF), CD molecules (CD)
Name	tumor necrosis factor receptor superfamily, member 21
Description	This gene encodes a member of the tumor necrosis factor receptor superfamily. The encoded protein activates nuclear factor kappa-B and mitogen-activated protein kinase 8 (also called c-Jun N-terminal kinase 1), and induces cell apoptosis. Through its death domain, the encoded receptor interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD) protein, which is known to mediate signal transduction of tumor necrosis factor receptors. Knockout studies in mice suggest that this gene plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. [provided by RefSeq, Jul 2013]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFRSF21, also known as Death Receptor 6 (DR6), is a transmembrane protein characterized by multiple cysteine‐rich domains in its ectodomain and a cytoplasmic death domain. Detailed structural and biochemical studies have revealed that DR6 undergoes extensive posttranslational modifications—including N‐ and O‑glycosylation as well as palmitoylation—that are critical for its plasma membrane targeting and partitioning into lipid microdomains. These structural features lay the foundation for its diverse signaling capabilities."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDR6 plays an important role in mediating apoptosis and regulating neuronal development. Overexpression studies indicate that DR6 can trigger a unique, mitochondria‐dependent apoptotic pathway that bypasses classical caspase‑8/Bid signaling and instead requires Bax translocation. In the nervous system, DR6 engagement—often in concert with its ligand derived from the amyloid precursor protein—has been implicated in developmental axonal pruning, modulation of synaptic density, and even neurodegeneration. Furthermore, DR6’s interaction with proteins such as presenilin‑associated protein (PSAP) supports a model in which binding partners facilitate the transfer of proapoptotic factors to the mitochondria, thereby initiating cell death."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in cell death and neurodevelopment, DR6 is a regulator of immune cell function. It is abundantly expressed in resting T cells and is modulated upon activation, where its expression is upregulated through NF‑κB and NF‑AT pathways. Functional studies in T lymphocytes have demonstrated that DR6 acts as a regulatory receptor that temperates CD4⁺ T‐cell proliferation and cytokine production, thereby influencing T‑helper cell polarization. These immune‐modulating functions suggest that DR6 has a role both in maintaining immune homeostasis and in fine‑tuning inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these fundamental cellular functions, TNFRSF21/DR6 is increasingly recognized for its involvement in various pathological processes. In oncogenesis, DR6 expressed on endothelial and tumor cells can initiate necroptosis in the endothelium, thereby facilitating tumor cell extravasation and metastasis. DR6 is also released from the cell surface via proteolytic cleavage by matrix metalloproteinase‑14, a process that can impair dendritic cell differentiation and contribute to tumor immune escape. In head and neck carcinoma, modulation of DR6 by microRNAs promotes tumor cell proliferation and migration. DR6 expression has emerged as a potential biomarker in several malignancies, including ovarian, breast, and gynecological cancers, and its levels correlate with disease progression in low‑grade gliomas. Moreover, dysregulated DR6 signaling has been observed in endometriosis, viral infection (HCV), and even in candidate gene studies of migraine, asthma, and cardiac fibrosis—underscoring its multifaceted roles in both cancer and non‑cancer pathophysiology. Notably, cross‐talk between DR6 and androgen receptor coactivators further hints at its potential involvement in hormone‑related tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "23"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Martin Klíma, Jitka Zájedová, Lenka Doubravská, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Death receptor 6 induces apoptosis not through type I or type II pathways, but via a unique mitochondria-dependent pathway by interacting with Bax protein."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.362038"}], "href": "https://doi.org/10.1074/jbc.M112.362038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22761420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22761420"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Olav Olsen, Dara Y Kallop, Todd McLaughlin, et al. 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Synonyms	DR6, BM-018, CD358
Proteins	TNR21_HUMAN
NCBI Gene ID	27242
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

TNFRSF21 has 10,355 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 118 datasets.

Click the + buttons to view associations for TNFRSF21 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

TNFRSF21 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TNFRSF21 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of TNFRSF21 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of TNFRSF21 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of TNFRSF21 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of TNFRSF21 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TNFRSF21 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFRSF21 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TNFRSF21 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TNFRSF21 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of TNFRSF21 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFRSF21 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with TNFRSF21 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with TNFRSF21 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TNFRSF21 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of TNFRSF21 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of TNFRSF21 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of TNFRSF21 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing TNFRSF21 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing TNFRSF21 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing TNFRSF21 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores 2025	cellular components containing TNFRSF21 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with TNFRSF21 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with TNFRSF21 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of TNFRSF21 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with TNFRSF21 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with TNFRSF21 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with TNFRSF21 gene/protein from the curated CTD Gene-Disease Associations dataset.
	dbGAP Gene-Trait Associations	traits associated with TNFRSF21 gene in GWAS and other genetic association datasets from the dbGAP Gene-Trait Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of TNFRSF21 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by TNFRSF21 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with TNFRSF21 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with TNFRSF21 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with TNFRSF21 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with TNFRSF21 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with TNFRSF21 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at TNFRSF21 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TNFRSF21 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of TNFRSF21 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing TNFRSF21 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with TNFRSF21 gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.