1. Gene Aliases

TNF Receptor Superfamily Member 12A, TweakR, FN14, CD266, Fibroblast Growth Factor-Inducible Immediate-Early Response Protein 14, Tumor Necrosis Factor Receptor Superfamily Member 12A, FGF-Inducible 14, Tweak-Receptor, Tumor Necrosis Factor Receptor Superfamily, Member 12A, Type I Transmembrane Protein Fn14, CD266 Antigen

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=TNFRSF12A]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

Interactions with text mining support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway: Activation of NF-kB is fundamental to signal transduction by members of the TNFRSF. Expression of NF-kB target genes is essential for mounting innate immune responses to infectious microorganisms but is also important for the proper development and cellular compartmentalization of secondary lymphoid organs necessary to orchestrate an adaptive immune response.

NF-kB transcription factor family is activated by two distinct pathways: the canonical pathway involving NF-kB1 and the non-canonical pathway involving NF-kB2. Unlike NF-kB1 signalling, which can be activated by a wide variety of receptors, the NF-kB2 pathway is typically activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor receptor (TNF) super family (TNFRSF) members. These members include TNFR2 (Rauert et al. 2010), B cell activating factor of the TNF family receptor (BAFFR also known as TNFRSF13C) (Kayagaki et al. 2002, CD40 (also known as TNFRSF5) (Coope et al. 2002, lymphotoxin beta-receptor (LTBR also known as TNFRSF3) (Dejardin et al. 2002), receptor activator for nuclear factor kB (RANK also known as TNFRSF11A) (Novack et al. 2003), CD27 and Fibroblast growth factor-inducible immediate-early response protein 14 (FN14 also known as TNFRSF12A) etc. These receptors each mediate specific biological roles of the non-canonical NF-kB. These non-canonical NF-kB-stimulating receptors have one thing in common and is the presence of a TRAF-binding motif, which recruits different TNF receptor-associated factor (TRAF) members, particularly TRAF2 and TRAF3, to the receptor complex during ligand ligation (Grech et al. 2004, Bishop & Xie 2007). Receptor recruitment of these TRAF members leads to their degradation which is a critical step leading to the activation of NIK and induction of p100 processing (Sun 2011, 2012).[https://reactome.org/PathwayBrowser/#/R-HSA-5676594].

GO terms:

cell adhesion [The attachment of a cell, either to another cell or to an underlying substrate such as the extracellular matrix, via cell adhesion molecules. GO:0007155]

extrinsic apoptotic signaling pathway [The series of molecular signals in which a signal is conveyed from the cell surface to trigger the apoptotic death of a cell. The pathway starts with either a ligand binding to a cell surface receptor, or a ligand being withdrawn from a cell surface receptor (e.g. in the case of signaling by dependence receptors), and ends when the execution phase of apoptosis is triggered.|Fas acts as a death receptor with a role in apoptosis, but can also act as a non-apoptotic signal transducer. GO:0097191]

positive regulation of apoptotic process [Any process that activates or increases the frequency, rate or extent of cell death by apoptotic process.|This term should only be used when it is not possible to determine which phase or subtype of the apoptotic process is positively regulated by a gene product. Whenever detailed information is available, the more granular children terms should be used. GO:0043065]

positive regulation of axon extension [Any process that activates or increases the frequency, rate or extent of axon extension. GO:0045773]

positive regulation of extrinsic apoptotic signaling pathway [Any process that activates or increases the frequency, rate or extent of extrinsic apoptotic signaling pathway. GO:2001238]

regulation of angiogenesis [Any process that modulates the frequency, rate or extent of angiogenesis. GO:0045765]

regulation of wound healing [Any process that modulates the rate, frequency, or extent of the series of events that restore integrity to a damaged tissue, following an injury. GO:0061041]

substrate-dependent cell migration, cell attachment to substrate [The formation of adhesions that stabilize protrusions at the leading edge of a migrating cell; involves integrin activation, clustering, and the recruitment of structural and signaling components to nascent adhesions. GO:0006931]

MSigDB Signatures:

SEAVEY_EPITHELIOID_HEMANGIOENDOTHELIOMA: Genes overexpressed in Epithelioid Hemangioendothelioma versus Angiosarcoma, Kaposi Sarcoma, Hemangioblastoma, and Liver [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/SEAVEY_EPITHELIOID_HEMANGIOENDOTHELIOMA.html]

REACTOME_TNFR2_NON_CANONICAL_NF_KB_PATHWAY: TNFR2 non-canonical NF-kB pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_TNFR2_NON_CANONICAL_NF_KB_PATHWAY.html]

ANDERSEN_CHOLANGIOCARCINOMA_CLASS1: Genes overexpressed in cholangiocarcinoma class 1 associated with good prognosis [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ANDERSEN_CHOLANGIOCARCINOMA_CLASS1.html]

CREIGHTON_AKT1_SIGNALING_VIA_MTOR_DN: Genes in the AKT1 [GeneID=207] pathway which depend on MTOR [GeneID=2475], sensitive to RAD001 (everolimus) [PubChem=6442177]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/CREIGHTON_AKT1_SIGNALING_VIA_MTOR_DN.html]

AMIT_EGF_RESPONSE_240_MCF10A: Genes whose expression peaked at 240 min after stimulation of MCF10A cells with EGF [GeneID=1950]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_EGF_RESPONSE_240_MCF10A.html]

IBRAHIM_NRF2_UP: Genes up-regulated in HEK293T cells overexpressing FLAG-NRF2 [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/IBRAHIM_NRF2_UP.html]

WANG_ESOPHAGUS_CANCER_VS_NORMAL_UP: Up-regulated genes specific to esophageal adenocarcinoma (EAC) relative to normal tissue. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WANG_ESOPHAGUS_CANCER_VS_NORMAL_UP.html]

AMIT_EGF_RESPONSE_480_HELA: Genes whose expression peaked at 480 min after stimulation of HeLa cells with EGF [GeneID=1950]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/AMIT_EGF_RESPONSE_480_HELA.html]

KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION: Cytokine-cytokine receptor interaction [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION.html]

REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM: Cytokine Signaling in Immune system [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM.html]

ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY: Genes transiently induced only by the second pulse of EGF [GeneID =1950] in 184A1 cells (mammary epithelium). [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY.html]

WANG_CLIM2_TARGETS_DN: Genes down-regulated in MCF7 cells (breast cancer) engineered to conditionally express a dominant negative form of CLIM2 [GeneID=8861] by a Tet Off system. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WANG_CLIM2_TARGETS_DN.html]

KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP: Genes up-regulated in MEWO cells (melanoma) after 48h of methionine [PubChem=876] deprivation. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KOKKINAKIS_METHIONINE_DEPRIVATION_48HR_UP.html]

REACTOME_TNF_RECEPTOR_SUPERFAMILY_TNFSF_MEMBERS_MEDIATING_NON_CANONICAL_NF_KB_PATHWAY: TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_TNF_RECEPTOR_SUPERFAMILY_TNFSF_MEMBERS_MEDIATING_NON_CANONICAL_NF_KB_PATHWAY.html]

KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_DN: Genes down-regulated in MEWO cells (melanoma) after 96 h of methionine [PubChem=876] deprivation. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KOKKINAKIS_METHIONINE_DEPRIVATION_96HR_DN.html]

BENPORATH_NANOG_TARGETS: Set 'Nanog targets': genes upregulated and identified by ChIP on chip as Nanog [GeneID=79923] transcription factor targets in human embryonic stem cells. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/BENPORATH_NANOG_TARGETS.html]

KOINUMA_TARGETS_OF_SMAD2_OR_SMAD3: Genes with promoters occupied by SMAD2 or SMAD3 [GeneID=4087, 4088] in HaCaT cells (keratinocyte) according to a ChIP-chip analysis. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KOINUMA_TARGETS_OF_SMAD2_OR_SMAD3.html]

KIM_WT1_TARGETS_UP: Genes up-regulated in UB27 cells (osteosarcoma) at any time point after inducing the expression of a mutant form of WT1 [GeneID=7490]. [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KIM_WT1_TARGETS_UP.html]

7. Gene Descriptions

NCBI Gene Summary: Involved in positive regulation of extrinsic apoptotic signaling pathway and regulation of wound healing. Predicted to be located in cell surface and ruffle. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

GeneCards Summary: TNFRSF12A (TNF Receptor Superfamily Member 12A) is a Protein Coding gene. Diseases associated with TNFRSF12A include Glioblastoma and Multiple Sclerosis. Among its related pathways are Akt Signaling and TNF Superfamily - Human Ligand-Receptor Interactions and their Associated Functions.

UniProtKB/Swiss-Prot Summary: Receptor for TNFSF12/TWEAK. Weak inducer of apoptosis in some cell types. Promotes angiogenesis and the proliferation of endothelial cells. May modulate cellular adhesion to matrix proteins.

8. Cellular Location of Gene Product

Cytoplasmic and membranous expression in most tissues. Mainly localized to the plasma membrane. In addition localized to the cytosol. Predicted location: Membrane, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000006327/subcellular]

9. Mechanistic Information

Summary

The Tnfrsf12a gene encodes Fn14, a receptor crucial for regulating wound healing as it modulates positive regulation of the extrinsic apoptotic signaling pathway and extracellular matrix adhesion, promoting angiogenesis and endothelial proliferation. In the context of liver injuries or diseases, such as NAFL and hepatocellular carcinoma, Fn14 plays a role in tissue remodeling through the upregulation of genes associated with TNF signaling and non-canonical NF-kappaB signaling pathways. This leads to the initiation of reparative processes and the moderation of apoptosis, assisting in the recovery and regeneration of liver tissue.

Elevated expression of Tnfrsf12a during liver toxicity, such as exposure to environmental toxins, initiates a cascade of signaling events through the TNF/TWEAK pathway, which is crucial for triggering proliferative and survival responses in liver cells. For instance, the increase in Fn14 expression in biliary atresia triggers profibrogenic pathways important for liver repair, suggesting its involvement in the regulation of fibrogenic responses to maintain liver function. Upregulation of Fn14 can act as a response mechanism to mitigate liver damage by modulating fibrosis and apoptosis, effectively contributing to the resolution of inflammation and the restoration of hepatic architecture.

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000006327/tissue]

Cell type enchanced: alveolar cells type 1, basal respiratory cells, ductal cells, exocrine glandular cells, pancreatic endocrine cells, secretory cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000006327/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: