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 662236838  42 CKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGC 121
Cdd:cd10582    1 CKEDEYPVGSECCPKCSPGYRVKKACGELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAMGLVTRRNCSSTENTVCGC 80

                         90       100
                 ....*....|....*....|.
gi 662236838 122 SPGHFCIVQDGDHCAACRAYA 142
Cdd:cd10582   81 IPGHFCSAQDGDHCVECVPHS 101

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 662236838  42 CKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGC 121
Cdd:cd10582    1 CKEDEYPVGSECCPKCSPGYRVKKACGELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAMGLVTRRNCSSTENTVCGC 80

                         90       100
                 ....*....|....*....|.
gi 662236838 122 SPGHFCIVQDGDHCAACRAYA 142
Cdd:cd10582   81 IPGHFCSAQDGDHCVECVPHS 101

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|..
gi 662236838   78 CPPGTYIAHLNGLsKCLQCQMCDPamGLRASRNCSRTENAVC 119
Cdd:pfam00020   1 CPPGTYTDNWNGL-KCLPCTVCPP--GQVVVRPCTPTSDTVC 39

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 662236838  42 CKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGC 121
Cdd:cd10582    1 CKEDEYPVGSECCPKCSPGYRVKKACGELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAMGLVTRRNCSSTENTVCGC 80

                         90       100
                 ....*....|....*....|.
gi 662236838 122 SPGHFCIVQDGDHCAACRAYA 142
Cdd:cd10582   81 IPGHFCSAQDGDHCVECVPHS 101

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) in teleost; also known as TNFR2; This subfamily of TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) is found in teleosts. It binds TNF-alpha, but lacks the death domain (DD) that is associated with the cytoplasmic domain of TNFRSF1A (TNFR1). It is inducible and expressed exclusively by oligodendrocytes, astrocytes, T cells, thymocytes, myocytes, endothelial cells, and in human mesenchymal stem cells. TNFRSF1B protects oligodendrocyte progenitor cells (OLGs) against oxidative stress, and induces the up-regulation of cell survival genes. While pro-inflammatory and pathogen-clearing activities of TNF are mediated mainly through activation of TNFRSF1A, a strong activator of NF-kappaB, TNFRSF1B is more responsible for suppression of inflammation. Although the affinities of both receptors for soluble TNF are similar, TNFRSF1B is sometimes more abundantly expressed and thought to associate with TNF, thereby increasing its concentration near TNFRSF1A receptors, and making TNF available to activate TNFRSF1A (a ligand-passing mechanism). 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-kB in endothelial cells. In goldfish (Carassius aurutus L.), TNFRSF1B expression is substantially higher than that of TNFRSF1 in tissues and various immune cell types. Both receptors are most robustly expressed in monocytes; mRNA levels of TNFRSF1B are lowest in peripheral blood leukocytes.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  53 CCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGCSPGHFCIVQ-D 131
Cdd:cd15835   20 CCSKCRPGTRLKTKCSETSDTVCEPCPSGQYSENWNYYPNCFSCPKCKERKGLQYAQNCSSTTNAVCVCKPGMYCIMGfD 99

                         90       100       110
                 ....*....|....*....|....*....|.
gi 662236838 132 GDHCAACRAYATSSPGQRVQKGGTESQDTLC 162
Cdd:cd15835  100 HPSCSECKKYRTCKPGYGVSVPGTPTSDVKC 130

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40; TNFRSF5 (commonly known as CD40 and also as CDW40, p50, Bp50) is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  42 CKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGC 121
Cdd:cd13407    1 CREKQYLHNGRCCSLCPPGQKLVSDCTEATDTECLPCEEGEFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTC 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|
gi 662236838 122 SPGHFCIvqdGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFS 171
Cdd:cd13407   81 QEGQHCT---SEACETCALHTSCKPGFGVKQIATGVSDTICEPCPVGFFS 127

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5) in teleosts; also known as CD40; TNFRSF5 (commonly known as CD40 and also as CDW40, p50, Bp50) is widely expressed in diverse cell types including B lymphocytes, dendritic cells, platelets, monocytes, endothelial cells, and fibroblasts. It is essential in mediating a wide variety of immune and inflammatory responses, including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. Its natural immunomodulating ligand is CD40L, and a primary defect in the CD40/CD40L system is associated with X-linked hyper-IgM (XHIM) syndrome. It is also involved in tumorigenesis; CD40 expression is significantly higher in gastric carcinomas and it is associated with the lymphatic metastasis of cancer cells and their tumor node metastasis (TNM) classification. Upregulated levels of CD40/CD40L on B cells and T cells may play an important role in the immune pathogenesis of breast cancer. Consequently, the CD40/CD40L system serves as a link between tumorigenesis, atherosclerosis, and the immune system, and offers a potential target for drug therapy for related diseases, such as cancer, atherosclerosis, diabetes mellitus, and immunological rejection. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  43 KEDEYPVGSECCPKCSPGYRVKEACGELTGTvCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVCGCS 122
Cdd:cd13422    3 PETQYEKDGECCKMCGPGTRMSSDSGCLDPQ-CQPCGEDEYQDKYTKENKCKRQPYCDPNKNFEISVNKSKTSRSVCKCK 81

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 662236838 123 PGHFCivqDGDHCAACRAYATSSPGQRVQKGGTESQDTLCQNCPPGTFSPNGTLEE-CQHQTK 184
Cdd:cd13422   82 PGFHC---SSEECLTCVPHTTCGPGQGVKSKGNHIRDTVCEECPDGTFSNNSSAEGvCKKWTE 141

Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  53 CCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAmGLRASRNCSRTENAVCGCSPGHFCIVQDG 132
Cdd:cd00185    1 CCQRCPPGEYLSSDCTATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGG-NQVEKTPCTATDNRCCTCKPGFYCDEGTN 79

                 ....*..
gi 662236838 133 D-HCAAC 138
Cdd:cd00185   80 VeECKPC 86

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 662236838  42 CKEDEYPVGSECCPKCSPGYRVKEACGElTGTVCEPCPPG-TYIAHLNGLSKCLQCQMCDPAMGLRASrnCSRTENAVCG 120
Cdd:cd13416    3 CPSGQYTSSGECCEQCPPGEGVARPCGD-NQTVCEPCLDGvTFSDVVSHTEPCQPCTRCPGLMSMRAP--CTATHDTVCE 79

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|.
gi 662236838 121 CSPGHFCIVQDGdHCAACRayaTSSPGQRVQKGGTESQDTLCQNCPPGTFS 171
Cdd:cd13416   80 CAYGYYLDEDSG-TCEPCT---VCPPGQGVVQSCGPNQDTVCEACPEGTYS 126

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 662236838  42 CKEDEYPVGSE--CCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQCQ-MCDPamGLRASRNCSRTENAV 118
Cdd:cd15839    1 CNGNDYNSNSNnlCCKSCPPGTYASHLCDTTSNTKCDPCPSDTFTSIPNHIPACLSCRgRCSS--NQVETKSCSNTQNRI 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*...
gi 662236838 119 CGCSPGHFCIVQDGDHCAACRAYATSSPGQRVqKGGTESQDTLCQNCP 166
Cdd:cd15839   79 CSCAPGYYCLLKGSDGCVACAPKTKCGVGYGV-SGHTSTGDVICKKCP 125

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 662236838  40 PSCKEDEYPVGSECCPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNgLSKCLQCQMCDPAMGLRASRNCSRTENAVC 119
Cdd:cd13406    1 LHCVGDTYPSGEKCCHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVN-YEPCKPCTQCNQRSGSEEKQKCTKTSDTVC 79

                 ....*
gi 662236838 120 GCSPG 124
Cdd:cd13406   80 RCRPG 84

Tumor necrosis factor receptor superfamily member 6 (TNFRSF6) in teleosts; also known as fas cell surface death receptor (FasR); This subfamily of TNFRSF6 (also known as fas cell surface death receptor (FasR) or Fas; APT1; CD95; FAS1; APO-1; FASTM; ALPS1A) is found in teleosts. It contains a death domain and plays a central role in the physiological regulation of programmed cell death. In humans, 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. In channel catfish and the Japanese rice fish, medaka, homologs of Fas receptor (FasR), as well as FADD and caspase 8, have been identified and characterized, and likely constitute the teleost equivalent of the death-inducing signaling complex (DISC). FasL/FasR are involved in the initiation of apoptosis and suggest that mechanisms of cell-mediated cytotoxicity in teleosts are similar to those used by mammals; presumably, the mechanism of apoptosis induction via death receptors was evolutionarily established during the appearance of vertebrates.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  41 SCKEDEYPVGSECCPKCSPGYRVKEACGE-LTGTVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRASRNCSRTENAVC 119
Cdd:cd13423    1 SCEDGTYQHEGLTCCLCPAGQHVEKHCTNnGTDGECEACEDGTYNSHPNSLDSCEPCTSCDPNANLEVEERCTPSSDTVC 80

                         90
                 ....*....|....*....
gi 662236838 120 GCSPGHFCivQDGDHCAAC 138
Cdd:cd13423   81 RCKEGHYC--DKGEECKVC 97

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  42 CKEDEYPVGSECCPKCSPGYRVKEACGELTG-TVCEPCPPGTYIAHLNGLSKCLQCQMCDPAMGLRAsrNCSRTENAVCG 120
Cdd:cd15837    1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGvGECAPCEPGTFTAHPNGETSCFPCSQCRDDQEVVA--ECSATSDRQCQ 78

                 ....*..
gi 662236838 121 CSPGHFC 127
Cdd:cd15837   79 CKQGHFY 85

tumor necrosis factor receptor superfamily member 25 (TNFRSF25), also known as death receptor 3 (DR3); TNFRSF25 (also known as death receptor 3 (DR3), death domain receptor 3 (DDR3), apoptosis-mediating receptor, lymphocyte associated receptor of death (LARD), apoptosis inducing receptor (AIR), APO-3, translocating chain-association membrane protein (TRAMP), WSL-1, WSL-LR or TNFRSF12) is preferentially expressed in thymocytes and lymphocytes, and may play a role in regulating lymphocyte homeostasis. It has been detected in lymphocyte-rich tissues such as colon, intestine, thymus and spleen, as well as in the prostate. Various death domain containing adaptor proteins mediate the signal transduction of this receptor; it activates nuclear factor kappa-B (NFkB) 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. DR3 associates with tumor necrosis factor (TNF)-like cytokine 1A (TL1A also known as TNFSF15) on activated lymphocytes and induces pro-inflammatory signals; TL1A also binds decoy receptor DcR3 (also known as TNFRSF6B). DR3/DcR3/TL1A expression is increased in both serum and inflamed tissues in autoimmune diseases such as in several autoimmune diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), allergic asthma, experimental autoimmune encephalomyelitis, type 1 diabetes, ankylosing spondylitis (AS), and primary biliary cirrhosis (PBC), making modulation of TL1A-DR3 interaction a potential therapeutic target.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  50 GSECCPKCSPGYRVKEACGELTGT-VCEPCPPGTYIAHLNGL-SKCLQCQMCDPAMGLRASRNCSRTENAVCGCSPGHF- 126
Cdd:cd13420   13 GPFCCRGCPAGHYLKAPCTEPCGNsTCLPCPRGTFLARENHHkTDCTRCQACDEQASQVALENCSAVSDTHCGCESGWFv 92

                         90
                 ....*....|....*...
gi 662236838 127 ------CIVQDGDHCAAC 138
Cdd:cd13420   93 ecsvkdCVSSSPFSCKPC 110

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        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  53 CCPKCSPGYRVKEACGEltgtvCEPCPPG-TYIAHLNGLSKCLQCQMCDPamGLRASRNCSRTENAVCGCSPGHFCIVQD 131
Cdd:cd10580    1 SCGLCPAGTYVSEDSGD-----CIPCKEGvDYTEHPNGLPSCLPCTVCKS--DEEELSPCTTTRNTECQCKPGTFCDPDS 73

                 ....*...
gi 662236838 132 GDHCAACR 139
Cdd:cd10580   74 PEVCQKCS 81

Tumor necrosis factor receptor superfamily 11B (TNFRSF11B) in teleost; also known as Osteoprotegerin (OPG); This subfamily of TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) is found in teleosts. It 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. Genetic analysis of the Japanese rice fish medaka (Oryzias latipes) has shown that entire networks for bone formation are conserved between teleosts and mammals; enabling medaka to be used as a genetic model to monitor bone homeostasis in vivo.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  54 CPKCSPGYRVKEACGELTGTVCEPCPPGTYIAHLNGLSKCLQC-QMCDPAMglRASRNCSRTENAVCGCSPGHFcivQDG 132
Cdd:cd13412   22 CKKCPPGTHMAAHCTATTQTKCLPCPAAHYTELWNYLPRCLYCnNFCSENQ--EVEIECSATNNRVCRCKEGYY---MDS 96

                         90       100       110
                 ....*....|....*....|....*....|....*.
gi 662236838 133 DHCAacrAYATSSPGQRVQKGGTESQDTLCQNCPPG 168
Cdd:cd13412   97 DFCI---RHTECGPGYGVKTKGTTKQDTVCEKCPSG 129

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 662236838  67 CGELTGTVCEPCPPGTYIAHLNGLSkclqCQMCDPAMG-LRASRNCSRTENAVCGCSPGHFCIvqdGDHCAACraYATSS 145
Cdd:cd13410   15 CGKNKDQTCIPCPPNSFSSTGGQQT----CDICRKCEGvFRTKKPCSSTSNAECECVPGFHCL---GPGCSMC--EPDCK 85

                         90       100
                 ....*....|....*....|....*.
gi 662236838 146 PGQRVQKGGtesqdtlCQNCPPGTFS 171
Cdd:cd13410   86 QGQELTKEG-------CKDCSFGTFN 104

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 662236838  36 APALPSCKEDEY-PVGSECCPKCSPG-YRVKEACGELTGTVCEPCPPG-TYIAHLNGLSKCLQCQMCDPAMGLRasrNCS 112
Cdd:cd13408   18 TPAPKSCPERHYwAQGKLCCQMCEPGtFLVKDCDQHGKAAQCDPCIPGvSFSPDHHARPHCESCRHCNSGLLIR---NCT 94

                         90       100
                 ....*....|....*....|...
gi 662236838 113 RTENAVCGCSPGHFCIVQDGDHC 135
Cdd:cd13408   95 ITANTECACPKGWQCRDKECTEC 117

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.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 662236838  98 MCDPAMGLRASRNCSRTENAVCGC-SPGHFCivqdGDH-CAACRAYaTSSPGQRVQKGGTESQDTLCQNCPPGTFS 171
Cdd:cd13417    1 RCCRKCPSEEADAPCCDAEGDCKCvQPGFHC----GDPqCKTCKKH-PCPPGQEVQRQGKFDFGFECVPCANGTFS 71