Tumor necrosis factor receptor superfamily member 10 (TNFRSF10), includes TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2); TNFRSF10 family contains TNFRSF10A (also known as DR4, Apo2, TRAIL-R1, CD261), TNFRSF10B (also known as DR5, KILLER, TRICK2A, TRAIL-R2, TRICKB, CD262), TNFRSF10C (also known as DcR1, TRAIL-R3, LIT, TRID, CD263), and TNFRSF10D (also known as DcR2, TRUNDD, TRAIL-R4, CD264). Tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL) binds to all 4 receptors. DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are membrane-bound and contain a death domain in their intracellular portion, which is able to transmit an apoptotic signal, thus often called death receptors. In contrast, DcR1 (TRAIL-R3), which lacks the complete intracellular portion and DcR2 (TRAIL-R4), which has a truncated cytoplasmic death domain, do not transmit an apoptotic signal, thus known as decoy receptors. Apoptosis mediated by DR4 and DR5 requires Fas (TNFRSF6)-associated via death domain (FADD), a death domain containing adaptor protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for TNFRSF10B/DR5. DcR1 appears to function as an antagonistic receptor that protects cells from TRAIL-induced apoptosis; it has been found to be a p53-regulated DNA damage-inducible gene. The expression of this gene is detected in many normal tissues but not in most cancer cell lines, which may explain the specific sensitivity of cancer cells to the apoptosis-inducing activity of TRAIL. DcR2 has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. The membrane expression of all of these receptors (DR4, DR5, DcR1, and DcR2) is greater in normal endometrium (NE) than in endometrioid adenocarcinoma (EAC). In EAC patients, membrane expression of these receptors are not independent predictors of survival. DcR1 and DcR2 expression is critical in cell growth and apoptosis in cutaneous or uveal melanoma; DcR1 and DcR2 are frequently methylated in both, leading to loss of gene expression and melanomagenesis. On the other hand, DR4 and DR5 methylation is rare in cutaneous melanoma and frequent in uveal melanoma; their expression is wholly independent of the promoter methylation status. DcR1 and DcR2 genes are also reported to be hyper-methylated in prostate cancer. The TRAIL ligand, a potent and specific inducer of apoptosis in cancer cells, has been explored as a therapeutic drug; experimental data has shown that DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  90 GEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCS 169
Cdd:cd10580   2 CGLCPAGTYVSEDSGDCIPCKEGVDYTEHPNGLPSCLPCTVCKSDEEELSPCTTTRNTECQCKPGTFCDPDSPEVCQKCS 81

                        90       100
                ....*....|....*....|..
gi 37181682 170 -RCPSGEVQVSNCTSWDDIQCV 190
Cdd:cd10580  82 tRCPEGMVEVSPCTPWSDLKCV 103

Tumor necrosis factor receptor superfamily member 10 (TNFRSF10), includes TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2); TNFRSF10 family contains TNFRSF10A (also known as DR4, Apo2, TRAIL-R1, CD261), TNFRSF10B (also known as DR5, KILLER, TRICK2A, TRAIL-R2, TRICKB, CD262), TNFRSF10C (also known as DcR1, TRAIL-R3, LIT, TRID, CD263), and TNFRSF10D (also known as DcR2, TRUNDD, TRAIL-R4, CD264). Tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL) binds to all 4 receptors. DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are membrane-bound and contain a death domain in their intracellular portion, which is able to transmit an apoptotic signal, thus often called death receptors. In contrast, DcR1 (TRAIL-R3), which lacks the complete intracellular portion and DcR2 (TRAIL-R4), which has a truncated cytoplasmic death domain, do not transmit an apoptotic signal, thus known as decoy receptors. Apoptosis mediated by DR4 and DR5 requires Fas (TNFRSF6)-associated via death domain (FADD), a death domain containing adaptor protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for TNFRSF10B/DR5. DcR1 appears to function as an antagonistic receptor that protects cells from TRAIL-induced apoptosis; it has been found to be a p53-regulated DNA damage-inducible gene. The expression of this gene is detected in many normal tissues but not in most cancer cell lines, which may explain the specific sensitivity of cancer cells to the apoptosis-inducing activity of TRAIL. DcR2 has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. The membrane expression of all of these receptors (DR4, DR5, DcR1, and DcR2) is greater in normal endometrium (NE) than in endometrioid adenocarcinoma (EAC). In EAC patients, membrane expression of these receptors are not independent predictors of survival. DcR1 and DcR2 expression is critical in cell growth and apoptosis in cutaneous or uveal melanoma; DcR1 and DcR2 are frequently methylated in both, leading to loss of gene expression and melanomagenesis. On the other hand, DR4 and DR5 methylation is rare in cutaneous melanoma and frequent in uveal melanoma; their expression is wholly independent of the promoter methylation status. DcR1 and DcR2 genes are also reported to be hyper-methylated in prostate cancer. The TRAIL ligand, a potent and specific inducer of apoptosis in cancer cells, has been explored as a therapeutic drug; experimental data has shown that DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  90 GEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCS 169
Cdd:cd10580   2 CGLCPAGTYVSEDSGDCIPCKEGVDYTEHPNGLPSCLPCTVCKSDEEELSPCTTTRNTECQCKPGTFCDPDSPEVCQKCS 81

                        90       100
                ....*....|....*....|..
gi 37181682 170 -RCPSGEVQVSNCTSWDDIQCV 190
Cdd:cd10580  82 tRCPEGMVEVSPCTPWSDLKCV 103

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 37181682   151 CKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWDDIQC 189
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQVVVRPCTPTSDTVC 39

UV excision repair protein Rad23; All proteins in this family for which functions are known are components of a multiprotein complex used for targeting nucleotide excision repair to specific parts of the genome. In humans, Rad23 complexes with the XPC protein. This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 37181682   207 TMNTSPGTPAPAAEetmntSPGTPAPAAEETMTTSPgTPAPAA----EETMTTSPGTPAPAAEETMTTSPGTPASS 278
Cdd:TIGR00601  79 TGTGKVAPPAATPT-----SAPTPTPSPPASPASGM-SAAPASaveeKSPSEESATATAPESPSTSVPSSGSDAAS 148

Tumor necrosis factor receptor superfamily member 10 (TNFRSF10), includes TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2); TNFRSF10 family contains TNFRSF10A (also known as DR4, Apo2, TRAIL-R1, CD261), TNFRSF10B (also known as DR5, KILLER, TRICK2A, TRAIL-R2, TRICKB, CD262), TNFRSF10C (also known as DcR1, TRAIL-R3, LIT, TRID, CD263), and TNFRSF10D (also known as DcR2, TRUNDD, TRAIL-R4, CD264). Tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL) binds to all 4 receptors. DR4 (TRAIL-R1) and DR5 (TRAIL-R2) are membrane-bound and contain a death domain in their intracellular portion, which is able to transmit an apoptotic signal, thus often called death receptors. In contrast, DcR1 (TRAIL-R3), which lacks the complete intracellular portion and DcR2 (TRAIL-R4), which has a truncated cytoplasmic death domain, do not transmit an apoptotic signal, thus known as decoy receptors. Apoptosis mediated by DR4 and DR5 requires Fas (TNFRSF6)-associated via death domain (FADD), a death domain containing adaptor protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for TNFRSF10B/DR5. DcR1 appears to function as an antagonistic receptor that protects cells from TRAIL-induced apoptosis; it has been found to be a p53-regulated DNA damage-inducible gene. The expression of this gene is detected in many normal tissues but not in most cancer cell lines, which may explain the specific sensitivity of cancer cells to the apoptosis-inducing activity of TRAIL. DcR2 has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. The membrane expression of all of these receptors (DR4, DR5, DcR1, and DcR2) is greater in normal endometrium (NE) than in endometrioid adenocarcinoma (EAC). In EAC patients, membrane expression of these receptors are not independent predictors of survival. DcR1 and DcR2 expression is critical in cell growth and apoptosis in cutaneous or uveal melanoma; DcR1 and DcR2 are frequently methylated in both, leading to loss of gene expression and melanomagenesis. On the other hand, DR4 and DR5 methylation is rare in cutaneous melanoma and frequent in uveal melanoma; their expression is wholly independent of the promoter methylation status. DcR1 and DcR2 genes are also reported to be hyper-methylated in prostate cancer. The TRAIL ligand, a potent and specific inducer of apoptosis in cancer cells, has been explored as a therapeutic drug; experimental data has shown that DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  90 GEECPAGSHRSEHTGACNPCTEGVDYTNASNNEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCS 169
Cdd:cd10580   2 CGLCPAGTYVSEDSGDCIPCKEGVDYTEHPNGLPSCLPCTVCKSDEEELSPCTTTRNTECQCKPGTFCDPDSPEVCQKCS 81

                        90       100
                ....*....|....*....|..
gi 37181682 170 -RCPSGEVQVSNCTSWDDIQCV 190
Cdd:cd10580  82 tRCPEGMVEVSPCTPWSDLKCV 103

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 37181682  91 EECPAGSHRSEhtgaCNPCTEGvDYTNASNNEPSCFPCTVCKSDQKHKSS-CTMTRDTVCQCKEGTFRNENSPEM--CRK 167
Cdd:cd15834  25 EECTAPGERSQ----CTPCPEG-TYLEQINYSPNCRRCTLCKVKNEEEVSpCKKSSNTVCRCKKGYYKSRIDSETreCLK 99

                        90       100
                ....*....|....*....|...
gi 37181682 168 CSRCPSGEVQVSNCTSWDDIQCV 190
Cdd:cd15834 100 CKTCGPGEIEIQPCTPESNTVCE 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
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  93 CPAGSHRSEHTGA------CNPCTEGVdYTNASNNEPSCFPCTVCKS--DQKHKSSCTMTRDTVCQCKEGTFRNENSPEM 164
Cdd:cd10576  18 CHKGTYLYNDCPGpgqdtvCRECENGT-FTASENYLRKCLSCSRCRKemGQVEISPCTVDQDTVCGCRKNQYQHYWSSLF 96

                        90       100       110
                ....*....|....*....|....*....|.
gi 37181682 165 -CRKCSRCPSGEVQVsNCTSWDDIQCVEEFG 194
Cdd:cd10576  97 qCKNCSLCLNGTIRQ-PCQEKQDTICTCHTG 126

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 37181682  93 CPAGSHRSEHTGA-----CNPCTEGVdYTNASNNEPSCFPCTVCKSDQ--KHKSSCTMTRDTVCQCKEGTF---RNENSP 162
Cdd:cd13405  16 CPPGSRVSRHCTEdtstsCVPCPDGT-YMDEPNGLEKCFPCTNCDPGFglRVKQGCTYTSDTVCEPLEGFYcidSTKDGC 94

                        90
                ....*....|...
gi 37181682 163 EMCRKCSRCPSGE 175
Cdd:cd13405  95 SAAQRHSSCKPGQ 107

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 37181682  91 EECPAGSHRSEHTGA-----CNPCTEgVDYTNASNNEPSCFPCTV-CKSDQKHKSSCTMTRDTVCQCKEGTFRNEnspEM 164
Cdd:cd10575  17 DQCPPGTFVAKHCTRdrptvCGPCPD-LHYTQFWNYLEKCRYCNVfCTERQVEKRQCNATHNRVCECKPGYYMEH---GF 92

                        90       100
                ....*....|....*....|....*
gi 37181682 165 CRKCSRCPSGEVQVSNCTSWDDIQC 189
Cdd:cd10575  93 CLRHSSCPPGEGVIKLGTPYSDTQC 117

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 37181682  93 CPAGSHRSEH------TGACNPCTEGVdYTNASNNEPSCFPCTVC--KSDQKHKSSCTMTRDTVCQCKEGTFRneNSPEM 164
Cdd:cd13423  17 CPAGQHVEKHctnngtDGECEACEDGT-YNSHPNSLDSCEPCTSCdpNANLEVEERCTPSSDTVCRCKEGHYC--DKGEE 93

                ....*..
gi 37181682 165 CRKCSRC 171
Cdd:cd13423  94 CKVCYPC 100

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 37181682   151 CKEGTFRNENSPEMCRKCSRCPSGEVQVSNCTSWDDIQC 189
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQVVVRPCTPTSDTVC 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        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  91 EECPAGSHRSEHTGA-----CNPCTEGVDYTNASnnEPSCFPCTVCKSDQKHKSSCTMTRDTVCQCKEGtFRNENSpemc 165
Cdd:cd13424  15 ESCHPGNRLVERCGPdpaelCKPCEPGTYTVKPL--DYSCYICTQCIGAQVLLKNCTPSSDTVCGCKEG-LRCGDA---- 87

                ....*.
gi 37181682 166 rKCSRC 171
Cdd:cd13424  88 -ECSFC 92

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 37181682  92 ECPAGSHRSEHTGA-----CNPCTEGvDYTNASNNEPSCFPC-TVCKSDQKHKSSCTMTRDTVCQCKEGTFRNEnspEMC 165
Cdd:cd13412  24 KCPPGTHMAAHCTAttqtkCLPCPAA-HYTELWNYLPRCLYCnNFCSENQEVEIECSATNNRVCRCKEGYYMDS---DFC 99

                        90       100
                ....*....|....*....|....*
gi 37181682 166 RKCSRCPSGEVQVSNCTSWDDIQCV 190
Cdd:cd13412 100 IRHTECGPGYGVKTKGTTKQDTVCE 124

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 37181682  91 EECPAGSHRSEHTGA-----CNPCTEGVdYTNASNNEPSCFPCTV-CKSDQKHKSSCTMTRDTVCQCKEGTFRNENSpem 164
Cdd:cd10583  16 DKCPAGTYVSKHCTEtslreCSPCPNGT-FTRHENGIEQCHRCRKpCPAPMIEKTPCTALTDRECTCPPGTFLSNDT--- 91

                        90       100
                ....*....|....*....|....*
gi 37181682 165 CRKCSRCPSGEVQVSNCTSWDDIQC 189
Cdd:cd10583  92 CVPHSVCPVGWGVRKKGTETEDVRC 116

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 37181682    109 CTEGvDYTNaSNNEPSCFPCTVCKSDQKHKSSCTMTRDTVC 149
Cdd:smart00208   1 CKEG-TYCS-DGNHSSCLRCRRCPPGLVVKQPCTATSDTVC 39

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|.
gi 37181682   109 CTEGvDYTNaSNNEPSCFPCTVCKSDQKHKSSCTMTRDTVC 149
Cdd:pfam00020   1 CPPG-TYTD-NWNGLKCLPCTVCPPGQVVVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 4 (TNFRSF4), also known as CD134 or OXO40; TNFRSF4 (also known as OX40, ACT35, CD134, IMD16, TXGP1L) activates NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. It also promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. It is primarily expressed on activated CD4+ and CD8+ T cells, where it is transiently expressed and upregulated on the most recently antigen-activated T cells within inflammatory lesions. This makes it an attractive target to modulate immune responses, i.e. TNFRSF4 (OX40) blocking agents to inhibit adverse inflammation or agonists to enhance immune responses. An artificially created biologic fusion protein, OX40-immunoglobulin (OX40-Ig), prevents OX40 from reaching the T-cell receptors, thus reducing the T-cell response. Some single nucleotide polymorphisms (SNPs) of its natural ligand OX40 ligand (OX40L, CD252), which is also found on activated T cells, have been associated with systemic lupus erythematosus.

                        10        20        30        40        50        60        70
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 37181682 106 CNPCTEGVdYTNASNNEPsCFPCTVCK--SDQKHKSSCTMTRDTVCQCKEGTfRNENSPEMCRKCSRCPSG 174
Cdd:cd13406  36 CSPCEPGF-YNEAVNYEP-CKPCTQCNqrSGSEEKQKCTKTSDTVCRCRPGT-QPLDSYKPGVDCVPCPPG 103

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 37181682 105 ACNPCTEGvDYTNASNNEPSCFPCTVCKSDQ--KHKSSCTMTRDTVCQCKEGTFRNENSPEMCRKCSRCPSGEVQVSNCT 182
Cdd:cd13407  33 ECLPCEEG-EFQDTWNRERHCHQHRYCDPNLglRVQTEGTAETDTTCTCQEGQHCTSEACETCALHTSCKPGFGVKQIAT 111

                ....*..
gi 37181682 183 SWDDIQC 189
Cdd:cd13407 112 GVSDTIC 118

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682   194 GANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPG 273
Cdd:PHA03247 2718 ATPLPPGPAAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAPAPPAAPAAGPPRRLTRPAVASLSESRES 2797

                  ....*
gi 37181682   274 TPASS 278
Cdd:PHA03247 2798 LPSPW 2802

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 37181682   202 PAAEETMNTSPGTPAP-AAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPGTPA 276
Cdd:PHA03247 2710 PAPHALVSATPLPPGPaAARQASPALPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAPAPPAAPAAGPPRRLTR 2785

multifunctional oxoglutarate decarboxylase/oxoglutarate dehydrogenase thiamine pyrophosphate-binding subunit/dihydrolipoyllysine-residue succinyltransferase subunit;

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 37181682   194 GANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPGTPAPAAEETMTT 270
Cdd:PRK12270   42 AAPTAAAAAAAAAASAPAAAPAAKAPAAPAPAPPAAAAPAAPPKPAAAAAAAAAPAAPPAAAAAAAPAAAAVEDEVT 118

ribonuclease E; Reviewed

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682   161 SPEMCrkcsrcpSGEVQVS-NCTSWDDIQCVEEFGANATVETPAAEETmNTSPGTPAPAAEETMNTSPGTPA-------- 231
Cdd:PRK10811  833 SPEMA-------SGKVWIRyPVVRPQDVQVEEQREAEEVQVQPVVAEV-PVAAAVEPVVSAPVVEAVAEVVEepvvvaep 904

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 37181682   232 --PAAEETMTTSPGT-PAPAAEETMTTSPGTPAPAAEETMTTSPGTPASSH 279
Cdd:PRK10811  905 qpEEVVVVETTHPEViAAPVTEQPQVITESDVAVAQEVAEHAEPVVEPQDE 955

bifunctional 2',3'-cyclic-nucleotide 2'-phosphodiesterase/3'-nucleotidase;

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 37181682  207 TMNTSPGTPApAAEETMNTSPGTPAPAAEETMTTSPGTpapaaeetmTTSPGTPAPAAEETMTTSPGTPASS 278
Cdd:PRK11907  17 LLTASNPKLA-QAEEIVTTTPATSTEAEQTTPVESDAT---------EEADNTETPVAATTAAEAPSSSETA 78

envelope glycoprotein I; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  195 ANATVETPAaeeTMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPGTPAPAAEETMTTS--P 272
Cdd:PHA03291 198 GPADVFVPA---TPRPTPRTTASPETTPTPSTTTSPPSTTIPAPSTTIAAPQAGTTPEAEGTPAPPTPGGGEAPPANatP 274

                         90
                 ....*....|..
gi 37181682  273 GTPASSHYLSCT 284
Cdd:PHA03291 275 APEASRYELTVT 286

DNA polymerase III subunits gamma and tau; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  190 VEEFGANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEetMTTSPGTPAPAAEETMTTSPGTPAPAAEETMT 269
Cdd:PRK14950 356 IEALLVPVPAPQPAKPTAAAPSPVRPTPAPSTRPKAAAAANIPPKE--PVRETATPPPVPPRPVAPPVPHTPESAPKLTR 433

                         90
                 ....*....|.
gi 37181682  270 TSPGTPASSHY 280
Cdd:PRK14950 434 AAIPVDEKPKY 444

1,4-beta-N-acetylmuramoylhydrolase;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  200 ETPAAEETM-----NTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTsPGTPAPAAEETMTTSPGT 274
Cdd:PRK06347  54 ETAPADEASksaeaNTTKEAPATATPENTTEPTVEPKQTETKEQTKTPEEKQPAAKQVEKA-PAEPATVSNPDNATSSST 132

                 ....*..
gi 37181682  275 PASSHYL 281
Cdd:PRK06347 133 PATYNLL 139

DNA polymerase III subunits gamma and tau; Validated

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 37181682  194 GANATVETPAAEETMNTSPGTPAPAAEETMNTSPGTPAPAAEETMTTSPGTPAPAAEETMTTSPG-------TPAPAAEE 266
Cdd:PRK07764 415 AAPAAAAAPAPAAAPQPAPAPAPAPAPPSPAGNAPAGGAPSPPPAAAPSAQPAPAPAAAPEPTAApapappaAPAPAAAP 494

                         90
                 ....*....|..
gi 37181682  267 TMTTSPGTPASS 278
Cdd:PRK07764 495 AAPAAPAAPAGA 506