Tumour necrosis factor receptor superfamily member 19; This family of proteins is found in eukaryotes. Proteins in this family are typically between 49 and 288 amino acids in length. There are two completely conserved residues (K and Y) that may be functionally important. The members of tumor necrosis factor receptor (TNFR) superfamily have been designated as the 'guardians of the immune system' due to their roles in immune cell proliferation, differentiation, activation, and death (apoptosis). The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1. RELT is a TNF receptor family member that is expressed in hematological tissues and can stimulate the proliferation of T-cells, the p38 and JNK MAPK pathways, and serves as a substrate for the closely related kinases OSR1 and SPAK. Furthermore, family members include the homologs RELL1 and RELL2 (RELT-like protein 1 and 2 respectively). RELT, RELL1 and RELL2 bind to each other in vitro and co-localize with one another at the plasma membrane. Functional studies of the role of RELT, show that overexpression of RELT in epithelial cells induces cell death by promoting cell rounding and DNA fragmentation.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1720422978 170 YAVIAIVPVFCLMGLLGILVCNLLKRKGYHCTAQKE 205
Cdd:pfam12606   1 YIAFALVPIFFLMGLLGVLICHVLKKKGYRCTTEKE 36

Tumour necrosis factor receptor superfamily member 19; This family of proteins is found in eukaryotes. Proteins in this family are typically between 49 and 288 amino acids in length. There are two completely conserved residues (K and Y) that may be functionally important. The members of tumor necrosis factor receptor (TNFR) superfamily have been designated as the 'guardians of the immune system' due to their roles in immune cell proliferation, differentiation, activation, and death (apoptosis). The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1. RELT is a TNF receptor family member that is expressed in hematological tissues and can stimulate the proliferation of T-cells, the p38 and JNK MAPK pathways, and serves as a substrate for the closely related kinases OSR1 and SPAK. Furthermore, family members include the homologs RELL1 and RELL2 (RELT-like protein 1 and 2 respectively). RELT, RELL1 and RELL2 bind to each other in vitro and co-localize with one another at the plasma membrane. Functional studies of the role of RELT, show that overexpression of RELT in epithelial cells induces cell death by promoting cell rounding and DNA fragmentation.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1720422978 170 YAVIAIVPVFCLMGLLGILVCNLLKRKGYHCTAQKE 205
Cdd:pfam12606   1 YIAFALVPIFFLMGLLGVLICHVLKKKGYRCTTEKE 36

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 1720422978   58 CPPGTFSASWNSYPCQPHYRCSLQKRlEAQAGTATHDTMC 97
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGLV-VKQPCTATSDTVC 39

Tumour necrosis factor receptor superfamily member 19; This family of proteins is found in eukaryotes. Proteins in this family are typically between 49 and 288 amino acids in length. There are two completely conserved residues (K and Y) that may be functionally important. The members of tumor necrosis factor receptor (TNFR) superfamily have been designated as the 'guardians of the immune system' due to their roles in immune cell proliferation, differentiation, activation, and death (apoptosis). The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1. RELT is a TNF receptor family member that is expressed in hematological tissues and can stimulate the proliferation of T-cells, the p38 and JNK MAPK pathways, and serves as a substrate for the closely related kinases OSR1 and SPAK. Furthermore, family members include the homologs RELL1 and RELL2 (RELT-like protein 1 and 2 respectively). RELT, RELL1 and RELL2 bind to each other in vitro and co-localize with one another at the plasma membrane. Functional studies of the role of RELT, show that overexpression of RELT in epithelial cells induces cell death by promoting cell rounding and DNA fragmentation.

                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1720422978 170 YAVIAIVPVFCLMGLLGILVCNLLKRKGYHCTAQKE 205
Cdd:pfam12606   1 YIAFALVPIFFLMGLLGVLICHVLKKKGYRCTTEKE 36

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1720422978  39 CPPGK--EPDPDPGQGTLCRTCPPGTFSASWNSY-PCQPHYRCSLQKRLEAQAGTATHDTMCGDC 100
Cdd:cd10575    99 CPPGEgvIKLGTPYSDTQCEPCPPGFFSASSSSTePCQPHTNCTQGGLETNVPGNDYHDTLCTSC 163

Tumor necrosis factor receptor superfamily member 19 (TNFRSF19), also known as TROY; TNFRSF19 (also known as TAJ; TROY; TRADE; TAJ-alpha) is expressed in progenitor cells of the hippocampus, thalamus, and cerebral cortex and highly expressed during embryonic development. It has been shown to interact with TRAF family members, and to activate JNK signaling pathway when overexpressed in cells. It is frequently overexpressed in colorectal cancer cell lines and primary colorectal carcinomas. TNFRSF19 is a beta-catenin target gene, in mesenchymal stem cells, and also activates NF-kappaB signaling, showing that beta-catenin regulates NF-kappaB activity via TNFRSF19. Since Wnt/beta-catenin signaling plays a crucial role in the regulation of colon tissue regeneration and the development of colon tumors, TNFRSF19 may contribute to the development of colorectal tumors. These findings define a role for death receptors DR6 and TROY in CNS-specific vascular development. TNFRSF19 has been shown to promote glioblastoma (GBM) survival signaling and therefore targeting it may increase tumor vulnerability and improve therapeutic response in glioblastoma. It may play an important role in myelin-associated inhibitory factors (MAIFs)-induced inhibition of neurite outgrowth in the postnatal central nervous system (CNS) or on axon regeneration following CNS injury.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720422978  39 CPPGKEPDPDPGQG----TLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMCGDCQHGWFGPQ---GVP 111
Cdd:cd13418    20 CGPGMELSKECGFGygedAQCVPCRPNRFKEDWGFQKCKPCLDCALLNRFQKANCSATSNAVCGDCLPGFYRKTklvGFQ 99

                          90
                  ....*....|..
gi 1720422978 112 HVPCQPCSKAPP 123
Cdd:cd13418   100 DMECVPCGDPPP 111

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 1720422978  39 CPPGKEPDP--DPGQGTLCRTCPPGTFSASWNSYPCQPHYRCSLQKRLEA-QAGTATHDTMCGD-----CQHGWfgPQGV 110
Cdd:cd13406    18 CPPGEGMESrcTGTQDTVCSPCEPGFYNEAVNYEPCKPCTQCNQRSGSEEkQKCTKTSDTVCRCrpgtqPLDSY--KPGV 95

                          90
                  ....*....|....*...
gi 1720422978 111 PHVPCQPCSKAPPSTGGC 128
Cdd:cd13406    96 DCVPCPPGHFSRGDNQAC 113

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720422978  53 TLCRTCPPGTFSASWNSYP-CQPHYRCSLQKRLE-AQAGTATHDTMCGdCQHGWFGPQGVPHVPCQPCSK 120
Cdd:cd15835    40 TVCEPCPSGQYSENWNYYPnCFSCPKCKERKGLQyAQNCSSTTNAVCV-CKPGMYCIMGFDHPSCSECKK 108

TNFR/NGFR cysteine-rich region;

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 1720422978  58 CPPGTFSASWNSYPCQPHYRCSLQKRlEAQAGTATHDTMC 97
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQV-VVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR); TNFRSF18 (also known as activation-inducible TNF receptor (AITR), glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), CD357, GITR-D) has increased expression upon T-cell activation, and is thought to play a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells. In inflammatory cells, GITR expression indicates a possible molecular link between steroid use and complicated acute sigmoid diverticulitis; increased MMP-9 expression by GITR signaling might explain morphological changes in the colonic wall in diverticulitis. Its ligand, GITRL, activates GITR which could then influence the activity of effector and regulatory T cells, participating in the development of several autoimmune and inflammatory diseases, including autoimmune thyroid disease and rheumatoid arthritis. In systemic lupus erythematosus (SLE) patients, serum GITRL levels are increased compared with healthy controls. GITR and its ligand, GITRL, are possibly involved in the pathogenesis of primary Sjogren's syndrome (pSS). GITR is inactivated during tumor progression in Multiple Myeloma (MM); restoration of GITR expression in GITR deficient MM cells leads to inhibition of MM proliferation and induction of apoptosis, thus playing a pivotal role in MM pathogenesis and disease progression. Regulatory T-cells (Tregs) in liver tumor up-regulate the expression of GITR compared with Tregs in tumor-free liver tissue and blood. Regulatory single nucleotide polymorphisms (SNPs) in the promoter regions of the TNFRSF18 gene have been identified in a group of male Gabonese individuals exposed to a wide array of parasitic diseases such as malaria, filariasis and schistosomiasis, and may serve as a basis to study parasite susceptibility in association studies.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1720422978  39 CPPGKEPDPdpgQGTL-----CRTCPPGTFSASWNSYpCQPHYRCSLQKRLEAQAGTATHDTMCG 98
Cdd:cd13417    44 CPPGQEVQR---QGKFdfgfeCVPCANGTFSDGHDGH-CKPWTDCSQFGFLTIFPGNKTHNAVCG 104

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 1720422978  39 CPPG---KEPDPDPGQgTLCRTCPPGTFSASWNSY-PCQPHYRCSLQkrleAQAGTATHDTMC 97
Cdd:cd10577   105 CGPGfgvARPGTASSD-VECKPCAPGTFSDTTSSTdTCRPHRICSSV----AIPGNASMDAVC 162

Tumor necrosis factor receptor superfamily member ectodysplasin A receptor (EDAR); Ectodysplasin A receptor (EDAR, also known as DL, ED3, ED5, ED1R, EDA3, HRM1, EDA1R, ECTD10A, ECTD10B, EDA-A1R) binds the soluble ligand ectodysplasin A and can activate the nuclear factor-kappaB, JNK, and caspase-independent cell death pathways. It is required for the development of hair, teeth, and other ectodermal derivatives. Mutations in this gene result in autosomal dominant and recessive forms of hypohidrotic ectodermal dysplasia. Patients present defects in the development of ectoderm-derived structures resulting in sparse hair, too few teeth (oligodontia), the absence or reduction in the ability to sweat as well as problems with mucous and saliva and the production and formation of pigment cells.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720422978  39 CPPGKEPDPDPGQGTL-----CRTCPPGTFSASWNSYpCQPHYRC-SLQKRLEAQAGTATHDTMCGDCQHGWF----GPQ 108
Cdd:cd13421    38 CRPGEEPYMSCGYGTKdedygCVPCPAEKFSKGGYQI-CRRHKDCeGFFRATVLTPGDMENDAECGPCLPGYYmlenRPR 116

                          90       100
                  ....*....|....*....|
gi 1720422978 109 GVPHVPCQPCSKAPPSTGGC 128
Cdd:cd13421   117 NIYGMVCYSCLLAPPNTKEC 136

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 1720422978  38 LCPPG---KEPDPDPGQGTLCRTCPPGTFSASWNS-YPCQPHYRCSLQKRLE-AQAGTATHDTMCGdCQHGWFGPQGVPH 112
Cdd:cd13423    16 LCPAGqhvEKHCTNNGTDGECEACEDGTYNSHPNSlDSCEPCTSCDPNANLEvEERCTPSSDTVCR-CKEGHYCDKGEEC 94

                  ....*...
gi 1720422978 113 VPCQPCSK 120
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 1720422978  53 TLCRTCPPGTFS-ASWNSYPCQPHYRCSLQKRLEAQAGTATHDTMC 97
Cdd:cd13407   116 TICEPCPVGFFSnVSSAFEKCHPWTSCETKGLVELQAGTNKTDVVC 161