Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as CD134 or OXO40; TNFRSF4 (also known as OX40, ACT35, CD134, IMD16, TXGP1L) activates NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. It also promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. It is primarily expressed on activated CD4+ and CD8+ T cells, where it is transiently expressed and upregulated on the most recently antigen-activated T cells within inflammatory lesions. This makes it an attractive target to modulate immune responses, i.e. TNFRSF4 (OX40) blocking agents to inhibit adverse inflammation or agonists to enhance immune responses. An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Some single nucleotide polymorphisms (SNPs) of its natural ligand OX40 ligand (OX40L, CD252), which is also found on activated T cells, have been associated with systemic lupus erythematosus.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   29 LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCR 108
Cdd:cd13406   1 LHCVGDTYPSGEKCCHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVNYEPCKPCTQCNQRSGSEEKQKCTKTSDTVCR 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507579  109 CRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRD 170
Cdd:cd13406  81 CRPGTQPLDSYKPGVDCVPCPPGHFSRGDNQACKPWTNCSLAGKRTLRPGSSTSDAVCEDRS 142

Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as CD134 or OXO40; TNFRSF4 (also known as OX40, ACT35, CD134, IMD16, TXGP1L) activates NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. It also promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. It is primarily expressed on activated CD4+ and CD8+ T cells, where it is transiently expressed and upregulated on the most recently antigen-activated T cells within inflammatory lesions. This makes it an attractive target to modulate immune responses, i.e. TNFRSF4 (OX40) blocking agents to inhibit adverse inflammation or agonists to enhance immune responses. An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Some single nucleotide polymorphisms (SNPs) of its natural ligand OX40 ligand (OX40L, CD252), which is also found on activated T cells, have been associated with systemic lupus erythematosus.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   29 LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCR 108
Cdd:cd13406   1 LHCVGDTYPSGEKCCHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVNYEPCKPCTQCNQRSGSEEKQKCTKTSDTVCR 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507579  109 CRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRD 170
Cdd:cd13406  81 CRPGTQPLDSYKPGVDCVPCPPGHFSRGDNQACKPWTNCSLAGKRTLRPGSSTSDAVCEDRS 142

Tumor necrosis factor receptor / nerve growth factor receptor repeats; Repeats in growth factor receptors that are involved in growth factor binding. TNF/TNFR

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 4507579      67 CGPGFYNDVVSSKPCKPCTWCNlrSGSERKQLCTATQDTVC 107
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCP--PGLVVKQPCTATSDTVC 39

Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as CD134 or OXO40; TNFRSF4 (also known as OX40, ACT35, CD134, IMD16, TXGP1L) activates NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. It also promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. It is primarily expressed on activated CD4+ and CD8+ T cells, where it is transiently expressed and upregulated on the most recently antigen-activated T cells within inflammatory lesions. This makes it an attractive target to modulate immune responses, i.e. TNFRSF4 (OX40) blocking agents to inhibit adverse inflammation or agonists to enhance immune responses. An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Some single nucleotide polymorphisms (SNPs) of its natural ligand OX40 ligand (OX40L, CD252), which is also found on activated T cells, have been associated with systemic lupus erythematosus.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   29 LHCVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCR 108
Cdd:cd13406   1 LHCVGDTYPSGEKCCHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVNYEPCKPCTQCNQRSGSEEKQKCTKTSDTVCR 80

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507579  109 CRAGTQPLDSYKPGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRD 170
Cdd:cd13406  81 CRPGTQPLDSYKPGVDCVPCPPGHFSRGDNQACKPWTNCSLAGKRTLRPGSSTSDAVCEDRS 142

Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), also known as receptor activator of nuclear factor-kappaB (RANK); TNFRSF11A (also known as RANK, FEO, OFE, ODFR, OSTS, PDB2, CD26, OPTB7, TRANCER, LOH18CR1) induces the activation of NF-kappa B and MAPK8/JNK through interactions with various TRAF adaptor proteins. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. The receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Juvenile Paget's disease (JPD) of bone. Alternatively spliced transcript variants have been described for this locus. Mutation analysis may improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   36 YPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDV-------VSSKPCKpCTWCNL-----RSGSERKQLCTA-- 101
Cdd:cd13411   8 YEYSGRCCSKCEPGKYMSSKCTVTSDSVCLPCGPDEYLDTwneedkcLLHKVCD-AGKALVavdpgNSTAPRRCACTAgy 86

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 4507579  102 --TQDTVCrCRAGTQ---------PLDSYKPGVdCAPCPPGHFSP--GDNQACKPWTNCTLAGKHTLQPASNSSDAIC 166
Cdd:cd13411  87 hwSEDCDC-CRRNTEcapgfgaqhPVQLNKDTV-CEPCLVGYFSDvfSSTDKCKPWTNCTILGLEEAVPGTNKSDVVC 162

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   36 YPSNDRCCHECRPGNGMVSRCSRSQnTVCRPCGPGF-YNDVVS-SKPCKPCTWCnlRSGSERKQLCTATQDTVCRCRAGT 113
Cdd:cd13416   8 YTSSGECCEQCPPGEGVARPCGDNQ-TVCEPCLDGVtFSDVVShTEPCQPCTRC--PGLMSMRAPCTATHDTVCECAYGY 84

                        90       100       110
                ....*....|....*....|....*....|...
gi 4507579  114 QPLDSYKPGVDCAPCPPGHfspGDNQACKPWTN 146
Cdd:cd13416  85 YLDEDSGTCEPCTVCPPGQ---GVVQSCGPNQD 114

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) in teleosts; also known as CD137; This subfamily of TNFRSF9 (also known as CD137, ILA, 4-1BB) is found in teleosts. CD137 plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors. Mostly, CD137 in teleosts have not been characterized.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   38 SNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCnlRSGSERKQLCTATQDTVCRCRAGTQPLD 117
Cdd:cd13424   9 KNYVCCESCHPGNRLVERCGPDPAELCKPCEPGTYTVKPLDYSCYICTQC--IGAQVLLKNCTPSSDTVCGCKEGLRCGD 86

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 4507579  118 SY--------------KPGVDCAPCPPGHFSPGDNQACKPW-TNCTLAGKHTLQPASNSSDAIC 166
Cdd:cd13424  87 AEcsfcvtecgkgqepLGKRDCRQCPVGTFNDQIHSKCKEWsTSCPDPNELIVFKGDATSDITC 150

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14) in teleost; also known as herpes virus entry mediator (HVEM); This subfamily of TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) is found in teleosts, many of which are as yet uncharacterized. It regulates T-cell immune responses by activating inflammatory as well as inhibitory signaling pathways. HVEM acts as a receptor for the canonical TNF-related ligand LIGHT (lymphotoxin-like), which exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM. It also acts as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules, thus, creating a functionally diverse set of intrinsic and bidirectional signaling pathways. HVEM is highly expressed in the gut epithelium. Genome-wide association studies have shown that HVEM is an inflammatory bowel disease (IBD) risk gene, suggesting that HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense, and the microbiota. Mouse models have revealed that HVEM is involved in colitis pathogenesis, mucosal host defense, and epithelial immunity, thus acting as a mucosal gatekeeper with multiple regulatory functions in the mucosa. HVEM plays a critical role in both tumor progression and resistance to antitumor immune responses, possibly through direct and indirect mechanisms. It is known to be expressed in several human malignancies, including esophageal squamous cell carcinoma, follicular lymphoma, and melanoma. HVEM network may therefore be an attractive target for drug intervention. In Asian seabass, the up-regulation of differentially expressed TNFRSF14 gene has been observed.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   36 YPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSS-KPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGTQ 114
Cdd:cd13405   6 YEINGECCPMCPPGSRVSRHCTEDTSTSCVPCPDGTYMDEPNGlEKCFPCTNCDPGFGLRVKQGCTYTSDTVCEPLEGFY 85

                        90       100
                ....*....|....*....|...
gi 4507579  115 PLDSYKPGVDCA----PCPPGHF 133
Cdd:cd13405  86 CIDSTKDGCSAAqrhsSCKPGQY 108

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                        10        20        30        40        50        60
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4507579   43 CHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSS-KPCKPCTWCnlRSGSERKQLCTATQDTVC 107
Cdd:cd13416  96 CTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSStDPCLPCTVC--EDGEVELRECTPVSDTVC 159

Tumor necrosis factor receptor superfamily member 21 (TNFRSF21), also known as death receptor (DR6); TNFRSF21 (also known as death receptor 6 (DR6), CD358, BM-018) is highly expressed in differentiating neurons as well as in the adult brain, and is upregulated in injured neurons. DR6 negatively regulates neurondendrocyte, axondendrocyte, and oligodendrocyte survival, hinders axondendrocyte and oligodendrocyte regeneration and its inhibition has a neuro-protective effect in nerve injury. 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. TNFRSF21 plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. Its possible ligand is alpha-amyloid precursor protein (APP), hence probably involved in the development of Alzheimer's disease; when released, APP binds in an autocrine/paracrine manner to activate a caspase-dependent self-destruction program that removes unnecessary or connectionless axons. 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. 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   43 CHECRPGNGMVSRCSRSQNTVCRPCGPGFY----NDVVSSKPC-KPCTWcnlrsGSERKQLCTATQDTVCRCRAGT---- 113
Cdd:cd10583  15 CDKCPAGTYVSKHCTETSLRECSPCPNGTFtrheNGIEQCHRCrKPCPA-----PMIEKTPCTALTDRECTCPPGTflsn 89

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579  114 ---QPLDSYKPG------------VDCAPCPPGHFS--PGDNQACKPWTNCTLAGKHTLQPASNSSDAIC 166
Cdd:cd10583  90 dtcVPHSVCPVGwgvrkkgtetedVRCKPCPRGTFSdvPSSVLKCKTYTDCLGLGLVVIKPGTKETDNVC 159

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137; TNFRSF9 (also known as CD137, ILA, 4-1BB) plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   43 CHECRPGngmvSRCSRSQNTVCRPCGPGFYNDVVSSKPCKPCTWCnlrSGSER-KQLCTATQDTVCRCRAG--------T 113
Cdd:cd13410   6 CSNCPAG----TFCGKNKDQTCIPCPPNSFSSTGGQQTCDICRKC---EGVFRtKKPCSSTSNAECECVPGfhclgpgcS 78

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 4507579  114 QPLDSYKPG-----VDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAIC 166
Cdd:cd13410  79 MCEPDCKQGqeltkEGCKDCSFGTFNDQEGGVCRPWTNCSLDGKSVLVNGTKERDVVC 136

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14), also known as herpes virus entry mediator (HVEM); TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) regulates T-cell immune responses by activating inflammatory, as well as inhibitory signaling pathways. HVEM acts as a receptor for the canonical TNF-related ligand LIGHT (lymphotoxin-like), which exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM. It also acts as a ligand for the immunoglobulin superfamily proteins BTLA (B and T lymphocyte attenuator) and CD160, a feature distinguishing HVEM from other immune regulatory molecules, thus, creating a functionally diverse set of intrinsic and bidirectional signaling pathways. HVEM is highly expressed in the gut epithelium. Genome-wide association studies have shown that Hvem is an inflammatory bowel disease (IBD) risk gene, suggesting that HVEM could have a regulatory role influencing the regulation of epithelial barrier, host defense, and the microbiota. Mouse models have revealed that HVEM is involved in colitis pathogenesis, mucosal host defense, and epithelial immunity, thus acting as a mucosal gatekeeper with multiple regulatory functions in the mucosa. HVEM plays a critical role in both tumor progression and resistance to antitumor immune responses, possibly through direct and indirect mechanisms. It is known to be expressed in several human malignancies, including esophageal squamous cell carcinoma, follicular lymphoma and melanoma. HVEM network may therefore be an attractive target for drug intervention.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   31 CVGDTYPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFY-NDVVSSKPCKPCTWCNLRSGSERKQLCTATQDTVCRC 109
Cdd:cd10582   1 CKEDEYPVGSECCPKCSPGYRVKKACGELTGTVCEPCPPGTYtAHLNGLSKCLQCRVCDPAMGLVTRRNCSSTENTVCGC 80

                ....*
gi 4507579  110 RAGTQ 114
Cdd:cd10582  81 IPGHF 85

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It binds TNF-alpha, through the death domain (DD), and activates NF-kappaB, mediates apoptosis and activates signaling pathways controlling inflammatory, immune, and stress responses. It mediates signal transduction by interacting with antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRAF2 and TRADD that play regulatory roles. The human genetic disorder called tumor necrosis factor associated periodic syndrome (TRAPS), or periodic fever syndrome, is associated with germline mutations of the extracellular domains of this receptor, possibly due to impaired receptor clearance. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Knockout studies in zebrafish embryos have shown that a signaling balance between TNFRSF1A and TNFRSF1B is required for endothelial cell integrity. TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 4507579   39 NDRCCHECRPGNGMVSRCSRS-QNTVCRPCGPGFYNDVVS-SKPCKPCTWCNlRSGSERKQLCTATQDTVCRCRAG 112
Cdd:cd15834  10 NGICCNKCHPGYKLKEECTAPgERSQCTPCPEGTYLEQINySPNCRRCTLCK-VKNEEEVSPCKKSSNTVCRCKKG 84

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), also known as TNFR1; TNFRSF1A (also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) binds TNF-alpha, through the death domain (DD), and activates NF-kappaB, mediates apoptosis and activates signaling pathways controlling inflammatory, immune, and stress responses. It mediates signal transduction by interacting with antiapoptotic protein BCL2-associated athanogene 4 (BAG4/SODD) and adaptor proteins TRAF2 and TRADD that play regulatory roles. The human genetic disorder called tumor necrosis factor associated periodic syndrome (TRAPS), or periodic fever syndrome, is associated with germline mutations of the extracellular domains of this receptor, possibly due to impaired receptor clearance. TNFRSF1A polymorphisms rs1800693 and rs4149584 are associated with elevated risk of multiple sclerosis. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. Patients with idiopathic recurrent acute pericarditis (IRAP), presumed to be an autoimmune process, have also been shown to carry rare mutations (R104Q and D12E) in the TNFRSF1A gene.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   36 YPSNDRCCHECRPGNGMVSRCSRS-QNTVCRPCGPGFYNDVV-SSKPCKPCTWCNLRSGSERKQLCTATQDTVCRCRAGt 113
Cdd:cd10576   8 HPNNNHCCTKCHKGTYLYNDCPGPgQDTVCRECENGTFTASEnYLRKCLSCSRCRKEMGQVEISPCTVDQDTVCGCRKN- 86

                        90
                ....*....|....*....
gi 4507579  114 QPLDSYKPGVDCAPCPPGH 132
Cdd:cd10576  87 QYQHYWSSLFQCKNCSLCL 105

Tumor necrosis factor receptor superfamily members, virus-encoded; This family contains viral TNFR homologs that include vaccinia virus (VACV) cytokine response modifier E (CrmE), an encoded TNFR that shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75, TNFR type 2), a cowpox virus encoded cytokine-response modifier B (crmB), which is a secreted form of TNF receptor that can contribute to the modification of TNF-mediated antiviral processes, and a myxoma virus (MYXV) T2 (M-T2) protein that binds and inhibits rabbit TNF-alpha. The CrmE structure confirms that the canonical TNFR fold is adopted, but only one of the two "ligand-binding" loops of TNFRSF1A is conserved, suggesting a mechanism for the higher affinity of poxvirus TNFRs for TNFalpha over lymphotoxin-alpha. CrmB protein specifically binds TNF-alpha and TNF-beta indicating that cowpox virus seeks to invade antiviral processes mediated by TNF. Intracellular M-T2 blocks virus-induced lymphocyte apoptosis via a highly conserved viral preligand assembly domain (vPLAD), which controls receptor signaling competency prior to ligand binding.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   36 YPSNDRCCHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKPCkpCTWCNLRSGSER--KQLCTATQDTVCRCRAGT 113
Cdd:cd15839   8 SNSNNLCCKSCPPGTYASHLCDTTSNTKCDPCPSDTFTSIPNHIPA--CLSCRGRCSSNQveTKSCSNTQNRICSCAPGY 85

                        90
                ....*....|....*....
gi 4507579  114 QPLdsYKPGVDCAPCPPGH 132
Cdd:cd15839  86 YCL--LKGSDGCVACAPKT 102

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR); TNFRSF18 (also known as activation-inducible TNF receptor (AITR), glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), CD357, GITR-D) has increased expression upon T-cell activation, and is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells. In inflammatory cells, GITR expression indicates a possible molecular link between steroid use and complicated acute sigmoid diverticulitis; increased MMP-9 expression by GITR signaling might explain morphological changes in the colonic wall in diverticulitis. Its ligand, GITRL, activates GITR which could then influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases, including autoimmune thyroid disease and rheumatoid arthritis. In systemic lupus erythematosus (SLE) patients, serum GITRL levels are increased compared with healthy controls. GITR and its ligand, GITRL, are possibly involved in the pathogenesis of primary Sjogren's syndrome (pSS). GITR is inactivated during tumor progression in Multiple Myeloma (MM); restoration of GITR expression in GITR deficient MM cells leads to inhibition of MM proliferation and induction of apoptosis, thus playing a pivotal role in MM pathogenesis and disease progression. Regulatory T-cells (Tregs) in liver tumor up-regulate the expression of GITR compared with Tregs in tumor-free liver tissue and blood. Regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of the TNFRSF18 gene have been identified in a group of male Gabonese individuals exposed to a wide array of parasitic diseases such as malaria, filariasis and schistosomiasis, and may serve as a basis to study parasite susceptibility in association studies.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   41 RCCHECRPGNGmvSRCSRSQNTVCRPCGPGFYndvVSSKPCKPCtwcnlrsgseRKQLCTATQdtvcrcraGTQPLDSYK 120
Cdd:cd13417   1 RCCRKCPSEEA--DAPCCDAEGDCKCVQPGFH---CGDPQCKTC----------KKHPCPPGQ--------EVQRQGKFD 57

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*
gi 4507579  121 PGVDCAPCPPGHFSPGDNQACKPWTNCTLAGKHTLQPASNSSDAICEDRDPPATQ 175
Cdd:cd13417  58 FGFECVPCANGTFSDGHDGHCKPWTDCSQFGFLTIFPGNKTHNAVCGPGPPPPEE 112

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6), also known as fas cell surface death receptor (Fas); TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas, APT1, CD95, FAS1, APO-1, FASTM, ALPS1A) contains a death domain and plays a central role in the physiological regulation of programmed cell death. It has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The receptor interactions with the Fas ligand (FasL), allowing the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10; autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, leading to apoptosis. This receptor has also been shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Of the several alternatively spliced transcript variants, some are candidates for nonsense-mediated mRNA decay (NMD). Isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   31 CVGDTYPSNDRCCHECRPGNGMVSRC-SRSQNTVCRPCGPGF-YNDVVS-SKPCKPCTWCNLRSGSERKQLCTATQDTVC 107
Cdd:cd10579  10 CSEGLYRGGQFCCQPCPPGTRKAIDCtTNGGKPDCVPCTEGKeYTDKKHySDKCRRCKICDEEHGLEVEKNCTRTQNTKC 89

                ...
gi 4507579  108 RCR 110
Cdd:cd10579  90 RCK 92

Tumor necrosis factor receptor superfamily member 26 (TNFRSF26), also known as tumor necrosis factor receptor homolog 3 (TNFRH3); TNFRSF26 (also known as tumor necrosis factor receptor homolog 3 (TNFRH3) or TNFRSF24) is predominantly expressed in embryos and lymphoid cell types, along with its closely related TNFRSF22 and TNFRSF23 orthologs, and is developmentally regulated. Unlike TNFRSF22/23, TNFRSF26 does not serve as a TRAIL decoy receptor; it remains an orphan receptor.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   31 CVGDTYPSNDRCCHECRPGNGMVSRCSRSQN-TVCRPCGPGFYNDVVSSKP-CKPCTWCnlRSGSERKQLCTATQDTVCR 108
Cdd:cd15837   1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGvGECAPCEPGTFTAHPNGETsCFPCSQC--RDDQEVVAECSATSDRQCQ 78

                ....*
gi 4507579  109 CRAGT 113
Cdd:cd15837  79 CKQGH 83

Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), also known as Osteoprotegerin (OPG); TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) is a secreted glycoprotein that regulates bone resorption. It binds to two ligands, RANKL (receptor activator of nuclear factor kappaB ligand, also known as osteoprotegerin ligand, OPGL, TRANCE, TNF-related activation induced cytokine), a critical cytokine for osteoclast differentiation, and TRAIL (TNF-related apoptosis-inducing ligand), involved in immune surveillance. Therefore, acting as a decoy receptor for RANKL and TRAIL, OPG inhibits the regulatory effects of nuclear factor-kappaB on inflammation, skeletal, and vascular systems, and prevents TRAIL-induced apoptosis. Studies in mice counterparts suggest that this protein and its ligand also play a role in lymph-node organogenesis and vascular calcification. Circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease. OPG has also been implicated in various inflammations and linked to diabetes and poor glycemic control. Alternatively spliced transcript variants of this gene have been reported, although their full length nature has not been determined.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 4507579   43 CHECRPGNGMVSRCSRSQNTVCRPCGPGFYNDVVSSKpcKPCTWCNL--RSGSERKQLCTATQDTVCRCRAG 112
Cdd:cd10581  36 CDQCPPGTYVKQHCSASRKTVCAPCPDHHYADDWNSN--DECQYCNTvcKELQYVKQECNSTHNRVCECVEG 105

Tumor necrosis factor receptor superfamily member 7 (TNFRSF7), also known as CD27; TNFRSF7 (also known as CD27, T14, S152, Tp55, S152, LPFS2) has a key role in the generation of immunological memory via effects on T-cell expansion and survival, and B cell development. It binds to ligand CD70, and plays a key role in regulating B-cell activation and immunoglobulin synthesis. CD27 transduces signals that lead to the activation of NF-kappaB and MAPK8/JNK, and mediates the signaling process through adaptor proteins TRAF2 and TRAF5. CD27-binding protein (SIVA), a pro-apoptotic protein, can bind to CD27 and may play an important role in the apoptosis induced by this receptor. The potential role of the CD27/CD70 pathway in the course of inflammatory diseases, such as arthritis, and inflammatory bowel disease, suggests that CD70 may be a target for immune intervention. The expression of CD27 and CD44 molecules correlates with the differentiation stage of B cell precursors and has been shown to have a biological significance in acute lymphoblastic leukemia.

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                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4507579   42 CCHECRPGNGMVSRCSR-SQNTVCRPCGPG--FYNDVVSSKPCKPCTWCNlrSGSERKQlCTATQDTVCRCRAGTQPLDS 118
Cdd:cd13408  36 CCQMCEPGTFLVKDCDQhGKAAQCDPCIPGvsFSPDHHARPHCESCRHCN--SGLLIRN-CTITANTECACPKGWQCRDK 112

                        90
                ....*....|..
gi 4507579  119 ykpgvDCAPCPP 130
Cdd:cd13408 113 -----ECTECDP 119

Tumor necrosis factor receptor superfamily member 10 (TNFRSF10), includes TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2); TNFRSF10 family contains TNFRSF10A (also known as DR4, Apo2, TRAIL-R1, CD261), TNFRSF10B (also known as DR5, KILLER, TRICK2A, TRAIL-R2, TRICKB, CD262), TNFRSF10C (also known as DcR1, TRAIL-R3, LIT, TRID, CD263), and TNFRSF10D (also known as DcR2, TRUNDD, TRAIL-R4, CD264). Tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL) binds to all 4 receptors. DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are membrane-bound and contain a death domain in their intracellular portion, which is able to transmit an apoptotic signal, thus often called death receptors. In contrast, DcR1 (TRAIL-R3), which lacks the complete intracellular portion and DcR2 (TRAIL-R4), which has a truncated cytoplasmic death domain, do not transmit an apoptotic signal, thus known as decoy receptors. Apoptosis mediated by DR4 and DR5 requires Fas (TNFRSF6)-associated via death domain (FADD), a death domain containing adaptor protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for TNFRSF10B/DR5. DcR1 appears to function as an antagonistic receptor that protects cells from TRAIL-induced apoptosis; it has been found to be a p53-regulated DNA damage-inducible gene. The expression of this gene is detected in many normal tissues but not in most cancer cell lines, which may explain the specific sensitivity of cancer cells to the apoptosis-inducing activity of TRAIL. DcR2 has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. The membrane expression of all of these receptors (DR4, DR5, DcR1, and DcR2) is greater in normal endometrium (NE) than in endometrioid adenocarcinoma (EAC). In EAC patients, membrane expression of these receptors are not independent predictors of survival. DcR1 and DcR2 expression is critical in cell growth and apoptosis in cutaneous or uveal melanoma; DcR1 and DcR2 are frequently methylated in both, leading to loss of gene expression and melanomagenesis. On the other hand, DR4 and DR5 methylation is rare in cutaneous melanoma and frequent in uveal melanoma; their expression is wholly independent of the promoter methylation status. DcR1 and DcR2 genes are also reported to be hyper-methylated in prostate cancer. The TRAIL ligand, a potent and specific inducer of apoptosis in cancer cells, has been explored as a therapeutic drug; experimental data has shown that DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.

                        10        20        30
                ....*....|....*....|....*....|...
gi 4507579   81 CKPCTWCnlRSGSERKQLCTATQDTVCRCRAGT 113
Cdd:cd10580  37 CLPCTVC--KSDEEELSPCTTTRNTECQCKPGT 67