Tumor necrosis factor receptor superfamily member 27 (TNFRSF27), also known as ectodysplasin A2 receptor (EDA2R) or X-linked ectodermal dysplasia receptor (XEDAR); TNFRSF27 (also known as ectodysplasin A2 receptor (EDA2R), X-linked ectodermal dysplasia receptor (XEDAR), EDAA2R, EDA-A2R) has two isoforms, EDA-A1 and EDA-A2, that are encoded by the anhidrotic ectodermal dysplasia (EDA) gene. It is highly expressed during embryonic development and binds to ectodysplasin-A2 (EDA-A2), playing a crucial role in the p53-signaling pathway. EDA2R is a direct p53 target that is frequently down-regulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. Mutations in the EDA-A2/XEDAR signaling give rise to ectodermal dysplasia, characterized by loss of hair, sweat glands, and teeth. A non-synonymous SNP on EDA2R, along with genetic variants in human androgen receptor is associated with androgenetic alopecia (AGA).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984   8 CQENEYWDQWGRCVTCQRCGPGQELSKDCGYGEGGDAYCTACPPRRYKSSWGHHRCQSCITCAVINRVQKVNCTATSNAV 87
Cdd:cd15838     1 CQEKEYLDEHGKCVPCRECGPGQELSKDCGYGEGGDAYCTACPPRRFKDSWGHHGCKTCLSCALINRVQKSNCTATSNAV 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1622968984  88 CGDCLPRFYRKTRIGGLQEQECIPCTKQTPTSEVQC 123
Cdd:cd15838    81 CGDCLPGFYRKTRIGGLQDQECIPCTKQTPSSEVQC 116

Tumor necrosis factor receptor superfamily member 27 (TNFRSF27), also known as ectodysplasin A2 receptor (EDA2R) or X-linked ectodermal dysplasia receptor (XEDAR); TNFRSF27 (also known as ectodysplasin A2 receptor (EDA2R), X-linked ectodermal dysplasia receptor (XEDAR), EDAA2R, EDA-A2R) has two isoforms, EDA-A1 and EDA-A2, that are encoded by the anhidrotic ectodermal dysplasia (EDA) gene. It is highly expressed during embryonic development and binds to ectodysplasin-A2 (EDA-A2), playing a crucial role in the p53-signaling pathway. EDA2R is a direct p53 target that is frequently down-regulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. Mutations in the EDA-A2/XEDAR signaling give rise to ectodermal dysplasia, characterized by loss of hair, sweat glands, and teeth. A non-synonymous SNP on EDA2R, along with genetic variants in human androgen receptor is associated with androgenetic alopecia (AGA).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984   8 CQENEYWDQWGRCVTCQRCGPGQELSKDCGYGEGGDAYCTACPPRRYKSSWGHHRCQSCITCAVINRVQKVNCTATSNAV 87
Cdd:cd15838     1 CQEKEYLDEHGKCVPCRECGPGQELSKDCGYGEGGDAYCTACPPRRFKDSWGHHGCKTCLSCALINRVQKSNCTATSNAV 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1622968984  88 CGDCLPRFYRKTRIGGLQEQECIPCTKQTPTSEVQC 123
Cdd:cd15838    81 CGDCLPGFYRKTRIGGLQDQECIPCTKQTPSSEVQC 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 1622968984   49 CPPRRYKSSWGHHRCQSCITCAVINRVqKVNCTATSNAVC 88
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGLVV-KQPCTATSDTVC 39

Tumor necrosis factor receptor superfamily member 27 (TNFRSF27), also known as ectodysplasin A2 receptor (EDA2R) or X-linked ectodermal dysplasia receptor (XEDAR); TNFRSF27 (also known as ectodysplasin A2 receptor (EDA2R), X-linked ectodermal dysplasia receptor (XEDAR), EDAA2R, EDA-A2R) has two isoforms, EDA-A1 and EDA-A2, that are encoded by the anhidrotic ectodermal dysplasia (EDA) gene. It is highly expressed during embryonic development and binds to ectodysplasin-A2 (EDA-A2), playing a crucial role in the p53-signaling pathway. EDA2R is a direct p53 target that is frequently down-regulated in colorectal cancer tissues due to its epigenetic alterations or through the p53 gene mutations. Mutations in the EDA-A2/XEDAR signaling give rise to ectodermal dysplasia, characterized by loss of hair, sweat glands, and teeth. A non-synonymous SNP on EDA2R, along with genetic variants in human androgen receptor is associated with androgenetic alopecia (AGA).

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984   8 CQENEYWDQWGRCVTCQRCGPGQELSKDCGYGEGGDAYCTACPPRRYKSSWGHHRCQSCITCAVINRVQKVNCTATSNAV 87
Cdd:cd15838     1 CQEKEYLDEHGKCVPCRECGPGQELSKDCGYGEGGDAYCTACPPRRFKDSWGHHGCKTCLSCALINRVQKSNCTATSNAV 80

                          90       100       110
                  ....*....|....*....|....*....|....*.
gi 1622968984  88 CGDCLPRFYRKTRIGGLQEQECIPCTKQTPTSEVQC 123
Cdd:cd15838    81 CGDCLPGFYRKTRIGGLQDQECIPCTKQTPSSEVQC 116

Tumor necrosis factor receptor superfamily (TNFRSF); Members of TNFR superfamily (TNFRSF) interactions with TNF superfamily (TNFSF) ligands (TNFL) control key cellular processes such as differentiation, proliferation, apoptosis, and cell growth. Dysregulation of these pathways has been shown to result in a wide range of pathological conditions, including autoimmune diseases, inflammation, cancer, and viral infection. There are 29 very diverse family members of TNFRSF reported in humans: 22 are type I transmembrane receptors (single pass with the N terminus on extracellular side of the cell membrane) and have a clear signal peptide; the remaining 7 members are either type III transmembrane receptors (single pass with the N terminus on extracellular side of the membrane but no signal sequence; TNFR13B, TNFR13C, TNFR17, and XEDAR), or attached to the membrane via a glycosylphosphatidylinositol (GPI) linker (TNFR10C), or secreted as soluble receptors (TNFR11B and TNFR6B). All TNFRs contain relatively short cysteine-rich domains (CRDs) in the ectodomain, and are involved in interaction with the TNF homology domain (THD) of their ligands. TNFRs often have multiple CRDs (between one and six), with the most frequent configurations of three or four copies; most CRDs possess three disulfide bridges, but could have between one and four. Localized or genome-wide duplication and evolution of the TNFRSF members appear to have paralleled the emergence of the adaptive immune system; teleosts (i.e. ray-finned, bony fish), which possess an immune system with B and T cells, possess primary and secondary lymphoid organs, and are capable of adaptive responses to pathogens also display several characteristics that are different from the mammalian immune system, making teleost TNFSF orthologs and paralogs of interest to better understand immune system evolution and the immunological pathways elicited to pathogens.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984  22 TCQRCGPGQELSKDCGYGegGDAYCTACPPRRYKSSWGH-HRCQSCITCAVINRVQKVNCTATSNAVCgDCLPRFYRKTr 100
Cdd:cd00185     1 CCQRCPPGEYLSSDCTAT--TDTVCSPCPPGTYSESWNSlSKCLPCTTCGGGNQVEKTPCTATDNRCC-TCKPGFYCDE- 76

                          90
                  ....*....|...
gi 1622968984 101 igGLQEQECIPCT 113
Cdd:cd00185    77 --GTNVEECKPCT 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 1622968984   8 CQENEYWDQWGRCvtCQRCGPGQELSKDCgYGEGGDAYCTACPPRRYKSSWGHH-RCQSCITCAVINRVQKVNCTATSNA 86
Cdd:cd15834     1 CLDSEYLSENGIC--CNKCHPGYKLKEEC-TAPGERSQCTPCPEGTYLEQINYSpNCRRCTLCKVKNEEEVSPCKKSSNT 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1622968984  87 VCgDCLPRFYRKT-----------RIGGLQEQECIPCTKQTPT 118
Cdd:cd15834    78 VC-RCKKGYYKSRidsetreclkcKTCGPGEIEIQPCTPESNT 119

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) in teleost; also known as TNFR2; This subfamily of TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) is found in teleosts. It binds TNF-alpha, but lacks the death domain (DD) that is associated with the cytoplasmic domain of TNFRSF1A (TNFR1). It is inducible and expressed exclusively by oligodendrocytes, astrocytes, T cells, thymocytes, myocytes, endothelial cells, and in human mesenchymal stem cells. TNFRSF1B protects oligodendrocyte progenitor cells (OLGs) against oxidative stress, and induces the up-regulation of cell survival genes. While pro-inflammatory and pathogen-clearing activities of TNF are mediated mainly through activation of TNFRSF1A, a strong activator of NF-kappaB, TNFRSF1B is more responsible for suppression of inflammation. Although the affinities of both receptors for soluble TNF are similar, TNFRSF1B is sometimes more abundantly expressed and thought to associate with TNF, thereby increasing its concentration near TNFRSF1A receptors, and making TNF available to activate TNFRSF1A (a ligand-passing mechanism). Knockout studies in zebrafish embryos have shown that a signaling balance between TNFRSF1A and TNFRSF1B is required for endothelial cell integrity. TNFRSF1A signals apoptosis through caspase-8, whereas TNFRSF1B signals survival via NF-kB in endothelial cells. In goldfish (Carassius aurutus L.), TNFRSF1B expression is substantially higher than that of TNFRSF1 in tissues and various immune cell types. Both receptors are most robustly expressed in monocytes; mRNA levels of TNFRSF1B are lowest in peripheral blood leukocytes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984  13 YWDQWGRCvtCQRCGPGQELSKDCgyGEGGDAYCTACPPRRYKSSWGHH-RCQSCITCAVINRVQKV-NCTATSNAVCGd 90
Cdd:cd15835    13 YNDGSNLC--CSKCRPGTRLKTKC--SETSDTVCEPCPSGQYSENWNYYpNCFSCPKCKERKGLQYAqNCSSTTNAVCV- 87

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1622968984  91 CLPRFYrktRIGGLQEQECIPCTKQ-------------TPTSEVQC 123
Cdd:cd15835    88 CKPGMY---CIMGFDHPSCSECKKYrtckpgygvsvpgTPTSDVKC 130

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9) in teleosts; also known as CD137; This subfamily of TNFRSF9 (also known as CD137, ILA, 4-1BB) is found in teleosts. CD137 plays a role in the immunobiology of human cancer where it is preferentially expressed on tumor-reactive subset of tumor-infiltrating lymphocytes. It can be expressed by activated T cells, but to a larger extent on CD8 than on CD4 T cells. In addition, CD137 expression is found on dendritic cells, follicular dendritic cells, natural killer cells, granulocytes and cells of blood vessel walls at sites of inflammation. It transduces signals that lead to the activation of NF-kappaB, mediated by the TRAF adaptor proteins. CD137 contributes to the clonal expansion, survival, and development of T cells. It can also induce proliferation in peripheral monocytes, enhance T cell apoptosis induced by TCR/CD3 triggered activation, and regulate CD28 co-stimulation to promote Th1 cell responses. CD137 is modulated by SAHA treatment in breast cancer cells, suggesting that the combination of SAHA with this receptor could be a new therapeutic approach for the treatment of tumors. Mostly, CD137 in teleosts have not been characterized.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1622968984  21 VTCQRCGPGQELSKDCGYGEggDAYCTACPPRRYKSSWGHHRCQSCITCaVINRVQKVNCTATSNAVCG 89
Cdd:cd13424    12 VCCESCHPGNRLVERCGPDP--AELCKPCEPGTYTVKPLDYSCYICTQC-IGAQVLLKNCTPSSDTVCG 77

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1622968984  49 CPPRRYKSSWGHHRCQSCITCAViNRVQKVNCTATSNAVC 88
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPP-GQVVVRPCTPTSDTVC 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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984   7 DCQENEYWDQW-GRCVTCQRCGPGQELSKDCgyGEGGDAYCTACPPRRY---KSSWghHRCQSCITCAViNRVQKVNCTA 82
Cdd:cd13416    79 ECAYGYYLDEDsGTCEPCTVCPPGQGVVQSC--GPNQDTVCEACPEGTYsdeDSST--DPCLPCTVCED-GEVELRECTP 153

                  ....*.
gi 1622968984  83 TSNAVC 88
Cdd:cd13416   154 VSDTVC 159

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 1622968984  23 CQRCGPGQELSKDCGyGEGGDAYCTACPPRRYKSSWGHH-RCQSCITC-AVINRVQKVNCTATSNAVCGdCLPRFYRKTR 100
Cdd:cd10576    15 CTKCHKGTYLYNDCP-GPGQDTVCRECENGTFTASENYLrKCLSCSRCrKEMGQVEISPCTVDQDTVCG-CRKNQYQHYW 92

                          90
                  ....*....|....*...
gi 1622968984 101 IGGLQEQECIPCTKQTPT 118
Cdd:cd10576    93 SSLFQCKNCSLCLNGTIR 110

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 1622968984  18 GRCvtCQRCGPGQELSKDCGygeGGDAYCTACPP-RRYKSSWGH-HRCQSCITCaVINRVQKVNCTATSNAVCgDCLPRF 95
Cdd:cd13416    12 GEC--CEQCPPGEGVARPCG---DNQTVCEPCLDgVTFSDVVSHtEPCQPCTRC-PGLMSMRAPCTATHDTVC-ECAYGY 84

                          90
                  ....*....|....*....
gi 1622968984  96 YRktrigGLQEQECIPCTK 114
Cdd:cd13416    85 YL-----DEDSGTCEPCTV 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 1622968984   49 CPPRRYKSSWGHHRCQSCITCAVINRVqKVNCTATSNAVC 88
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGLVV-KQPCTATSDTVC 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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622968984   6 MDCQENEYwDQWGRCvtCQRCGPGQELSKDCGYGEggDAYCTACPPRRYKSSWGHHRCQSCITCAVIN-RVQKVNCTATS 84
Cdd:cd13406     1 LHCVGDTY-PSGEKC--CHECPPGEGMESRCTGTQ--DTVCSPCEPGFYNEAVNYEPCKPCTQCNQRSgSEEKQKCTKTS 75

                  ....*.
gi 1622968984  85 NAVCGD 90
Cdd:cd13406    76 DTVCRC 81