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 720642787  26 CREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTC 105
Cdd:cd13407    1 CREKQYLHNGRCCSLCPPGQKLVSDCTEATDTECLPCEEGEFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTC 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 106 EEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVV 185
Cdd:cd13407   81 QEGQHCTSEACETCALHTSCKPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKGLVELQAGTNKTDVV 160

                 .
gi 720642787 186 C 186
Cdd:cd13407  161 C 161

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 720642787  26 CREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTC 105
Cdd:cd13407    1 CREKQYLHNGRCCSLCPPGQKLVSDCTEATDTECLPCEEGEFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTC 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 106 EEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVV 185
Cdd:cd13407   81 QEGQHCTSEACETCALHTSCKPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKGLVELQAGTNKTDVV 160

                 .
gi 720642787 186 C 186
Cdd:cd13407  161 C 161

TNF-alpha-receptor-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 720642787   4 LPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHC 77
Cdd:PHA02637  10 LFLSCIIINGRDIAPHAPSDGKCKDNEYKRHNLCCLSCPPGTYASRLCDIKTNTQCTPCGSGTFTSHNNHLPAC 83

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 720642787  26 CREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTC 105
Cdd:cd13407    1 CREKQYLHNGRCCSLCPPGQKLVSDCTEATDTECLPCEEGEFQDTWNRERHCHQHRYCDPNLGLRVQTEGTAETDTTCTC 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 106 EEGWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVV 185
Cdd:cd13407   81 QEGQHCTSEACETCALHTSCKPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKGLVELQAGTNKTDVV 160

                 .
gi 720642787 186 C 186
Cdd:cd13407  161 C 161

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 720642787  28 EKQYLINSQCCSLCQPGQKLVSDCTeFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEE 107
Cdd:cd13422    4 ETQYEKDGECCKMCGPGTRMSSDSG-CLDPQCQPCGEDEYQDKYTKENKCKRQPYCDPNKNFEISVNKSKTSRSVCKCKP 82

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 108 GWHCTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCEtKDLVVQQAGTNKTDVVCG 187
Cdd:cd13422   83 GFHCSSEECLTCVPHTTCGPGQGVKSKGNHIRDTVCEECPDGTFSNNSSAEGVCKKWTECE-SGYKVEAAGTNTSDNICV 161

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 720642787  26 CREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTC 105
Cdd:cd13405    1 CGPAEYEINGECCPMCPPGSRVSRHCTEDTSTSCVPCPDGTYMDEPNGLEKCFPCTNCDPGFGLRVKQGCTYTSDTVCEP 80

                         90       100       110
                 ....*....|....*....|....*....|.
gi 720642787 106 EEGWHCTSEACESCVL---HRSCSPGFGVKQ 133
Cdd:cd13405   81 LEGFYCIDSTKDGCSAaqrHSSCKPGQYIKQ 111

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 720642787  37 CCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTS--- 113
Cdd:cd15835   20 CCSKCRPGTRLKTKCSETSDTVCEPCPSGQYSENWNYYPNCFSCPKCKERKGLQYAQNCSSTTNAVCVCKPGMYCIMgfd 99

                         90       100       110
                 ....*....|....*....|....*....|.
gi 720642787 114 -EACESCVLHRSCSPGFGVKQIATGVSDTIC 143
Cdd:cd15835  100 hPSCSECKKYRTCKPGYGVSVPGTPTSDVKC 130

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 720642787  38 CSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQ-HKYCDPnlGLRVQQKGTSETDTICTCEEGwhcTSEAC 116
Cdd:cd10583   15 CDKCPAGTYVSKHCTETSLRECSPCPNGTFTRHENGIEQCHRcRKPCPA--PMIEKTPCTALTDRECTCPPG---TFLSN 89

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 117 ESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVC 186
Cdd:cd10583   90 DTCVPHSVCPVGWGVRKKGTETEDVRCKPCPRGTFSDVPSSVLKCKTYTDCLGLGLVVIKPGTKETDNVC 159

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 720642787  25 ACREKQYLINSQCCSLCQPGQKLVSDCTEfTETECLPCGESE-FLDTWNRETHCHQHKYCDPNLglRVQQKGTSETDTIC 103
Cdd:cd13416    2 ACPSGQYTSSGECCEQCPPGEGVARPCGD-NQTVCEPCLDGVtFSDVVSHTEPCQPCTRCPGLM--SMRAPCTATHDTVC 78

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 104 TCEEGWHcTSEACESCVLHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCEtKDLVVQQAGTNKTD 183
Cdd:cd13416   79 ECAYGYY-LDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCE-DGEVELRECTPVSD 156

                 ...
gi 720642787 184 VVC 186
Cdd:cd13416  157 TVC 159

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787  24 TACREKQYLINSQCCSLCQPGQKLVSDCTEFT-ETECLPCGE-SEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDT 101
Cdd:cd10579    8 INCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGgKPDCVPCTEgKEYTDKKHYSDKCRRCKICDEEHGLEVEKNCTRTQNT 87

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|..
gi 720642787 102 ICTCEEGWHCTSEACESCVLHRSCspGFGVKQIATGVSDTIC 143
Cdd:cd10579   88 KCRCKSNFFCNSSPCEHCDPCTTC--EHGIIEECTPTSNTKC 127

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 720642787  26 CREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNREThCHQHKYCDPNLGLRVQQKGTSETDTICTC 105
Cdd:cd13406    3 CVGDTYPSGEKCCHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVNYEP-CKPCTQCNQRSGSEEKQKCTKTSDTVCRC 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787 106 EEGWHCTSeacescvlhrscSPGFGVKqiatgvsdtiCEPCPVGFFSNVSSafEKCHPWTSCETKDLVVQQAGTNKTDVV 185
Cdd:cd13406   82 RPGTQPLD------------SYKPGVD----------CVPCPPGHFSRGDN--QACKPWTNCSLAGKRTLRPGSSTSDAV 137

                 ..
gi 720642787 186 CG 187
Cdd:cd13406  138 CE 139

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 720642787  25 ACREKQYLINSQCCSLCQPGQKLVSDCTE-FTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTIC 103
Cdd:cd13423    1 SCEDGTYQHEGLTCCLCPAGQHVEKHCTNnGTDGECEACEDGTYNSHPNSLDSCEPCTSCDPNANLEVEERCTPSSDTVC 80

                         90       100
                 ....*....|....*....|....
gi 720642787 104 TCEEGWHCTSEacESCVLHRSCSP 127
Cdd:cd13423   81 RCKEGHYCDKG--EECKVCYPCDT 102

Tumor necrosis factor receptor superfamily member 3 (TNFRSF3), also known as lymphotoxin beta receptor (LTBR); TNFRSF3 (also known as lymphotoxin beta receptor, LTbetaR, CD18, TNFCR, TNFR3, D12S370, TNFR-RP, TNFR2-RP, LT-BETA-R, TNF-R-III) plays a role in signaling during development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Its ligands include lymphotoxin (LT) alpha/beta membrane form (heterotrimer) and tumor necrosis factor ligand superfamily member 14 (also known as LIGHT). TNFRSF3 agonism by these ligands initiates canonical, as well as non-canonical nuclear factor-kappaB (NF-kappaB) signaling, and preferentially results in the translocation of p52-RELB complexes into the nucleus. While these ligands are often expressed by T and B cells, TNFRSF3 is conspicuous absence on T and B lymphocytes and NK cells, suggesting that signaling may be unidirectional for TNFRSF3. Activity of this receptor has also been linked to carcinogenesis; it helps trigger apoptosis and can also lead to release of the interleukin 8 (IL8). Alternatively spliced transcript variants encoding multiple isoforms have been observed.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 720642787  37 CCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEA- 115
Cdd:cd10578   48 CCSRCPPGTHVSAECSRSQDTVCATCPENSYNEHWNHLSICQLCRPCDPVLGFEEVAPCTSDRKTQCRCQPGMFCVHWDn 127

                         90
                 ....*....|....
gi 720642787 116 -CESCVLHRSCSPG 128
Cdd:cd10578  128 eCEHCEPLSDCPPG 141

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 720642787  26 CREKQYLINSQ--CCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHCHQHK-YCDPNlglRVQQKGTSET-DT 101
Cdd:cd15839    1 CNGNDYNSNSNnlCCKSCPPGTYASHLCDTTSNTKCDPCPSDTFTSIPNHIPACLSCRgRCSSN---QVETKSCSNTqNR 77

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 720642787 102 ICTCEEGWHC---TSEACESCVLHRSCSPGFGVKQiATGVSDTICEPCP 147
Cdd:cd15839   78 ICSCAPGYYCllkGSDGCVACAPKTKCGVGYGVSG-HTSTGDVICKKCP 125

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 720642787  90 RVQQKGTSETDTICTCEEGWHCTSEACESCvlHRSCSPGfgvkqiaTGVSDTICEPCPVGFFSNVSSafEKCHPWTSCET 169
Cdd:cd13410   51 RTKKPCSSTSNAECECVPGFHCLGPGCSMC--EPDCKQG-------QELTKEGCKDCSFGTFNDQEG--GVCRPWTNCSL 119

                         90
                 ....*....|....*...
gi 720642787 170 KDLVVQQAGTNKTDVVCG 187
Cdd:cd13410  120 DGKSVLVNGTKERDVVCG 137

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 720642787   8 CVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEF-TETECLPCGES-EFLDTWNRETHCHQHKYCDP 85
Cdd:cd13408    7 WVLGTLAGLSATPAPKSCPERHYWAQGKLCCQMCEPGTFLVKDCDQHgKAAQCDPCIPGvSFSPDHHARPHCESCRHCNS 86

                         90       100       110
                 ....*....|....*....|....*....|....
gi 720642787  86 NLGLRvqqKGTSETDTICTCEEGWHCTSEACESC 119
Cdd:cd13408   87 GLLIR---NCTITANTECACPKGWQCRDKECTEC 117

tumor necrosis factor receptor superfamily member 19-like (TNFRSF19L), also known as receptor expressed in lymphoid tissues (RELT); TNFRSF19L (also known as receptor expressed in lymphoid tissues (RELT)) is especially abundant in hematologic tissues and can stimulate the proliferation of T-cells. It serves as a substrate for the closely related kinases, odd-skipped related transcription factor 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK); RELT binds SPAK and uses it to mediate p38 and JNK activation, rather than rely on the canonical TRAF pathways for its function. RELT is capable of stimulating T-cell proliferation in the presence of CD3 signaling, which suggests its regulatory role in immune response. It interacts with phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein that mediates antiviral activity against DNA and RNA viruses; PLSCR1 is a regulator of hepatitis B virus X (HBV X) protein. RELT and PLSCR1 co-localize in intracellular regions of human embryonic kidney-293 cells, with RELT over-expression appearing to alter the localization of PLSCR1.

                         10        20        30        40        50
                 ....*....|....*....|....*....|....*....|....*....|.
gi 720642787 141 TICEPCPVGFFSNvSSAFEKCHPWTSCETKDLVVQQAGTNKTDVVCGESWT 191
Cdd:cd13419   25 VLCRSCPPGTFSD-SLGSEPCRPHTSCEVLKRKVATSGTATSDAVCGDCLP 74

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 720642787  26 CREKQYLINSQCCSLCQPGQKLVSDCTE-FTETECLPCGESEFLDTWNRETHCHQHKYCDPNlgLRVQQKGTSETDTICT 104
Cdd:cd15837    1 CGPGEYKSANLCCQLCPAGHYVSEPCQEnHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDD--QEVVAECSATSDRQCQ 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|
gi 720642787 105 CEEGWHCTSEAC-ESCVLHRSCSPGFGVKQIATGVSDTIC 143
Cdd:cd15837   79 CKQGHFYCDENClESCFRCSRCPGGRVVLQPCNATRDTVC 118

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 720642787 123 RSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSC-ETKDLVVQQAGTNKTDVVCG 187
Cdd:cd15835   22 SKCRPGTRLKTKCSETSDTVCEPCPSGQYSENWNYYPNCFSCPKCkERKGLQYAQNCSSTTNAVCV 87

TNF-alpha-receptor-like protein; Provisional

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 720642787   4 LPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECLPCGESEFLDTWNRETHC 77
Cdd:PHA02637  10 LFLSCIIINGRDIAPHAPSDGKCKDNEYKRHNLCCLSCPPGTYASRLCDIKTNTQCTPCGSGTFTSHNNHLPAC 83