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 2044129737 172 EACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRC 251
Cdd:cd13416     1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2044129737 252 AYGYYQDETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAEC 330
Cdd:cd13416    81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 159

Tumor necrosis factor receptor member 16 trans-membrane domain; This is the helical trans-membrane domain found in tumor necrosis factor receptor superfamily member 16 (also known as p75 neurotrophin receptor, and nerve growth factor receptor-NGFR). p75 plays prominent biological functions such the induction of cell death, and it demonstrates several other activities, like survival, axonal growth, and cell migration. The trans-membrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signalling Structural and mutational analysis indicate that Cys257 plays the key role in this stabilization process. Furthermore, although the p75-C257A mutant is still capable to form dimers and bind to NGF, it is unable to transduce the signals triggered by NGF binding in some cell signalling paradigms.

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 2044129737 388 GTADNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQ 425
Cdd:pfam18422   1 GTSDNLIPVYCSILAAVVLGLVAYIAFKRWNSCKQNKQ 38

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 2044129737 172 EACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRC 251
Cdd:cd13416     1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2044129737 252 AYGYYQDETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAEC 330
Cdd:cd13416    81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 159

Tumor necrosis factor receptor member 16 trans-membrane domain; This is the helical trans-membrane domain found in tumor necrosis factor receptor superfamily member 16 (also known as p75 neurotrophin receptor, and nerve growth factor receptor-NGFR). p75 plays prominent biological functions such the induction of cell death, and it demonstrates several other activities, like survival, axonal growth, and cell migration. The trans-membrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signalling Structural and mutational analysis indicate that Cys257 plays the key role in this stabilization process. Furthermore, although the p75-C257A mutant is still capable to form dimers and bind to NGF, it is unable to transduce the signals triggered by NGF binding in some cell signalling paradigms.

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 2044129737 388 GTADNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQ 425
Cdd:pfam18422   1 GTSDNLIPVYCSILAAVVLGLVAYIAFKRWNSCKQNKQ 38

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 2044129737 291 CPDGTYSDEANHVdPCLPCTVCEDTERQLRECTRWADAEC 330
Cdd:pfam00020   1 CPPGTYTDNWNGL-KCLPCTVCPPGQVVVRPCTPTSDTVC 39

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2044129737 486 REEVEKLLNGSA--GDTWRHLAGELGYQPEHIDSFTHE----ACPARALLASWAAQDSATLDAL--LAALRRIQRADIVE 557
Cdd:pfam00531   1 RKQLDRLLDPPPplGKDWRELARKLGLSENEIDEIESEnprlRSQTYELLRLWEQREGKNATVGtlLEALRKLGRRDAAE 80

                  ..
gi 2044129737 558 SL 559
Cdd:pfam00531  81 KI 82

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 2044129737 172 EACPTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRC 251
Cdd:cd13416     1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2044129737 252 AYGYYQDETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAEC 330
Cdd:cd13416    81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 159

Tumor necrosis factor receptor member 16 trans-membrane domain; This is the helical trans-membrane domain found in tumor necrosis factor receptor superfamily member 16 (also known as p75 neurotrophin receptor, and nerve growth factor receptor-NGFR). p75 plays prominent biological functions such the induction of cell death, and it demonstrates several other activities, like survival, axonal growth, and cell migration. The trans-membrane (TM) domain of p75 stabilizes the receptor dimers through a disulfide bond, essential for the NGF signalling Structural and mutational analysis indicate that Cys257 plays the key role in this stabilization process. Furthermore, although the p75-C257A mutant is still capable to form dimers and bind to NGF, it is unable to transduce the signals triggered by NGF binding in some cell signalling paradigms.

                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 2044129737 388 GTADNLIPVYCSILAAVVVGLVAYIAFKRWNSCKQNKQ 425
Cdd:pfam18422   1 GTSDNLIPVYCSILAAVVLGLVAYIAFKRWNSCKQNKQ 38

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 2044129737 179 YTHSGECCKACNLGEGVAQPC-GANQTVCEPClDSVTFSDVVSATEPCKP---CTECVGLQSMSaPCVEADDAVCRCAYG 254
Cdd:cd13407     6 YLHNGRCCSLCPPGQKLVSDCtEATDTECLPC-EEGEFQDTWNRERHCHQhryCDPNLGLRVQT-EGTAETDTTCTCQEG 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2044129737 255 yyQDETTGRCEACRV---CEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTE-RQLRECTRWADAEC 330
Cdd:cd13407    84 --QHCTSEACETCALhtsCKPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKGlVELQAGTNKTDVVC 161

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 2044129737 174 CPTGLYTHSGECCKACNLGEGVAQPCGANQTV--CEPClDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRC 251
Cdd:cd15837     1 CGPGEYKSANLCCQLCPAGHYVSEPCQENHGVgeCAPC-EPGTFTAHPNGETSCFPCSQCRDDQEVVAECSATSDRQCQC 79

                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 2044129737 252 AYG--YYQDETTGRCEACRVCEAGSGLVFSCQDRQNTVC 288
Cdd:cd15837    80 KQGhfYCDENCLESCFRCSRCPGGRVVLQPCNATRDTVC 118

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 2044129737 267 CRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVC-EDTERQLRECTRWADAECE 331
Cdd:cd00185     2 CQRCPPGEYLSSDCTATTDTVCSPCPPGTYSESWNSLSKCLPCTTCgGGNQVEKTPCTATDNRCCT 67

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 2044129737 186 CKACNLGEGVAQPCGAN-QTVCEPCLDSvTFSDVVSATEPCKPCTE-CVGLQSMSAPCVEADDAVCRCAYGYYQdeTTGR 263
Cdd:cd10575    16 CDQCPPGTFVAKHCTRDrPTVCGPCPDL-HYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCECKPGYYM--EHGF 92

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|...
gi 2044129737 264 CEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTE 316
Cdd:cd10575    93 CLRHSSCPPGEGVIKLGTPYSDTQCEPCPPGFFSASSSSTEPCQPHTNCTQGG 145

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 2044129737 174 CPTGLYTHSGECCKACNLGEGVAQPCGAN--QTVCEPCLDSVTFSDVVSATEPCKPCTECVGLQSMSA--PCVEADDAVC 249
Cdd:cd10579    10 CSEGLYRGGQFCCQPCPPGTRKAIDCTTNggKPDCVPCTEGKEYTDKKHYSDKCRRCKICDEEHGLEVekNCTRTQNTKC 89

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 2044129737 250 RCAYGYYQDET-TGRCEACRVCEagSGLVFSCQDRQNTVCEE 290
Cdd:cd10579    90 RCKSNFFCNSSpCEHCDPCTTCE--HGIIEECTPTSNTKCKK 129

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 2044129737 175 PTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSvTFSDVVSATEPCKPCTECVGLQSMSAPCVEA--DDAVCRCA 252
Cdd:cd13422     3 PETQYEKDGECCKMCGPGTRMSSDSGCLDPQCQPCGED-EYQDKYTKENKCKRQPYCDPNKNFEISVNKSktSRSVCKCK 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2044129737 253 YGYYQDetTGRCEACR---VCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTERQLRECTRWADAE 329
Cdd:cd13422    82 PGFHCS--SEECLTCVphtTCGPGQGVKSKGNHIRDTVCEECPDGTFSNNSSAEGVCKKWTECESGYKVEAAGTNTSDNI 159

                  ..
gi 2044129737 330 CE 331
Cdd:cd13422   160 CV 161

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2044129737 174 CPTGLYTHSGE--CCKACNLGEGVAQPC-GANQ-TVCEPClDSVTFSDVVSATEPCKPCTECVG--LQSMSAPCVEADDA 247
Cdd:cd10576     1 CPQGKYLHPNNnhCCTKCHKGTYLYNDCpGPGQdTVCREC-ENGTFTASENYLRKCLSCSRCRKemGQVEISPCTVDQDT 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....
gi 2044129737 248 VCRCAYGYYQDeTTGRCEACRVCEAG-SGLV-FSCQDRQNTVCE 289
Cdd:cd10576    80 VCGCRKNQYQH-YWSSLFQCKNCSLClNGTIrQPCQEKQDTICT 122

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 2044129737 185 CCKACNLGEGVAQPCGAN-QTVCEPClDSVTFSdVVSATEPCKPCTECVGLQSMSAPCVEADDAVCRCAYGYYQDEttGR 263
Cdd:cd13424    13 CCESCHPGNRLVERCGPDpAELCKPC-EPGTYT-VKPLDYSCYICTQCIGAQVLLKNCTPSSDTVCGCKEGLRCGD--AE 88

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 2044129737 264 CEAC-RVCEAGSglvfscQDRQNTVCEECPDGTYSDEANH 302
Cdd:cd13424    89 CSFCvTECGKGQ------EPLGKRDCRQCPVGTFNDQIHS 122

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 2044129737 258 DETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPC-TVCEDTERQLRECTRWADAECEEIPGR 336
Cdd:cd10581    27 DPVTSRQLMCDQCPPGTYVKQHCSASRKTVCAPCPDHHYADDWNSNDECQYCnTVCKELQYVKQECNSTHNRVCECVEGR 106

                  ..
gi 2044129737 337 WI 338
Cdd:cd10581   107 YL 108

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 2044129737 173 ACPTGLYTHSGECCKACNLGEGVAQPC--GANQTVCEPCLDSvTFSDVVSATEPCKPCTECVGLQSMSA--PCVEADDAV 248
Cdd:cd13423     1 SCEDGTYQHEGLTCCLCPAGQHVEKHCtnNGTDGECEACEDG-TYNSHPNSLDSCEPCTSCDPNANLEVeeRCTPSSDTV 79

                          90       100
                  ....*....|....*....|..
gi 2044129737 249 CRCAYGYYQDeTTGRCEACRVC 270
Cdd:cd13423    80 CRCKEGHYCD-KGEECKVCYPC 100

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 2044129737 186 CKACNLGEGVAQPCG-ANQTVCEPCLDSvTFSDVVSATEPCKPCTE-CVGLQSMSAPCVEADDAVCRCAYGYYQDETTgr 263
Cdd:cd10583    15 CDKCPAGTYVSKHCTeTSLRECSPCPNG-TFTRHENGIEQCHRCRKpCPAPMIEKTPCTALTDRECTCPPGTFLSNDT-- 91

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*....
gi 2044129737 264 CEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVC 312
Cdd:cd10583    92 CVPHSVCPVGWGVRKKGTETEDVRCKPCPRGTFSDVPSSVLKCKTYTDC 140

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 2044129737 174 CPTGLYTHSGECCKACNLGEGVAQPC-GANQTVCEPCLDSvTFSDVVSATEPCKPCTEC---VGLQSMSaPCVEADDAVC 249
Cdd:cd13405     1 CGPAEYEINGECCPMCPPGSRVSRHCtEDTSTSCVPCPDG-TYMDEPNGLEKCFPCTNCdpgFGLRVKQ-GCTYTSDTVC 78

                          90       100
                  ....*....|....*....|....*...
gi 2044129737 250 RCAYGYY-QDETTGRCEACR---VCEAG 273
Cdd:cd13405    79 EPLEGFYcIDSTKDGCSAAQrhsSCKPG 106

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 2044129737 251 CAYGYYQDETtgrcEACRVCEAGSGLVFSCQDRQN-TVCEECPDGTYSDEANHVDPCLPCTVC--EDTERQLRECTRWAD 327
Cdd:cd13423     2 CEDGTYQHEG----LTCCLCPAGQHVEKHCTNNGTdGECEACEDGTYNSHPNSLDSCEPCTSCdpNANLEVEERCTPSSD 77

                  ...
gi 2044129737 328 AEC 330
Cdd:cd13423    78 TVC 80

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 2044129737 258 DETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTV-CEDTERQLRECTRWADAECEEIPG 335
Cdd:cd10575     7 DDVTGESLTCDQCPPGTFVAKHCTRDRPTVCGPCPDLHYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCECKPG 85

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 2044129737 257 QDETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDT--ERQLRECTRWADAECEEIP 334
Cdd:cd10582     3 EDEYPVGSECCPKCSPGYRVKKACGELTGTVCEPCPPGTYTAHLNGLSKCLQCRVCDPAmgLVTRRNCSSTENTVCGCIP 82

                          90
                  ....*....|..
gi 2044129737 335 GRWITRSTPSED 346
Cdd:cd10582    83 GHFCSAQDGDHC 94

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 2044129737 186 CKACNLGEGVAQPCGA-NQTVCEPCLDSvTFSDVVSATEPCKPCTE-CVGLQSMSAPCVEADDAVCRCAYGYYQDEttGR 263
Cdd:cd13412    22 CKKCPPGTHMAAHCTAtTQTKCLPCPAA-HYTELWNYLPRCLYCNNfCSENQEVEIECSATNNRVCRCKEGYYMDS--DF 98

                          90       100       110
                  ....*....|....*....|....*....|.
gi 2044129737 264 CEACRVCEAGSGLVFSCQDRQNTVCEECPDG 294
Cdd:cd13412    99 CIRHTECGPGYGVKTKGTTKQDTVCEKCPSG 129

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 2044129737 251 CAYGYYQDETTGRCeaCRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCT-VCEDTERQLRECTRWADAE 329
Cdd:cd15839     1 CNGNDYNSNSNNLC--CKSCPPGTYASHLCDTTSNTKCDPCPSDTFTSIPNHIPACLSCRgRCSSNQVETKSCSNTQNRI 78

                  ....*.
gi 2044129737 330 CEEIPG 335
Cdd:cd15839    79 CSCAPG 84

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 2044129737 179 YTHSGECCKACNLGEGVAQPCG-ANQTVCEPCLDSVTFSDVVSATE--PCKPCTECVGLQSMSApCVEADDAVCRCAYGY 255
Cdd:cd10582     6 YPVGSECCPKCSPGYRVKKACGeLTGTVCEPCPPGTYTAHLNGLSKclQCRVCDPAMGLVTRRN-CSSTENTVCGCIPGH 84

                          90
                  ....*....|....
gi 2044129737 256 YQDETTG-RCEACR 268
Cdd:cd10582    85 FCSAQDGdHCVECV 98

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 2044129737  291 CPDGTYSDEANHvDPCLPCTVCEDTERQLRECTRWADAEC 330
Cdd:smart00208   1 CKEGTYCSDGNH-SSCLRCRRCPPGLVVKQPCTATSDTVC 39

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 2044129737 256 YQDETTGRCEACRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPC-TVCEDTERQLRECTRWADAECE 331
Cdd:cd13412    11 HRDPSTGKILTCKKCPPGTHMAAHCTATTQTKCLPCPAAHYTELWNYLPRCLYCnNFCSENQEVEIECSATNNRVCR 87

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

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 2044129737 172 EACPTGLY----THSGEC--CKACNLG-EGVAQPCGANQ-TVCEpCLDSVTFSDVVSATEPCKPCTECVGLQSMSAPCVE 243
Cdd:cd15834    37 TPCPEGTYleqiNYSPNCrrCTLCKVKnEEEVSPCKKSSnTVCR-CKKGYYKSRIDSETRECLKCKTCGPGEIEIQPCTP 115

                          90       100       110
                  ....*....|....*....|....*....|
gi 2044129737 244 ADDAVCRCAYGYYQDETTgrCEACRVCEAG 273
Cdd:cd15834   116 ESNTVCECKDNYYRNNNK--CKPCQKCSLD 143

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 2044129737 249 CRCAYGYYQDETTGRCeaCRVCEAGSGLVFSCQDRQNTVCEECPDGTYSDEANHVDPCLPCTVCEDTE--RQLRECTRWA 326
Cdd:cd10578    33 CWDQEKEYYEPRHQVC--CSRCPPGTHVSAECSRSQDTVCATCPENSYNEHWNHLSICQLCRPCDPVLgfEEVAPCTSDR 110

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 2044129737 327 DAECEEIPG----RWITRSTPSEDSDSTAPSTEEPELPPDQEI 365
Cdd:cd10578   111 KTQCRCQPGmfcvHWDNECEHCEPLSDCPPGTEAELTDEVGEA 153