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 1937369584  44 CPQGKYAHPKNNsICCTKCHKGTYLVSDCPSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPCKADMDT 123
Cdd:cd10576     1 CPQGKYLHPNNN-HCCTKCHKGTYLYNDCPGPGQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDT 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1937369584 124 VCGCKKNQFQRYLSEtHFQCVDCSPCFNGTVTIPCKEKQNTVCNCHAGFFL 174
Cdd:cd10576    80 VCGCRKNQYQHYWSS-LFQCKNCSLCLNGTIRQPCQEKQDTICTCHTGFFL 129

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 1937369584  44 CPQGKYAHPKNNsICCTKCHKGTYLVSDCPSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPCKADMDT 123
Cdd:cd10576     1 CPQGKYLHPNNN-HCCTKCHKGTYLYNDCPGPGQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDT 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1937369584 124 VCGCKKNQFQRYLSEtHFQCVDCSPCFNGTVTIPCKEKQNTVCNCHAGFFL 174
Cdd:cd10576    80 VCGCRKNQYQHYWSS-LFQCKNCSLCLNGTIRQPCQEKQDTICTCHTGFFL 129

DEATH domain, found in proteins involved in cell death (apoptosis); Alpha-helical domain present in a variety of proteins with apoptotic functions. Some (but not all) of these domains form homotypic and heterotypic dimers.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584  360 TADPAMLYAVVDGVPPTRWKEFMRLLGLSEHEIERLELQNGRCLREAHYSMLEAWRRRTPRHeATLDVVGRVLCDMNLRG 439
Cdd:smart00005   2 ELTRQKLAKLLDHPLGLDWRELARKLGLSEADIDQIRTEAPRDLAEQSVQLLRLWEQREGKN-ATLGTLLEALRKMGRDD 80

                   ....*...
gi 1937369584  440 CLENIRET 447
Cdd:smart00005  81 AVELLRSE 88

TNF-alpha-receptor-like protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584  41 DNLCPQGKYahpKNNSICCTKCHKGTYLVSDCPSPgQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPCKAD 120
Cdd:PHA02637   29 DGKCKDNEY---KRHNLCCLSCPPGTYASRLCDIK-TNTQCTPCGSGTFTSHNNHLPACLSCNGRCDRVTRLTIESVNAL 104

                          90
                  ....*....|....*.
gi 1937369584 121 MDTVCGCKKNQFQRYL 136
Cdd:PHA02637  105 EAIIVFSKDHPDARHV 120

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 1937369584  127 CKKNQFqrYLSETHFQCVDCSPCFNGTVTI-PCKEKQNTVC 166
Cdd:smart00208   1 CKEGTY--CSDGNHSSCLRCRRCPPGLVVKqPCTATSDTVC 39

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 1937369584  44 CPQGKYAHPKNNsICCTKCHKGTYLVSDCPSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPCKADMDT 123
Cdd:cd10576     1 CPQGKYLHPNNN-HCCTKCHKGTYLYNDCPGPGQDTVCRECENGTFTASENYLRKCLSCSRCRKEMGQVEISPCTVDQDT 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1937369584 124 VCGCKKNQFQRYLSEtHFQCVDCSPCFNGTVTIPCKEKQNTVCNCHAGFFL 174
Cdd:cd10576    80 VCGCRKNQYQHYWSS-LFQCKNCSLCLNGTIRQPCQEKQDTICTCHTGFFL 129

Death Domain of Death Receptors; Death domain (DD) found in death receptor proteins. Death receptors are members of the tumor necrosis factor (TNF) receptor superfamily, characterized by having a cytoplasmic DD. Known members of the family are Fas (CD95/APO-1), TNF-receptor 1 (TNFR1/TNFRSF1A/p55/CD120a), TNF-related apoptosis-inducing ligand receptor 1 (TRAIL-R1 /DR4), and receptor 2 (TRAIL-R2/DR5/APO-2/KILLER), as well as Death Receptor 3 (DR3/APO-3/TRAMP/WSL-1/LARD). They are involved in apoptosis signaling pathways. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584 366 LYAVVDGVPPTRWKEFMRLLGLSEHEIERLELQNGRCLREAHYSMLEAWRRRTPRhEATLDVVGRVLCDMNLRGCLENIR 445
Cdd:cd08784     2 ITTIAGVVPLSQWKGFVRKLGLNEAEIDEIKNDNVQDTAEAKYQMLRNWHQLTGR-KAAYDTLIKDLKKMNLCTLAEKIQ 80

Death domain of Tumor Necrosis Factor Receptor superfamily 25; Death Domain (DD) found in Tumor Necrosis Factor (TNF) receptor superfamily 25 (TNFRSF25), also known as TRAMP (TNF receptor-related apoptosis-mediating protein), LARD, APO-3, WSL-1, or DR3 (Death Receptor-3). TNFRSF25 is primarily expressed in T cells, is activated by binding to its ligand TL1A, and plays an important role in T-cell function. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584 366 LYAVVDGVPPTRWKEFMRLLGLSEHEIERLELQNGRcLREAHYSMLEAWRRRTPrheATLDVVGRVLCDMNLRGCLENIR 445
Cdd:cd08815     2 LYAVMDAVPARRWKEFVRTLGLREAEIEAVELEIGR-FRDQQYEMLKRWRQQQP---AGLDAVYAALERMGLAGCAEDLR 77

Death domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584 366 LYAVVDGVPPT--RWKEFMRLLGLSEHEIERLELQNGRcLREAHYSMLEAWRRRTPRHeATLDVVGRVLCDMNLRGCLEN 443
Cdd:pfam00531   4 LDRLLDPPPPLgkDWRELARKLGLSENEIDEIESENPR-LRSQTYELLRLWEQREGKN-ATVGTLLEALRKLGRRDAAEK 81

                  ....*
gi 1937369584 444 IRETL 448
Cdd:pfam00531  82 IQSIL 86

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 1937369584  58 CCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMfQVEISPCKADMDTVCGCKKNQFQRYLS 137
Cdd:cd00185     1 CCQRCPPGEYLSSDC-TATTDTVCSPCPPGTYSESWNSLSKCLPCTTCGGGN-QVEKTPCTATDNRCCTCKPGFYCDEGT 78

                          90
                  ....*....|..
gi 1937369584 138 EthfqCVDCSPC 149
Cdd:cd00185    79 N----VEECKPC 86

Tumor necrosis factor receptor superfamily member 26 (TNFRSF26), also known as tumor necrosis factor receptor homolog 3 (TNFRH3); TNFRSF26 (also known as tumor necrosis factor receptor homolog 3 (TNFRH3) or TNFRSF24) is predominantly expressed in embryos and lymphoid cell types, along with its closely related TNFRSF22 and TNFRSF23 orthologs, and is developmentally regulated. Unlike TNFRSF22/23, TNFRSF26 does not serve as a TRAIL decoy receptor; it remains an orphan receptor.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584  44 CPQGKYAHpknNSICCTKCHKGTYLVSDCPSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEmfQVEISPCKADMDT 123
Cdd:cd15837     1 CGPGEYKS---ANLCCQLCPAGHYVSEPCQENHGVGECAPCEPGTFTAHPNGETSCFPCSQCRDD--QEVVAECSATSDR 75

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1937369584 124 VCGCKKNQFqrYLSETHFQ-CVDCSPCFNGTVTI-PCKEKQNTVC 166
Cdd:cd15837    76 QCQCKQGHF--YCDENCLEsCFRCSRCPGGRVVLqPCNATRDTVC 118

Death Domain: a protein-protein interaction domain; Death Domains (DDs) are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. Structural analysis of DD-DD complexes show that the domains interact with each other in many different ways. DD-containing proteins serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes. In mammals, they are prominent components of the programmed cell death (apoptosis) pathway and are found in a number of other signaling pathways. In invertebrates, they are involved in transcriptional regulation of zygotic patterning genes in insect embryogenesis, and are components of the ToII/NF-kappaB pathway, a conserved innate immune pathway in animal cells.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1937369584 378 WKEFMRLLGLSEHEIERLELQNGRCLREAHYSMLEAWRRRTPrHEATLDVVGRVLCDMNLRGCLENIR 445
Cdd:cd01670    13 WKKLARKLGLSEGDIDQIEEDNRDDLKEQAYQMLERWREREG-DEATLGRLIQALREIGRRDLAEKLE 79

Tumor necrosis factor receptor superfamily member 3 (TNFRSF3), also known as lymphotoxin beta receptor (LTBR); TNFRSF3 (also known as lymphotoxin beta receptor, LTbetaR, CD18, TNFCR, TNFR3, D12S370, TNFR-RP, TNFR2-RP, LT-BETA-R, TNF-R-III) plays a role in signaling during development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Its ligands include lymphotoxin (LT) alpha/beta membrane form (heterotrimer) and tumor necrosis factor ligand superfamily member 14 (also known as LIGHT). TNFRSF3 agonism by these ligands initiates canonical, as well as non-canonical nuclear factor-kappaB (NF-kappaB) signaling, and preferentially results in the translocation of p52-RELB complexes into the nucleus. While these ligands are often expressed by T and B cells, TNFRSF3 is conspicuous absence on T and B lymphocytes and NK cells, suggesting that signaling may be unidirectional for TNFRSF3. Activity of this receptor has also been linked to carcinogenesis; it helps trigger apoptosis and can also lead to release of the interleukin 8 (IL8). Alternatively spliced transcript variants encoding multiple isoforms have been observed.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584  38 EKRDNLCPQGKYAHPKNNsICCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPC 117
Cdd:cd10578    29 ENQTCWDQEKEYYEPRHQ-VCCSRCPPGTHVSAEC-SRSQDTVCATCPENSYNEHWNHLSICQLCRPCDPVLGFEEVAPC 106

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1937369584 118 KADMDTVCGCKKNQFQRYLSETHFQCVDCSPCFNGTVTIPCKEKQNTVCNC 168
Cdd:cd10578   107 TSDRKTQCRCQPGMFCVHWDNECEHCEPLSDCPPGTEAELTDEVGEADNNC 157

Tumor necrosis factor receptor superfamily members, virus-encoded; This family contains viral TNFR homologs that include vaccinia virus (VACV) cytokine response modifier E (CrmE), an encoded TNFR that shares significant sequence similarity with mammalian type 2 TNF receptors (TNFSFR1B, p75, TNFR type 2), a cowpox virus encoded cytokine-response modifier B (crmB), which is a secreted form of TNF receptor that can contribute to the modification of TNF-mediated antiviral processes, and a myxoma virus (MYXV) T2 (M-T2) protein that binds and inhibits rabbit TNF-alpha. The CrmE structure confirms that the canonical TNFR fold is adopted, but only one of the two "ligand-binding" loops of TNFRSF1A is conserved, suggesting a mechanism for the higher affinity of poxvirus TNFRs for TNFalpha over lymphotoxin-alpha. CrmB protein specifically binds TNF-alpha and TNF-beta indicating that cowpox virus seeks to invade antiviral processes mediated by TNF. Intracellular M-T2 blocks virus-induced lymphocyte apoptosis via a highly conserved viral preligand assembly domain (vPLAD), which controls receptor signaling competency prior to ligand binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584  44 CPQGKYAHPKNNsICCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSCKTcRKEMFQVEISPCKADMDT 123
Cdd:cd15839     1 CNGNDYNSNSNN-LCCKSCPPGTYASHLC-DTTSNTKCDPCPSDTFTSIPNHIPACLSCRG-RCSSNQVETKSCSNTQNR 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1937369584 124 VCGCKKNQFqrYLSETHFQCVDCSP---CFNGTVTIPCKEKQNTVC 166
Cdd:cd15839    78 ICSCAPGYY--CLLKGSDGCVACAPktkCGVGYGVSGHTSTGDVIC 121

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 1937369584  44 CPQGKYAHPKNNsIC--CTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEmfQVEISPCKADM 121
Cdd:cd13416    80 CAYGYYLDEDSG-TCepCTVCPPGQGVVQSC-GPNQDTVCEACPEGTYSDEDSSTDPCLPCTVCEDG--EVELRECTPVS 155

                  ....
gi 1937369584 122 DTVC 125
Cdd:cd13416   156 DTVC 159

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 1937369584  44 CPQGKYahpKNNSICCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPCKADMDT 123
Cdd:cd13405     1 CGPAEY---EINGECCPMCPPGSRVSRHC-TEDTSTSCVPCPDGTYMDEPNGLEKCFPCTNCDPGFGLRVKQGCTYTSDT 76

                  ....*.
gi 1937369584 124 VCGCKK 129
Cdd:cd13405    77 VCEPLE 82

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 1937369584  48 KYAH---PKNNSICCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSC-KTCRKEMfqVEISPCKADMDT 123
Cdd:cd10583     1 KYRHvdpATGTQLTCDKCPAGTYVSKHC-TETSLRECSPCPNGTFTRHENGIEQCHRCrKPCPAPM--IEKTPCTALTDR 77

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584 124 VCGCKKNQFQrylseTHFQCVDCSPCFNGT-VTIPCKEKQNTVCN-CHAGFFlsGNECTPCSHCKKNQECMKLCLPPVAN 201
Cdd:cd10583    78 ECTCPPGTFL-----SNDTCVPHSVCPVGWgVRKKGTETEDVRCKpCPRGTF--SDVPSSVLKCKTYTDCLGLGLVVIKP 150

                  ....*.
gi 1937369584 202 VTNPQD 207
Cdd:cd10583   151 GTKETD 156

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.

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gi 1937369584  58 CCTKCHKGTYLVSDcpsPGQetvCEVCDKG-TFTASQNHVRQCLSCKTCRKEmfQVEISPCKADMDTVCGCKKNQFQ 133
Cdd:cd10580     1 SCGLCPAGTYVSED---SGD---CIPCKEGvDYTEHPNGLPSCLPCTVCKSD--EEELSPCTTTRNTECQCKPGTFC 69

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.

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gi 1937369584  54 NNSICCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRqCLSCKTCRKEmfQVEISPCKADMDTVCGCKK 129
Cdd:cd13424     9 KNYVCCESCHPGNRLVERC-GPDPAELCKPCEPGTYTVKPLDYS-CYICTQCIGA--QVLLKNCTPSSDTVCGCKE 80

Fas-associated Death Domain protein-protein interaction domain; Death domain (DD) found in FAS-associated via death domain (FADD). FADD is a component of the death-inducing signaling complex (DISC) and serves as an adaptor in the signaling pathway of death receptor proteins. It modulates apoptosis as well as non-apoptotic processes such as cell cycle progression, survival, innate immune signaling, and hematopoiesis. FADD contains an N-terminal DED and a C-terminal DD. Its DD interacts with the DD of the activated death receptor, FAS, and its DED recruits the initiator caspases, caspase-8 and -10, to the DISC complex via a homotypic interaction with the N-terminal DED of the caspase. DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and they can recruit other proteins into signaling complexes.

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gi 1937369584 378 WKEFMRLLGLSEHEIERLELQNGRCLREAHYSMLEAWRRRTpRHEATLDVVGRVL--CDMNL 437
Cdd:cd08306    16 WRQLARKLGLSETKIESISEAHPRNLREQVRQSLREWKKIK-KAEATVADLIKALrdCQLNL 76

TNFR/NGFR cysteine-rich region;

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gi 1937369584  84 CDKGTFTASQNHvRQCLSCKTCRKEmfQVEISPCKADMDTVC 125
Cdd:pfam00020   1 CPPGTYTDNWNG-LKCLPCTVCPPG--QVVVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A), also known as receptor activator of nuclear factor-kappaB (RANK); TNFRSF11A (also known as RANK, FEO, OFE, ODFR, OSTS, PDB2, CD26, OPTB7, TRANCER, LOH18CR1) induces the activation of NF-kappa B and MAPK8/JNK through interactions with various TRAF adaptor proteins. This receptor and its ligand are important regulators of the interaction between T cells and dendritic cells. The receptor is also an essential mediator for osteoclast and lymph node development. Mutations at this locus have been associated with familial expansile osteolysis, autosomal recessive osteopetrosis, and Juvenile Paget's disease (JPD) of bone. Alternatively spliced transcript variants have been described for this locus. Mutation analysis may improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1937369584  51 HPKNNSICCTKCHKGTYLVSDCpSPGQETVCEVCDKGTFTASQNHVRQCLSCKTCRKEMFQVEISPCKADMDTVCGCKKN 130
Cdd:cd13411     7 HYEYSGRCCSKCEPGKYMSSKC-TVTSDSVCLPCGPDEYLDTWNEEDKCLLHKVCDAGKALVAVDPGNSTAPRRCACTAG 85

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1937369584 131 QfqrYLSETHFQC---VDCSPCFNgtVTIPCKEKQNTVCN-CHAGFF----LSGNECTPCSHC 185
Cdd:cd13411    86 Y---HWSEDCDCCrrnTECAPGFG--AQHPVQLNKDTVCEpCLVGYFsdvfSSTDKCKPWTNC 143

Death Domain of Receptor-Interacting Protein 1; Death domain (DD) found in Receptor-Interacting Protein 1 (RIP1) and related proteins. RIP kinases serve as essential sensors of cellular stress. Vertebrates contain several types containing a homologous N-terminal kinase domain and varying C-terminal domains. RIP1 harbors a C-terminal DD, which binds death receptors (DRs) including TNF receptor 1, Fas, TNF-related apoptosis-inducing ligand receptor 1 (TRAILR1), and TRAILR2. It also interacts with other DD-containing adaptor proteins such as TRADD and FADD. RIP1 plays a crucial role in determining a cell's fate, between survival or death, following exposure to stress signals. It is important in the signaling of NF-kappaB and MAPKs, and it links DR-associated signaling to reactive oxygen species (ROS) production. Abnormal RIP1 function may result in ROS accumulation affecting inflammatory responses, innate immunity, stress responses, and cell survival. In general, DDs are protein-protein interaction domains found in a variety of domain architectures. Their common feature is that they form homodimers by self-association or heterodimers by associating with other members of the DD superfamily including CARD (Caspase activation and recruitment domain), DED (Death Effector Domain), and PYRIN. They serve as adaptors in signaling pathways and can recruit other proteins into signaling complexes.

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gi 1937369584 377 RWKEFMRLLGLSEHEIERLELQNGR-CLREAHYSMLEAWRRRTPRHEATldvVGRVLcdMNLRGCLE 442
Cdd:cd08777    15 KWKRCARRLGLTEVEIEEIDHDYERdGLKEKVHQMLEKWKMKEGSKGAT---VGKLA--KALEGCIK 76

TNFR/NGFR cysteine-rich region;

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                  ....*....|....*....|....*....|....*....|.
gi 1937369584 127 CKKNQFqrYLSETHFQCVDCSPCFNGTVTI-PCKEKQNTVC 166
Cdd:pfam00020   1 CPPGTY--TDNWNGLKCLPCTVCPPGQVVVrPCTPTSDTVC 39

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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                   ....*....|....*....|....*....|....*....|..
gi 1937369584   84 CDKGTFTASQNHvRQCLSCKTCrkEMFQVEISPCKADMDTVC 125
Cdd:smart00208   1 CKEGTYCSDGNH-SSCLRCRRC--PPGLVVKQPCTATSDTVC 39