TNFs bind their physiological receptors (Homo sapiens)
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Members of the tumour necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) have crucial roles in both innate and adaptive immunity. These members are implicated in various acquired or genetic human diseases, ranging from septic shock to autoimmune disorders, allograft rejection and cancer (So et al. 2006).
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| 3xOX40:OX40L trimer | Arrow | R-HSA-5692315 (Reactome)  | ||
| CD27:CD70 homotrimer | Arrow | R-HSA-5669024 (Reactome) | ||
| CD27 | R-HSA-5669024 (Reactome) | |||
| CD70 homotrimer | R-HSA-5669024 (Reactome) | |||
| EDA-3:EDA2R | Arrow | R-HSA-5669013 (Reactome) | ||
| EDA-3 | R-HSA-5669013 (Reactome) | |||
| EDA2R | R-HSA-5669013 (Reactome) | |||
| EDA:EDAR:EDARADD | Arrow | R-HSA-5675656 (Reactome) | ||
| EDA:EDAR | Arrow | R-HSA-5669012 (Reactome) | ||
| EDA:EDAR | R-HSA-5675656 (Reactome) | |||
| EDA | R-HSA-5669012 (Reactome) | |||
| EDARADD | R-HSA-5675656 (Reactome) | |||
| EDAR | R-HSA-5669012 (Reactome) | |||
| LTA trimer:TNFRSF1A,1B,14 | Arrow | R-HSA-5669097 (Reactome) | ||
| LTA trimer | R-HSA-5669097 (Reactome) | |||
| OX40L trimer | R-HSA-5692315 (Reactome) | |||
| OX40 | R-HSA-5692315 (Reactome) | |||
| R-HSA-5669012 (Reactome) | Ectodysplasin-A (EDA) is a trimeric type II membrane protein whose sequence includes an interrupted collagenous domain of 19 Gly-X-Y repeats and a motif conserved in the tumor necrosis factor (TNF)-related ligand family. EDA regulates ectodermal appendage formation by colocalising with cytoskeletal structures on cell surfaces (Ezer et al. 1999). Activation of the NF-kappaB pathway by the tumor necrosis factor receptor superfamily member EDAR (EDAR) and its downstream adaptator EDAR-associated death domain (EDARADD) is essential for the development of hair follicles, teeth, exocrine glands and other ectodermal structures. EDA isoform 1 specifically binds EDAR. Defects in EDA can cause X-linked hypohydrotic ectodermal dysplasia 1 (ECTD1), the most common of many distinct ectodermal dysplasias characterised by sparse hair, abnormal or missing teeth and the inability to sweat (Cluzeau et al. 2011, Sadier et al. 2014). | |||
| R-HSA-5669013 (Reactome) | Ectodysplasin-A (EDA) is a trimeric type II membrane protein whose sequence includes an interrupted collagenous domain of 19 Gly-X-Y repeats and a motif conserved in the tumor necrosis factor (TNF)-related ligand family. EDA regulates ectodermal appendage formation by colocalising with cytoskeletal structures on cell surfaces (Ezer et al. 1999). Activation of the NF-kappaB pathway by the tumor necrosis factor receptor superfamily member EDAR (EDAR) and its downstream adaptator EDAR-associated death domain (EDARADD) is essential for the development of hair follicles, teeth, exocrine glands and other ectodermal structures. EDA isoform 3 specifically binds tumor necrosis factor receptor superfamily member 27 (EDA2R aka XEDAR) whilst EDA isoform 1 specifcally binds EDAR (Hymowitz et al. 2003). | |||
| R-HSA-5669024 (Reactome) | The CD70 antigen (CD70) is a cytokine that is found on the surface of activated but not resting T and B lymphocytes (Bowman et al. 1994). CD70 can bind to the CD27 antigen receptor (CD27), a dimeric membrane glycoprotein belonging to the tumor necrosis factor receptor family and found on the surface of most T lymphocytes (Camerini et al. 1991). This complex is thought to influence T-, B- and NK-cell functions (Salzer et al. 2013). Defects in CD27 can cause lymphoproliferative syndrome 2 (LPFS2), an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impaired T-cell-dependent B-cell responses and T-cell dysfunction (van Montfrans et al. 2012, Salzer et al. 2013). | |||
| R-HSA-5669035 (Reactome) | Tumor necrosis factor ligand superfamily member 11 (TNFSF11 aka osteoclast differentiation factor, ODF) is a cytokine that is involved in the regulation of bone remodeling and playing multiple roles in the immune system. Its effects are mediated by its binding to tumor necrosis factor receptor superfamily members TNFRSF11A (aka RANK) (Nakagawa et al. 1998) and TNFRSF11B (aka OPG) (Luan et al. 2012). Defects in TNFSF11 can cause autosomal recessive osteopetrosis 2 (OPTB2; MIM:259710), characterised by abnormally dense bone due to defective resorption of immature bone (Sobacchi et al. 2007). Defects in TNFRSF11A and B cause bone remodelling/osteopathy disorders (Hughes et al. 2000, Guerrini et al. 2008, Cundy et al. 2002). | |||
| R-HSA-5669097 (Reactome) | Lymphotoxin-alpha (LTA) is a cytokine produced by lymphocytes that plays an important role in the inflammatory and immunologic response. LTA is a product of stimulated T cells and can help elicit cytotoxic effects on cancer cells. In its homotrimeric form, LTA binds the tumor necrosis factor receptor superfamily members TNFRSF1A, 1B and 14 (Aggarwal 2003). | |||
| R-HSA-5675656 (Reactome) | Ectodysplasin-A (EDA) is a trimeric type II membrane protein related to the tumor necrosis factor (TNF)-related ligand family. Activation of the NF-kappaB pathway by the tumor necrosis factor receptor superfamily member EDAR (EDAR) and its downstream adaptator EDAR-associated death domain (EDARADD) is essential for the development and regulation of hair follicles, teeth, exocrine glands and other ectodermal structures (Yan et al. 2002). EDA isoform 1 specifically binds EDAR. A small number of hypohidrotic ectodermal dysplasias (HEDs) are caused by mutations in EDARADD (Chassaing et al. 2010). | |||
| R-HSA-5675947 (Reactome) | Tumor necrosis factor ligand superfamily member 18 (TNFSF18) is a cytokine that regulates T-cell receptor-mediated cell death and promotes leukocyte adhesion to endothelial cells. It binds to tumor necrosis factor receptor superfamily member 18 (TNFRSF18 aka GITR) (Gurney et al. 1999). | |||
| R-HSA-5675948 (Reactome) | Tumor necrosis factor ligand superfamily member 15 (TNFSF15 aka VEGI) mediates the activation of NF-kappaB and subsequently can inhibit vascular endothelial growth, angiogenesis and promote activation of caspases and apoptosis (Haridas et al. 1999). TNFSF15 can bind the secreted decoy receptor tumor necrosis factor receptor superfamily member 6B (TNFRSF6B aka DcR3). Upon binding, the cytotoxic effects of TNFSF15 are neutralised thereby protecting against apoptosis. TNFRSF6B can also neutralise the cytotoxic ligands TNFSF14 (aka LIGHT) and TNFSF6 (aka FASL) (Zhan et al. 2011). | |||
| R-HSA-5676607 (Reactome) | B cell activating factor (BAFF also known as TNFSF13B) and a proliferation inducing ligand (APRIL also known as TNFSF13) are two related members of the tumour necrosis factor ligand super family (TNFSF) that promote B-cell proliferation. BAFF binds to three receptors B-cell activating factor belonging to the TNF family receptor (BAFFR also known as TNFRSF13C ), B-cell maturation antigen (BCMA also known as TNFRSF17) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI also known as TNFRSF13B), whereas APRIL interacts with TACI and BCMA. BAFF and APRIL exhibit structural similarity and overlapping yet distinct receptor binding specificity. Both BAFF and APRIL bind BCMA, but the APRIL:BCMA interaction is of higher affinity. TACI binds to both BAFF and APRIL with similar affinity (Day et al. 2005, Marsters et al. 2000, Gross et al. 2000, Rickert et al. 2011). BAFF or APRIL binding to BCMA or TACI promotes B cell development, proliferation, activation, and survival (Moore et al. 1999, Schneider et al. 1999). BAFF and APRIL are secreted as trimers, but BAFF trimers can be ordered into 60-mer arrays (Liu et al. 2003, Lopez-Fraga et al. 2001). | |||
| R-HSA-5692315 (Reactome) | T-cell activation is mediated not only by antigen stimulation through T-cell receptors but also by costimulatory signals through costimulatory molecules. Among several costimulatory molecules, the tumor necrosis factor (TNF) receptor family member OX40 (also known as TNFRSF4 or CD134) plays a key role in the survival and homeostasis of effector and memory T cells (Godfrey et al. 1994, Kashiwakura et al. 2004, Zingoni et al. 2004). OX40 mediates this costimulation by binding to its partner OX40L (also known as TNFSF4 or CD252). OX40 is a type I transmembrane protein expressed predominantly on T-lymphocytes early after antigen activation. It binds with OX40L trimer expressed on activated antigen presenting cells and endothelial cells within acute inflammatory environments. OX40 mediates signalling independently and also can augment antigen-driven TCR signalling. OX40 signalling leads to the activation of NFkB1 (p50-RELA) to stimulate survival signals to T cells in the absence of antigen recognition. It can also activate hence to activation of noncanonical NF-κB2 (p52-RELB) through NIK which might also be necessary for transmitting survival signals (Kawamata et al. 1998, Arch et al. 1998). OX40 can also enhance TCR-induced calcium influx, leading to strong nuclear accumulation of NFATc1 and NFATc2 that likely regulate production of cytokines (So et al. 2006, Croft 2010). | |||
| R-HSA-5693012 (Reactome) | TNFRSF25 (also referred as DR3/TRAMP/LARD/WSL1) is a death-domain-containing tumor necrosis factor (TNF)-family receptor primarily expressed on T cells. It binds with TNFSF15 (TL1A), the TNF family ligand and induces T cell costimulation (Meylan et al. 2008). | |||
| RANKL,sRANKL trimer | R-HSA-5669035 (Reactome) | |||
| TAC1,BCMA | R-HSA-5676607 (Reactome) | |||
| TNFRSF11B | R-HSA-5669035 (Reactome) | |||
| TNFRSF18 | R-HSA-5675947 (Reactome) | |||
| TNFRSF1A,1B,14 | R-HSA-5669097 (Reactome) | |||
| TNFRSF25:TNFSF15 | Arrow | R-HSA-5693012 (Reactome) | ||
| TNFRSF25 | R-HSA-5693012 (Reactome) | |||
| TNFRSF6B:TNFSF6,14,15 | Arrow | R-HSA-5675948 (Reactome) | ||
| TNFRSF6B | R-HSA-5675948 (Reactome) | |||
| TNFSF11,sTNFSF11 trimer:3xTNFRSF11B | Arrow | R-HSA-5669035 (Reactome) | ||
| TNFSF15 | R-HSA-5693012 (Reactome) | |||
| TNFSF18:TNFRSF18 | Arrow | R-HSA-5675947 (Reactome) | ||
| TNFSF18 | R-HSA-5675947 (Reactome) | |||
| TNFSF6,14,15 | R-HSA-5675948 (Reactome) | |||
| sBAFF,sAPRIL trimers | R-HSA-5676607 (Reactome) | |||
| sBAFF,sAPRIL:3xTAC1,BCMA | Arrow | R-HSA-5676607 (Reactome) |
