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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C        2 ETCSTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECLGLQSMSAPCVEADDAVCRC 81
Cdd:cd13416   1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
3BUK_C       82 AYGYYQDEETGHCEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVCEDTERQLRECTPWADAEC 160
Cdd:cd13416  81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C        2 ETCSTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECLGLQSMSAPCVEADDAVCRC 81
Cdd:cd13416   1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
3BUK_C       82 AYGYYQDEETGHCEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVCEDTERQLRECTPWADAEC 160
Cdd:cd13416  81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 159

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
                   ....*....|....*....|....*....|....
3BUK_C          85 YYQDEETGHCEACSVCEVGSGLVFSCQDKQNTVC 118
Cdd:smart00208   6 YCSDGNHSSCLRCRRCPPGLVVKQPCTATSDTVC 39

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C        2 ETCSTGLYTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSVTFSDVVSATEPCKPCTECLGLQSMSAPCVEADDAVCRC 81
Cdd:cd13416   1 EACPSGQYTSSGECCEQCPPGEGVARPCGDNQTVCEPCLDGVTFSDVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCEC 80

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
3BUK_C       82 AYGYYQDEETGHCEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVCEDTERQLRECTPWADAEC 160
Cdd:cd13416  81 AYGYYLDEDSGTCEPCTVCPPGQGVVQSCGPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDGEVELRECTPVSDTVC 159

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C       16 CKACNLGEGVAQPCGAN-QTVCEPCLDSvTFSDVVSATEPCKPCTE-CLGLQSMSAPCVEADDAVCRCAYGYYQdeETGH 93
Cdd:cd10575  16 CDQCPPGTFVAKHCTRDrPTVCGPCPDL-HYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCECKPGYYM--EHGF 92

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|...
3BUK_C       94 CEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVCEDTE 146
Cdd:cd10575  93 CLRHSSCPPGEGVIKLGTPYSDTQCEPCPPGFFSASSSSTEPCQPHTNCTQGG 145

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C       16 CKACNLGEGVAQPCGAN-QTVCEPCLDSvTFSDVVSATEPCKPC-TECLGLQSMSAPCVEADDAVCRCAYGYYQDEEtgH 93
Cdd:cd10581  36 CDQCPPGTYVKQHCSASrKTVCAPCPDH-HYADDWNSNDECQYCnTVCKELQYVKQECNSTHNRVCECVEGRYLELE--F 112

                        90       100       110
                ....*....|....*....|....*....|....*
3BUK_C       94 CEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSD 128
Cdd:cd10581 113 CLKHTECPPGFGVVQPGTPESDTVCERCPEGFFSN 147

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C       15 CCKACNLGEGVAQPCGANQ-TVCEPCLDSvTFSDVVSATEPCKPCTECL-GLQSMSAPCVEADDAVCRCAYGYYQDEETg 92
Cdd:cd00185   1 CCQRCPPGEYLSSDCTATTdTVCSPCPPG-TYSESWNSLSKCLPCTTCGgGNQVEKTPCTATDNRCCTCKPGFYCDEGT- 78

                ....*....
3BUK_C       93 HCEACSVCE 101
Cdd:cd00185  79 NVEECKPCT 87

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
3BUK_C       97 CSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVC-EDTERQLRECTPWADAECE 161
Cdd:cd00185   2 CQRCPPGEYLSSDCTATTDTVCSPCPPGTYSESWNSLSKCLPCTTCgGGNQVEKTPCTATDNRCCT 67

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C        9 YTHSGECCKACNLGEGVAQPCGANQTVCEPCLDSvTFSDVVSATEPCKPCTECLGLQSMSAPCVEA--DDAVCRCAYGYY 86
Cdd:cd13422   7 YEKDGECCKMCGPGTRMSSDSGCLDPQCQPCGED-EYQDKYTKENKCKRQPYCDPNKNFEISVNKSktSRSVCKCKPGFH 85

                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
3BUK_C       87 QDeeTGHCEAC---SVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVCEDTERQLRECTPWADAECE 161
Cdd:cd13422  86 CS--SEECLTCvphTTCGPGQGVKSKGNHIRDTVCEECPDGTFSNNSSAEGVCKKWTECESGYKVEAAGTNTSDNICV 161

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C       16 CKACNLGEGVAQPCG-ANQTVCEPCLDSvTFSDVVSATEPCKPCTE-CLGLQSMSAPCVEADDAVCRCAYGYYQDEETgh 93
Cdd:cd10583  15 CDKCPAGTYVSKHCTeTSLRECSPCPNG-TFTRHENGIEQCHRCRKpCPAPMIEKTPCTALTDRECTCPPGTFLSNDT-- 91

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*....
3BUK_C       94 CEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVC 142
Cdd:cd10583  92 CVPHSVCPVGWGVRKKGTETEDVRCKPCPRGTFSDVPSSVLKCKTYTDC 140

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C       81 CAYGYYQDEETGHCeaCSVCEVGSGLVFSCQDK-QNTVCEECPEGTYSDEANHVDPCLPCTVCEDTERQ--LRECTPWAD 157
Cdd:cd10576   1 CPQGKYLHPNNNHC--CTKCHKGTYLYNDCPGPgQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQveISPCTVDQD 78

                ...
3BUK_C      158 AEC 160
Cdd:cd10576  79 TVC 81

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C       15 CCKACNLGEGVAQPCGAN-QTVCEPCLDSVTFsdVVSATEPCKPCTECLGLQSMSAPCVEADDAVCRCAYGYYQdeETGH 93
Cdd:cd13424  13 CCESCHPGNRLVERCGPDpAELCKPCEPGTYT--VKPLDYSCYICTQCIGAQVLLKNCTPSSDTVCGCKEGLRC--GDAE 88

                        90       100       110       120
                ....*....|....*....|....*....|....*....|
3BUK_C       94 CEAC-SVCEVGSglvfscQDKQNTVCEECPEGTYSDEANH 132
Cdd:cd13424  89 CSFCvTECGKGQ------EPLGKRDCRQCPVGTFNDQIHS 122

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
3BUK_C        4 CSTGLYTHSGE--CCKACNLGEGVAQPCGANQ--TVCEPClDSVTFSDVVSATEPCKPCTECLG--LQSMSAPCVEADDA 77
Cdd:cd10576   1 CPQGKYLHPNNnhCCTKCHKGTYLYNDCPGPGqdTVCREC-ENGTFTASENYLRKCLSCSRCRKemGQVEISPCTVDQDT 79

                        90       100       110       120
                ....*....|....*....|....*....|....*....|....
3BUK_C       78 VCRCAYGYYQD--EETGHCEACSVCEVGSgLVFSCQDKQNTVCE 119
Cdd:cd10576  80 VCGCRKNQYQHywSSLFQCKNCSLCLNGT-IRQPCQEKQDTICT 122

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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
3BUK_C       97 CSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHvDPCLPCTVCEDTE--RQLRECTPWADAEC 160
Cdd:cd13406  15 CHECPPGEGMESRCTGTQDTVCSPCEPGFYNEAVNY-EPCKPCTQCNQRSgsEEKQKCTKTSDTVC 79

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.

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3BUK_C       88 DEETGHCEACSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTV-CEDTERQLRECTPWADAECE 161
Cdd:cd10575   7 DDVTGESLTCDQCPPGTFVAKHCTRDRPTVCGPCPDLHYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCE 81

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.

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3BUK_C       97 CSVCEVGSGLVFSC-QDKQNTVCEECPEGTYSDEANHVDPCLPCTVCE-DTERQLRECTPWADAECE 161
Cdd:cd15834  14 CNKCHPGYKLKEECtAPGERSQCTPCPEGTYLEQINYSPNCRRCTLCKvKNEEEVSPCKKSSNTVCR 80

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.

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3BUK_C       79 CRCAYGYYQDEETGHCeaCSVCEVGSGLVFSCQDKQNTVCEECPEGTYSDEANHVDPCLPCTVCED 144
Cdd:cd10578  33 CWDQEKEYYEPRHQVC--CSRCPPGTHVSAECSRSQDTVCATCPENSYNEHWNHLSICQLCRPCDP 96

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.

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3BUK_C       16 CKACNLGEGVAQPCGA-NQTVCEPCLDSvTFSDVVSATEPCKPCTE-CLGLQSMSAPCVEADDAVCRCAYGYYQDEEtgH 93
Cdd:cd13412  22 CKKCPPGTHMAAHCTAtTQTKCLPCPAA-HYTELWNYLPRCLYCNNfCSENQEVEIECSATNNRVCRCKEGYYMDSD--F 98

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3BUK_C       94 CEACSVCEVGSGLVFSCQDKQNTVCEECPEG 124
Cdd:cd13412  99 CIRHTECGPGYGVKTKGTTKQDTVCEKCPSG 129

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

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3BUK_C          85 YYQDEETGHCEACSVCEVGSGLVFSCQDKQNTVC 118
Cdd:smart00208   6 YCSDGNHSSCLRCRRCPPGLVVKQPCTATSDTVC 39