Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137; TNFRSF9 (also known as CD137, ILA, 4-1BB) 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   23 SLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMC 102
Cdd:cd13410   1 SVQDSCSNCPAGTFCGKNKDQTCIPCPPNSFSSTGGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMC 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 5730095  103 EQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGP 160
Cdd:cd13410  81 EPDCKQGQELTKEGCKDCSFGTFNDQEGGVCRPWTNCSLDGKSVLVNGTKERDVVCGP 138

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137; TNFRSF9 (also known as CD137, ILA, 4-1BB) 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   23 SLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMC 102
Cdd:cd13410   1 SVQDSCSNCPAGTFCGKNKDQTCIPCPPNSFSSTGGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMC 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 5730095  103 EQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGP 160
Cdd:cd13410  81 EPDCKQGQELTKEGCKDCSFGTFNDQEGGVCRPWTNCSLDGKSVLVNGTKERDVVCGP 138

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
                   ....*....|....*....|....*....|....*....
gi 5730095      48 CPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAEC 86
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGLVVKQPCTATSDTVC 39

Tumor necrosis factor receptor superfamily member 9 (TNFRSF9), also known as CD137; TNFRSF9 (also known as CD137, ILA, 4-1BB) 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   23 SLQDPCSNCPAGTFCDNNRNQICSPCPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSMC 102
Cdd:cd13410   1 SVQDSCSNCPAGTFCGKNKDQTCIPCPPNSFSSTGGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMC 80

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|....*...
gi 5730095  103 EQDCKQGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNGTKERDVVCGP 160
Cdd:cd13410  81 EPDCKQGQELTKEGCKDCSFGTFNDQEGGVCRPWTNCSLDGKSVLVNGTKERDVVCGP 138

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 5730095   28 CSNCPAGTF----CDNNRNQICSPCPPNSFSSA-GGQRTCDICRQ-CKGVFRTRKECSSTSNAECDCTPGFHCLGAGCSM 101
Cdd:cd10583  15 CDKCPAGTYvskhCTETSLRECSPCPNGTFTRHeNGIEQCHRCRKpCPAPMIEKTPCTALTDRECTCPPGTFLSNDTCVP 94

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 5730095  102 cEQDCKQGQELTKKG-------CKDCCFGTFNDQKRGI--CRPWTNCSLDGKSVLVNGTKERDVVC 158
Cdd:cd10583  95 -HSVCPVGWGVRKKGtetedvrCKPCPRGTFSDVPSSVlkCKTYTDCLGLGLVVIKPGTKETDNVC 159

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        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   67 QCKGVFRTRKECSSTSNAECDCT---PGFHCLGAGCSMCEQ-DCKQGQELTKKG-------CKDCCFGTFNDQKRGICRP 135
Cdd:cd13417   1 RCCRKCPSEEADAPCCDAEGDCKcvqPGFHCGDPQCKTCKKhPCPPGQEVQRQGkfdfgfeCVPCANGTFSDGHDGHCKP 80

                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 5730095  136 WTNCSLDGKSVLVNGTKERDVVCGPSPADLSPGASSVTPPAP 177
Cdd:cd13417  81 WTDCSQFGFLTIFPGNKTHNAVCGPGPPPPEEDGHLTILAIP 122

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        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   28 CSNCPAG----TFCDNNRNQICSPCPPNSFSSAGGQ-RTCDICRQC--KGVFRTRKECSSTSNAECDCTPGFHCLGAGCS 100
Cdd:cd13407  13 CSLCPPGqklvSDCTEATDTECLPCEEGEFQDTWNReRHCHQHRYCdpNLGLRVQTEGTAETDTTCTCQEGQHCTSEACE 92

                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 5730095  101 MCEQD--CKQGQELTKKG-------CKDCCFGTFNDQKRGI--CRPWTNCSLDGKSVLVNGTKERDVVC 158
Cdd:cd13407  93 TCALHtsCKPGFGVKQIAtgvsdtiCEPCPVGFFSNVSSAFekCHPWTSCETKGLVELQAGTNKTDVVC 161

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 5730095   28 CSNCPAGTF----CDNNRNQICSPCPPNSFSSAGGQ-RTCDICRQCK-GVFRTRKECSSTSNAECDCTPGFHC-LGAGCS 100
Cdd:cd00185   2 CQRCPPGEYlssdCTATTDTVCSPCPPGTYSESWNSlSKCLPCTTCGgGNQVEKTPCTATDNRCCTCKPGFYCdEGTNVE 81

                ....
gi 5730095  101 MCEQ 104
Cdd:cd00185  82 ECKP 85

Tumor necrosis factor receptor superfamily member 5 (TNFRSF5) in teleosts; 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. Salmon CD40 and CD40L are widely expressed, particularly in immune tissues, and their importance for the immune response is indicated by their relatively high expression in salmon lymphoid organs and gills.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   72 FRTRKECSSTSNAECDCTPGFHCLGAGCSMC--EQDCKQGQELTKKG-------CKDCCFGTF--NDQKRGICRPWTNCS 140
Cdd:cd13422  64 FEISVNKSKTSRSVCKCKPGFHCSSEECLTCvpHTTCGPGQGVKSKGnhirdtvCEECPDGTFsnNSSAEGVCKKWTECE 143

                        90
                ....*....|....*....
gi 5730095  141 lDGKSVLVNGTKERDVVCG 159
Cdd:cd13422 144 -SGYKVEAAGTNTSDNICV 161

Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B), also known as Osteoprotegerin (OPG); TNFRSF11B (also known as Osteoprotegerin, OPG, TR1, OCIF) is a secreted glycoprotein that regulates bone resorption. It binds to two ligands, RANKL (receptor activator of nuclear factor kappaB ligand, also known as osteoprotegerin ligand, OPGL, TRANCE, TNF-related activation induced cytokine), a critical cytokine for osteoclast differentiation, and TRAIL (TNF-related apoptosis-inducing ligand), involved in immune surveillance. Therefore, acting as a decoy receptor for RANKL and TRAIL, OPG inhibits the regulatory effects of nuclear factor-kappaB on inflammation, skeletal, and vascular systems, and prevents TRAIL-induced apoptosis. Studies in mice counterparts suggest that this protein and its ligand also play a role in lymph-node organogenesis and vascular calcification. Circulating OPG levels have emerged as independent biomarkers of cardiovascular disease (CVD) in patients with acute or chronic heart disease. OPG has also been implicated in various inflammations and linked to diabetes and poor glycemic control. Alternatively spliced transcript variants of this gene have been reported, although their full length nature has not been determined.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   16 LNFERTRSLQDPCSNCPAGTF----CDNNRNQICSPCPPNSFSSAGGQRT-CDICRQ-CKGVFRTRKECSSTSNAECDCT 89
Cdd:cd10581  24 LHYDPVTSRQLMCDQCPPGTYvkqhCSASRKTVCAPCPDHHYADDWNSNDeCQYCNTvCKELQYVKQECNSTHNRVCECV 103

                ....
gi 5730095   90 PGFH 93
Cdd:cd10581 104 EGRY 107

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 5730095   28 CSNCPAGTF----CDNNRNQICSPCPPNSF-SSAGGQRTCDICRQCKGVF--RTRKECSSTSNAECDCTPGFHCL---GA 97
Cdd:cd13405  13 CPMCPPGSRvsrhCTEDTSTSCVPCPDGTYmDEPNGLEKCFPCTNCDPGFglRVKQGCTYTSDTVCEPLEGFYCIdstKD 92

                        90
                ....*....|....*
gi 5730095   98 GCSMCEQ--DCKQGQ 110
Cdd:cd13405  93 GCSAAQRhsSCKPGQ 107

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

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   28 CSNCPAGTF----CDNNRNQICSPCPPNSFSS----AGGQRTCDICRQCKGVfRTRKECSSTSNAECDCTPGFHC----L 95
Cdd:cd15835  21 CSKCRPGTRlktkCSETSDTVCEPCPSGQYSEnwnyYPNCFSCPKCKERKGL-QYAQNCSSTTNAVCVCKPGMYCimgfD 99

                        90       100
                ....*....|....*....|...
gi 5730095   96 GAGCSMCEQ--DCKQGQELTKKG 116
Cdd:cd15835 100 HPSCSECKKyrTCKPGYGVSVPG 122

Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) in teleost; also known as 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. This 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.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   28 CSNCPAGTF----CDNNRNQICSPCPPNSFSSAGGQRTCDI----CRQCKGVFRTRKEcSSTSNAECDCTPGFHCLGAGC 99
Cdd:cd15836  16 CRKCEPGSFvfahCSGSSDTICRDCGRNEYQPDWTSEMKCIpqkfCDEGKGFNRTRPH-NPTALEPCQCKPGFQCSPLNC 94

                        90       100
                ....*....|....*....|....*...
gi 5730095  100 SMCEQ--DCKQGQELT-----KKGCKDC 120
Cdd:cd15836  95 EFCEKipTCPPGYGLEgeengRKICVPC 122

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 5730095     48 CPPNSFSSAGGQRTCDICRQCKGVFRTRKECSSTSNAEC 86
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQVVVRPCTPTSDTVC 39

Tumor necrosis factor receptor superfamily member 16 (TNFRSF16), also known as p75 neurotrophin receptor (p75NTR) or CD271; TNFRSF16 (also known as nerve growth factor receptor (NGFR) or p75 neurotrophin receptor (p75NTR or p75(NTR)), CD271, Gp80-LNGFR) is a common receptor for both neurotrophins and proneurotrophins, and plays a diverse role in many tissues, including the nervous system. It has been shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. p75NTR owes its signaling to the recruitment of intracellular binding proteins, leading to the activation of different signaling pathways. It binds nerve growth factor (NGF) and the complex can initiate a signaling cascade which has been associated with both neuronal apoptosis and neuronal survival of discrete populations of neurons, depending on the presence or absence of intracellular signaling molecules downstream of p75NTR (e.g. NF-kB, JNK, or p75NTR intracellular death domain). p75NTR can also bind NGF in concert with the neurotrophic tyrosine kinase receptor type 1 (TrkA) protein where it is thought to modulate the formation of the high-affinity neurotrophin binding complex. On melanoma cell, p75NTR is an immunosuppressive factor, induced by interferon (IFN)-gamma, and mediates down-regulation of melanoma antigens. It can interact with the aggregated form of amyloid beta (Abeta) peptides, and plays an important role in etiopathogenesis of Alzheimer's disease by influencing protein tau hyper-phosphorylation. p75(NTR) is involved in the formation and progression of retina diseases; its expression is induced in retinal pigment epithelium (RPE) cells and its knockdown rescues RPE cell proliferation activity and inhibits RPE apoptosis induced by hypoxia. It can therefore be a potential therapeutic target for RPE hypoxia or oxidative stress diseases.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 5730095   28 CSNCPAGT----FCDNNrNQICSPCPPN-SFS-SAGGQRTCDICRQCKGVFRTRKECSSTSNAECDCTPGFHcLGAGCSM 101
Cdd:cd13416  15 CEQCPPGEgvarPCGDN-QTVCEPCLDGvTFSdVVSHTEPCQPCTRCPGLMSMRAPCTATHDTVCECAYGYY-LDEDSGT 92

                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|
gi 5730095  102 CEQ--DCKQGQELTKK-------GCKDCCFGTFNDQKRGI--CRPWTNCS 140
Cdd:cd13416  93 CEPctVCPPGQGVVQScgpnqdtVCEACPEGTYSDEDSSTdpCLPCTVCE 142

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 5730095   99 CSMCEQdCKQGQELTKKG---------CKDCCFGTFND-QKRGICRPWTNCSLDGKSVLVNGTKERDVVCGPS-PADLSP 167
Cdd:cd13419   1 CVPCLQ-CPPGQEPDRACgqgqglgvlCRSCPPGTFSDsLGSEPCRPHTSCEVLKRKVATSGTATSDAVCGDClPGFHSP 79

                        90
                ....*....|
gi 5730095  168 GASSVTPPAP 177
Cdd:cd13419  80 AAPPPSTCLP 89