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 578803520  13 LPVLVVSLMCSARAEYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKD 92
Cdd:cd13421    1 LPFLVVSLMCSASAEYSNCGENEYYNQTTGLCQQCPPCRPGEEPYMSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 578803520  93 CEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKEC 148
Cdd:cd13421   81 CEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKEC 136

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 578803520  13 LPVLVVSLMCSARAEYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKD 92
Cdd:cd13421    1 LPFLVVSLMCSASAEYSNCGENEYYNQTTGLCQQCPPCRPGEEPYMSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 578803520  93 CEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKEC 148
Cdd:cd13421   81 CEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKEC 136

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 578803520  13 LPVLVVSLMCSARAEYSNCGENEYYNQTTGLCQECPPCGPGEEPYLSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKD 92
Cdd:cd13421    1 LPFLVVSLMCSASAEYSNCGENEYYNQTTGLCQQCPPCRPGEEPYMSCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKD 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....*.
gi 578803520  93 CEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKEC 148
Cdd:cd13421   81 CEGFFRATVLTPGDMENDAECGPCLPGYYMLENRPRNIYGMVCYSCLLAPPNTKEC 136

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 578803520  30 NCGENEYYNQTtGLCQECPPCGPGEEPYLSCGYGTkDEDYGCVPCPAEKFSKG-GYQICRRHKDCEGFFRatvLTPGDME 108
Cdd:cd13418    1 DCREQEYRDKA-GNCIPCRQCGPGMELSKECGFGY-GEDAQCVPCRPNRFKEDwGFQKCKPCLDCALLNR---FQKANCS 75

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 578803520 109 --NDAECGPCLPGYYMlENRPRNIYGMVCYSCLLAPP 143
Cdd:cd13418   76 atSNAVCGDCLPGFYR-KTKLVGFQDMECVPCGDPPP 111

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 578803520  47 CPPCGPGEEPYLSCGYGTkdeDYGCVPCPAEKFS--KGGYQICRRHKDCEGFFRaTVLTPGDMENDAECGpCLPGYYMLE 124
Cdd:cd00185    2 CQRCPPGEYLSSDCTATT---DTVCSPCPPGTYSesWNSLSKCLPCTTCGGGNQ-VEKTPCTATDNRCCT-CKPGFYCDE 76

                         90
                 ....*....|....
gi 578803520 125 nrprNIYGMVCYSC 138
Cdd:cd00185   77 ----GTNVEECKPC 86

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        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 578803520  44 CQECP--PCGPGEEPylsCGYGTKDEDYGCVPCPAEKFSKGGYQICRRHKDCEGFFRATvLTPGDMENDAECGPCLPG 119
Cdd:cd13417   36 CKTCKkhPCPPGQEV---QRQGKFDFGFECVPCANGTFSDGHDGHCKPWTDCSQFGFLT-IFPGNKTHNAVCGPGPPP 109

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        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 578803520  44 CQEC-PPCGPGEEPYLSCgygTKDEDYGCVpCPAEKF----SKGGYQICRRHKDCEGFFRatVLTPGDMENDAECGPCLP 118
Cdd:cd10577   55 CLSCsSPCSSDQVETQAC---TRQQNRICS-CKPGWYcvlkLQEGCRQCRPLKKCGPGFG--VARPGTASSDVECKPCAP 128

                 .
gi 578803520 119 G 119
Cdd:cd10577  129 G 129