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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEIPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQEMVADCSATSDRKCQCR 127
Cdd:cd15837     1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDDQEVVAECSATSDRQCQCK 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1720424735 128 TGLYYYDPKFPESCRPCTKCPQGIPVLQECNSTANTVC 165
Cdd:cd15837    81 QGHFYCDENCLESCFRCSRCPGGRVVLQPCNATRDTVC 118

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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEIPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQEMVADCSATSDRKCQCR 127
Cdd:cd15837     1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDDQEVVAECSATSDRQCQCK 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1720424735 128 TGLYYYDPKFPESCRPCTKCPQGIPVLQECNSTANTVC 165
Cdd:cd15837    81 QGHFYCDENCLESCFRCSRCPGGRVVLQPCNATRDTVC 118

TNF-alpha-receptor-like protein; Provisional

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*...
gi 1720424735  47 KCPAGEYWSKDVCCKNCSAGTFVKAPCEIpHTQGQCEKCHPGTFTEKDNYLDACILCS 104
Cdd:PHA02637   31 KCKDNEYKRHNLCCLSCPPGTYASRLCDI-KTNTQCTPCGSGTFTSHNNHLPACLSCN 87

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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEIPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQEMVADCSATSDRKCQCR 127
Cdd:cd15837     1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDDQEVVAECSATSDRQCQCK 80

                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 1720424735 128 TGLYYYDPKFPESCRPCTKCPQGIPVLQECNSTANTVC 165
Cdd:cd15837    81 QGHFYCDENCLESCFRCSRCPGGRVVLQPCNATRDTVC 118

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 1720424735  47 KCPAGEYWSKDVCCKNCSAGTFVKAPCEIPHTQGQCEKCHPGT-FTEKDNYLDACILCSTCDKDQ--EMVADCSATSDRK 123
Cdd:cd10579     9 NCSEGLYRGGQFCCQPCPPGTRKAIDCTTNGGKPDCVPCTEGKeYTDKKHYSDKCRRCKICDEEHglEVEKNCTRTQNTK 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1720424735 124 CQCRTGlYYYDPKFPESCRPCTKCPQGIpvLQECNSTANTVC 165
Cdd:cd10579    89 CRCKSN-FFCNSSPCEHCDPCTTCEHGI--IEECTPTSNTKC 127

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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEIphTQGQCEKCHPG-TFTEKDNYLDACILCSTCDKDQEMVADCSATSDRKCQC 126
Cdd:cd13416     3 CPSGQYTSSGECCEQCPPGEGVARPCGD--NQTVCEPCLDGvTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1720424735 127 RTGLYYYDPKFpeSCRPCTKCPQGIPVLQECNSTANTVC 165
Cdd:cd13416    81 AYGYYLDEDSG--TCEPCTVCPPGQGVVQSCGPNQDTVC 117

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 1720424735  59 CCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKD-QEMVADCSATSDRKCQCRTGLYYYDPKF 137
Cdd:cd00185     1 CCQRCPPGEYLSSDCT-ATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGGnQVEKTPCTATDNRCCTCKPGFYCDEGTN 79

                  ....*...
gi 1720424735 138 PESCRPCT 145
Cdd:cd00185    80 VEECKPCT 87

Tumor necrosis factor receptor superfamily member 6B (TNFRSF6B), also known as decoy receptor 3 (DcR3); The subfamily TNFRSF6B is also known as decoy receptor 3 (DcR3), M68, or TR6. This protein is a soluble receptor without death domain and cytoplasmic domain, and secreted by cells. It acts as a decoy receptor that competes with death receptors for ligand binding. It is a pleiotropic immunomodulator and biomarker for inflammatory diseases, autoimmune diseases, and cancer. Over-expression of this gene has been noted in several cancers, including pancreatic carcinoma, and gastrointestinal tract tumors. It can neutralize the biological effects of three tumor necrosis factor superfamily (TNFSF) members: TNFSF6 (Fas ligand/FasL/CD95L) and TNFSF14 (LIGHT) which are both involved in apoptosis and inflammation, and TNFSF15 (TNF-like molecule 1A/TL1A), which is a T cell co-stimulator and involved in gut inflammation. DcR3 is a novel inflammatory marker; higher DcR3 levels strongly correlate with inflammation and independently predict cardiovascular and all-cause mortality in chronic kidney disease (CKD) patients on hemodialysis. Increased synovial inflammatory cells infiltration in rheumatoid arthritis and ankylosing spondylitis is also associated with the elevated DcR3 expression. In cartilaginous fish, mRNA expression of DcR3 in the thymus and leydig, which are the representative lymphoid tissues of elasmobranchs, suggests that DcR3 may act as a modulator in the immune system. Interestingly, in banded dogfish (Triakis scyllia), DcR3 mRNA is strongly expressed in the gill, compared with human expression in the normal lung; both are respiratory organs, suggesting potential relevance of DcR3 to respiratory function.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720424735  58 VCCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCST-CDKDQEMVADCSATSDRKCQCRTGLYYYDpk 136
Cdd:cd10575    14 LTCDQCPPGTFVAKHCT-RDRPTVCGPCPDLHYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCECKPGYYMEH-- 90

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1720424735 137 fpESCRPCTKCPQGIPVLQECNSTANTVCS-------SSVSSKTD 174
Cdd:cd10575    91 --GFCLRHSSCPPGEGVIKLGTPYSDTQCEpcppgffSASSSSTE 133

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 1720424735  49 PAGEYWSKDV--CCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCSTC--DKDQEMVADCSATSDRKC 124
Cdd:cd15835     8 TTTEYYNDGSnlCCSKCRPGTRLKTKCS-ETSDTVCEPCPSGQYSENWNYYPNCFSCPKCkeRKGLQYAQNCSSTTNAVC 86

                          90       100
                  ....*....|....*....|....*....
gi 1720424735 125 QCRTGLY---YYDPKFPESCRPCTKCPQG 150
Cdd:cd15835    87 VCKPGMYcimGFDHPSCSECKKYRTCKPG 115

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), also known as TNFR2; TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) 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).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720424735  52 EYWSKDV--CCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCST-CDKDQEMVADCSATSDRKCQCRT 128
Cdd:cd10577     6 EYYDEKAqmCCSKCPPGQHVKHSCT-KTSDTVCAPCEESTYTQLWNWVPECLSCSSpCSSDQVETQACTRQQNRICSCKP 84

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1720424735 129 GLYYYDPKFP--ESCRPCTKCPQGIPVLQECNSTANTVCS 166
Cdd:cd10577    85 GWYCVLKLQEgcRQCRPLKKCGPGFGVARPGTASSDVECK 124

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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEIPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQEMVAD--CSATSDRKCQ 125
Cdd:cd13423     2 CEDGTYQHEGLTCCLCPAGQHVEKHCTNNGTDGECEACEDGTYNSHPNSLDSCEPCTSCDPNANLEVEerCTPSSDTVCR 81

                          90       100
                  ....*....|....*....|..
gi 1720424735 126 CRTGLYYYDPKFPESCRPCTKC 147
Cdd:cd13423    82 CKEGHYCDKGEECKVCYPCDTC 103

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720424735  55 SKDVCCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCST-CDKDQEMVADCSATSDRKCQCRTGlYYY 133
Cdd:cd10581    31 SRQLMCDQCPPGTYVKQHCS-ASRKTVCAPCPDHHYADDWNSNDECQYCNTvCKELQYVKQECNSTHNRVCECVEG-RYL 108

                          90       100       110
                  ....*....|....*....|....*....|....
gi 1720424735 134 DPKFpesCRPCTKCPQGIPVLQECNSTANTVCSS 167
Cdd:cd10581   109 ELEF---CLKHTECPPGFGVVQPGTPESDTVCER 139

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 1720424735  58 VCCKNCSAGTFVKAPCEIPHTQGQCEKCHPGTFTEKDNYLDA-CILCSTCDKD--QEMVADCSATSDRKCQCRTGLYYY- 133
Cdd:cd13420    15 FCCRGCPAGHYLKAPCTEPCGNSTCLPCPRGTFLARENHHKTdCTRCQACDEQasQVALENCSAVSDTHCGCESGWFVEc 94

                          90       100
                  ....*....|....*....|
gi 1720424735 134 -----DPKFPESCRPCTKCP 148
Cdd:cd13420    95 svkdcVSSSPFSCKPCLDCG 114

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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQEMVA--DCSATSDRKCQ 125
Cdd:cd10582     1 CKEDEYPVGSECCPKCSPGYRVKKACG-ELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAMGLVTrrNCSSTENTVCG 79

                  ....
gi 1720424735 126 CRTG 129
Cdd:cd10582    80 CIPG 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 1720424735  48 CPAGEYWSKDVCCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQ--EMVADCSATSDRKCQ 125
Cdd:cd13407     1 CREKQYLHNGRCCSLCPPGQKLVSDCT-EATDTECLPCEEGEFQDTWNRERHCHQHRYCDPNLglRVQTEGTAETDTTCT 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1720424735 126 CRTGLYYYDPKFpESCRPCTKCPQGIPVLQECNSTANTVCS-------SSVSSKTD 174
Cdd:cd13407    80 CQEGQHCTSEAC-ETCALHTSCKPGFGVKQIATGVSDTICEpcpvgffSNVSSAFE 134

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 1720424735  57 DVCCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDaCILCSTCDKDQEMVADCSATSDRKCQCRTGLYYYDPK 136
Cdd:cd13424    11 YVCCESCHPGNRLVERCG-PDPAELCKPCEPGTYTVKPLDYS-CYICTQCIGAQVLLKNCTPSSDTVCGCKEGLRCGDAE 88

                          90       100
                  ....*....|....*....|....*.
gi 1720424735 137 F------------PESCRPCTKCPQG 150
Cdd:cd13424    89 CsfcvtecgkgqePLGKRDCRQCPVG 114

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 1720424735  49 PAGEYWSKDVCCKNCSAGTFVKAPCEiPHTQGQCEKCHPGTFTEKDNYLDACILCSTCDKDQEMVA--DCSATSDRKCQC 126
Cdd:cd13411     4 SERHYEYSGRCCSKCEPGKYMSSKCT-VTSDSVCLPCGPDEYLDTWNEEDKCLLHKVCDAGKALVAvdPGNSTAPRRCAC 82

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1720424735 127 RTGlYYYDPKFpESCRPCTKCPQGIPVLQECNSTANTVCS-------SSVSSKTD 174
Cdd:cd13411    83 TAG-YHWSEDC-DCCRRNTECAPGFGAQHPVQLNKDTVCEpclvgyfSDVFSSTD 135

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1720424735 103 CSTCDKDQEMVADCSATSDRKCQ-CRTGLYYYDPKFPESCRPCTKCPQGI-PVLQECNSTANTVC 165
Cdd:cd00185     2 CQRCPPGEYLSSDCTATTDTVCSpCPPGTYSESWNSLSKCLPCTTCGGGNqVEKTPCTATDNRCC 66

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 1720424735   85 CHPGTFTEKDNYlDACILCSTCDKDQEMVADCSATSDRKC 124
Cdd:smart00208   1 CKEGTYCSDGNH-SSCLRCRRCPPGLVVKQPCTATSDTVC 39

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1720424735 101 ILCSTCDKDQEMVADCSATSDRKCQ-CRTGLYYYDPKFPEsCRPCTKCPQGIPVLQECNSTANTVC 165
Cdd:cd13424    12 VCCESCHPGNRLVERCGPDPAELCKpCEPGTYTVKPLDYS-CYICTQCIGAQVLLKNCTPSSDTVC 76