tumor necrosis factor receptor superfamily member 19-like (TNFRSF19L), also known as receptor expressed in lymphoid tissues (RELT); TNFRSF19L (also known as receptor expressed in lymphoid tissues (RELT)) is especially abundant in hematologic tissues and can stimulate the proliferation of T-cells. It serves as a substrate for the closely related kinases, odd-skipped related transcription factor 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK); RELT binds SPAK and uses it to mediate p38 and JNK activation, rather than rely on the canonical TRAF pathways for its function. RELT is capable of stimulating T-cell proliferation in the presence of CD3 signaling, which suggests its regulatory role in immune response. It interacts with phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein that mediates antiviral activity against DNA and RNA viruses; PLSCR1 is a regulator of hepatitis B virus X (HBV X) protein. RELT and PLSCR1 co-localize in intracellular regions of human embryonic kidney-293 cells, with RELT over-expression appearing to alter the localization of PLSCR1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568950850  73 PITPWLCPPGKEPDPD----PGQGTLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMCGDCQHGWFGPQ 148
Cdd:cd13419    1 CVPCLQCPPGQEPDRAcgqgQGLGVLCRSCPPGTFSDSLGSEPCRPHTSCEVLKRKVATSGTATSDAVCGDCLPGFHSPA 80

                         90
                 ....*....|.
gi 568950850 149 GVPHVPCQPCS 159
Cdd:cd13419   81 APPPSTCLPCS 91

tumor necrosis factor receptor superfamily member 19-like (TNFRSF19L), also known as receptor expressed in lymphoid tissues (RELT); TNFRSF19L (also known as receptor expressed in lymphoid tissues (RELT)) is especially abundant in hematologic tissues and can stimulate the proliferation of T-cells. It serves as a substrate for the closely related kinases, odd-skipped related transcription factor 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK); RELT binds SPAK and uses it to mediate p38 and JNK activation, rather than rely on the canonical TRAF pathways for its function. RELT is capable of stimulating T-cell proliferation in the presence of CD3 signaling, which suggests its regulatory role in immune response. It interacts with phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein that mediates antiviral activity against DNA and RNA viruses; PLSCR1 is a regulator of hepatitis B virus X (HBV X) protein. RELT and PLSCR1 co-localize in intracellular regions of human embryonic kidney-293 cells, with RELT over-expression appearing to alter the localization of PLSCR1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568950850  73 PITPWLCPPGKEPDPD----PGQGTLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMCGDCQHGWFGPQ 148
Cdd:cd13419    1 CVPCLQCPPGQEPDRAcgqgQGLGVLCRSCPPGTFSDSLGSEPCRPHTSCEVLKRKVATSGTATSDAVCGDCLPGFHSPA 80

                         90
                 ....*....|.
gi 568950850 149 GVPHVPCQPCS 159
Cdd:cd13419   81 APPPSTCLPCS 91

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 568950850   98 CPPGTFSASWNSYPCQPHYRCSLQKRlEAQAGTATHDTMC 137
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQV-VVRPCTPTSDTVC 39

tumor necrosis factor receptor superfamily member 19-like (TNFRSF19L), also known as receptor expressed in lymphoid tissues (RELT); TNFRSF19L (also known as receptor expressed in lymphoid tissues (RELT)) is especially abundant in hematologic tissues and can stimulate the proliferation of T-cells. It serves as a substrate for the closely related kinases, odd-skipped related transcription factor 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK); RELT binds SPAK and uses it to mediate p38 and JNK activation, rather than rely on the canonical TRAF pathways for its function. RELT is capable of stimulating T-cell proliferation in the presence of CD3 signaling, which suggests its regulatory role in immune response. It interacts with phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein that mediates antiviral activity against DNA and RNA viruses; PLSCR1 is a regulator of hepatitis B virus X (HBV X) protein. RELT and PLSCR1 co-localize in intracellular regions of human embryonic kidney-293 cells, with RELT over-expression appearing to alter the localization of PLSCR1.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 568950850  73 PITPWLCPPGKEPDPD----PGQGTLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMCGDCQHGWFGPQ 148
Cdd:cd13419    1 CVPCLQCPPGQEPDRAcgqgQGLGVLCRSCPPGTFSDSLGSEPCRPHTSCEVLKRKVATSGTATSDAVCGDCLPGFHSPA 80

                         90
                 ....*....|.
gi 568950850 149 GVPHVPCQPCS 159
Cdd:cd13419   81 APPPSTCLPCS 91

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 568950850  78 LCPPGKEPDPD--PGQGTLCRTCPPGTFSASWNSYP-CQPHYRCSLQKRLEAQAGTATHDTmCGDCQHGWFGPQGVPHVP 154
Cdd:cd00185    4 RCPPGEYLSSDctATTDTVCSPCPPGTYSESWNSLSkCLPCTTCGGGNQVEKTPCTATDNR-CCTCKPGFYCDEGTNVEE 82

                 ....*
gi 568950850 155 CQPCS 159
Cdd:cd00185   83 CKPCT 87

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 568950850  79 CPPGKEPDPDPGQG----TLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMCGDCQHGWFGPQ---GVP 151
Cdd:cd15838   19 CGPGQELSKDCGYGeggdAYCTACPPRRFKDSWGHHGCKTCLSCALINRVQKSNCTATSNAVCGDCLPGFYRKTrigGLQ 98

                         90
                 ....*....|....
gi 568950850 152 HVPCQPCSKAPPST 165
Cdd:cd15838   99 DQECIPCTKQTPSS 112

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 568950850  70 TPTPITPWLCPPGKEPDPDPGQGTLCRTCPPGTFSASWNSyPCQPHYRCSLQKRLEAQAGTATHDTMCGD 139
Cdd:cd13406   72 TKTSDTVCRCRPGTQPLDSYKPGVDCVPCPPGHFSRGDNQ-ACKPWTNCSLAGKRTLRPGSSTSDAVCED 140

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 568950850  79 CPPGKEPDP--DPGQGTLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEA-QAGTATHDTMCGD-----CQHGWfgPQGV 150
Cdd:cd13406   18 CPPGEGMESrcTGTQDTVCSPCEPGFYNEAVNYEPCKPCTQCNQRSGSEEkQKCTKTSDTVCRCrpgtqPLDSY--KPGV 95

                         90
                 ....*....|....*...
gi 568950850 151 PHVPCQPCSKAPPSTGGC 168
Cdd:cd13406   96 DCVPCPPGHFSRGDNQAC 113

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 568950850  87 PDPGQGTLCRTCPPGTFSASWNSYP-CQPHYRCSLQ-KRLEAQAGTATHDTMCGdCQHGWFGPQGVPHVPCQPCS 159
Cdd:cd10576   29 PGPGQDTVCRECENGTFTASENYLRkCLSCSRCRKEmGQVEISPCTVDQDTVCG-CRKNQYQHYWSSLFQCKNCS 102

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 568950850  79 CPPGK--EPDPDPGQGTLCRTCPPGTFSASWNSYP-CQPHYRC-SLQKRLEAQAGTATHDTMCGdCQHGWFGPQGVPHVP 154
Cdd:cd10578   52 CPPGThvSAECSRSQDTVCATCPENSYNEHWNHLSiCQLCRPCdPVLGFEEVAPCTSDRKTQCR-CQPGMFCVHWDNECE 130

                         90
                 ....*....|..
gi 568950850 155 -CQPCSKAPPST 165
Cdd:cd10578  131 hCEPLSDCPPGT 142

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
                 ....*....|....*....|....*....|....*....|....*....|
gi 568950850  89 PGQGTLCRTCPPGTFSASWNSY-PCQPHYRCSlQKRLEAQAGTATHDTMC 137
Cdd:cd13416  111 PNQDTVCEACPEGTYSDEDSSTdPCLPCTVCE-DGEVELRECTPVSDTVC 159

Tumor necrosis factor receptor superfamily member 1B (TNFRSF1B), also known as TNFR2; TNFRSF1B (also known as TNFR2, type 2 TNFR, TNFBR, TNFR80, TNF-R75, TNF-R-II, p75, CD120b) 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).

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 568950850  79 CPPG---KEPDPDPGQgTLCRTCPPGTFSASWNSY-PCQPHYRCSLQkrleAQAGTATHDTMC 137
Cdd:cd10577  105 CGPGfgvARPGTASSD-VECKPCAPGTFSDTTSSTdTCRPHRICSSV----AIPGNASMDAVC 162

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 568950850  78 LCPPG---KEPDPDPGQGTLCRTCPPGTFSASWNS-YPCQPHYRCSLQKRLE-AQAGTATHDTMCGdCQHGWFGPQGVPH 152
Cdd:cd13423   16 LCPAGqhvEKHCTNNGTDGECEACEDGTYNSHPNSlDSCEPCTSCDPNANLEvEERCTPSSDTVCR-CKEGHYCDKGEEC 94

                 ....*...
gi 568950850 153 VPCQPCSK 160
Cdd:cd13423   95 KVCYPCDT 102

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
                 ....*....|....*....|....*....|....*....|....*.
gi 568950850  93 TLCRTCPPGTFS-ASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMC 137
Cdd:cd13407  116 TICEPCPVGFFSnVSSAFEKCHPWTSCETKGLVELQAGTNKTDVVC 161