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 1958778193  23 ATRNPCDSCEAGTFCSKY-PPVCTSCPPSTYSSTGGQPNCDICRVCQGYFRFKKPCSSTHNAECECVEGFHCLGPKCTRC 101
Cdd:cd13410     1 SVQDSCSNCPAGTFCGKNkDQTCIPCPPNSFSSTGGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMC 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1958778193 102 EKDCRPGQELTEQGCKNCGLGTFNDQDGaGVCRPWTNCSLDGRSVLKNGTKEKDVVCGP 160
Cdd:cd13410    81 EPDCKQGQELTKEGCKDCSFGTFNDQEG-GVCRPWTNCSLDGKSVLVNGTKERDVVCGP 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 1958778193  23 ATRNPCDSCEAGTFCSKY-PPVCTSCPPSTYSSTGGQPNCDICRVCQGYFRFKKPCSSTHNAECECVEGFHCLGPKCTRC 101
Cdd:cd13410     1 SVQDSCSNCPAGTFCGKNkDQTCIPCPPNSFSSTGGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMC 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1958778193 102 EKDCRPGQELTEQGCKNCGLGTFNDQDGaGVCRPWTNCSLDGRSVLKNGTKEKDVVCGP 160
Cdd:cd13410    81 EPDCKQGQELTKEGCKDCSFGTFNDQEG-GVCRPWTNCSLDGKSVLVNGTKERDVVCGP 138

TNFR/NGFR cysteine-rich region;

                          10        20        30
                  ....*....|....*....|....*....|....*....
gi 1958778193  47 CPPSTYSSTGGQPNCDICRVCQGYFRFKKPCSSTHNAEC 85
Cdd:pfam00020   1 CPPGTYTDNWNGLKCLPCTVCPPGQVVVRPCTPTSDTVC 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 1958778193  23 ATRNPCDSCEAGTFCSKY-PPVCTSCPPSTYSSTGGQPNCDICRVCQGYFRFKKPCSSTHNAECECVEGFHCLGPKCTRC 101
Cdd:cd13410     1 SVQDSCSNCPAGTFCGKNkDQTCIPCPPNSFSSTGGQQTCDICRKCEGVFRTKKPCSSTSNAECECVPGFHCLGPGCSMC 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1958778193 102 EKDCRPGQELTEQGCKNCGLGTFNDQDGaGVCRPWTNCSLDGRSVLKNGTKEKDVVCGP 160
Cdd:cd13410    81 EPDCKQGQELTKEGCKDCSFGTFNDQEG-GVCRPWTNCSLDGKSVLVNGTKERDVVCGP 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 1958778193  28 CDSCEAGTFCSKYPP-----VCTSCPPSTYSS-TGGQPNCDICRV-CQGYFRFKKPCSSTHNAECECVEGFHCLGPKCTR 100
Cdd:cd10583    15 CDKCPAGTYVSKHCTetslrECSPCPNGTFTRhENGIEQCHRCRKpCPAPMIEKTPCTALTDRECTCPPGTFLSNDTCVP 94

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958778193 101 cEKDCRPGQELTEQG-------CKNCGLGTFNDQDGAGV-CRPWTNCSLDGRSVLKNGTKEKDVVC 158
Cdd:cd10583    95 -HSVCPVGWGVRKKGtetedvrCKPCPRGTFSDVPSSVLkCKTYTDCLGLGLVVIKPGTKETDNVC 159

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 1958778193  72 RFKKPCSSTHNAECECVEGFHCLGPKCTRCEKD--CRPGQELTEQG-------CKNCGLGTFNDQDGA-GVCRPWTNCSL 141
Cdd:cd13407    65 RVQTEGTAETDTTCTCQEGQHCTSEACETCALHtsCKPGFGVKQIAtgvsdtiCEPCPVGFFSNVSSAfEKCHPWTSCET 144

                          90
                  ....*....|....*..
gi 1958778193 142 DGRSVLKNGTKEKDVVC 158
Cdd:cd13407   145 KGLVELQAGTNKTDVVC 161

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 1958778193  28 CDSCEAGT----FCSKYPPVCTSCPPS-TYSST-GGQPNCDICRVCQGYFRFKKPCSSTHNAECECVEGFHCLGP--KCT 99
Cdd:cd13416    15 CEQCPPGEgvarPCGDNQTVCEPCLDGvTFSDVvSHTEPCQPCTRCPGLMSMRAPCTATHDTVCECAYGYYLDEDsgTCE 94

                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1958778193 100 RCEKdCRPGQELTEQ-------GCKNCGLGTFNDQDGAGV-CRPWTNCSlDGRSVLKNGTKEKDVVC 158
Cdd:cd13416    95 PCTV-CPPGQGVVQScgpnqdtVCEACPEGTYSDEDSSTDpCLPCTVCE-DGEVELRECTPVSDTVC 159

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 1958778193  42 PVCTSCPPSTYSSTGGQPNCDICRVCQgyfrfkKPCSSTHNAECECVEGFHCLGPKCTRCEKDCRPGQElteqgCKNCGL 121
Cdd:cd13406    34 TVCSPCEPGFYNEAVNYEPCKPCTQCN------QRSGSEEKQKCTKTSDTVCRCRPGTQPLDSYKPGVD-----CVPCPP 102

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 1958778193 122 GTFNDQDGaGVCRPWTNCSLDGRSVLKNGTKEKDVVCGPPV 162
Cdd:cd13406   103 GHFSRGDN-QACKPWTNCSLAGKRTLRPGSSTSDAVCEDRS 142

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 1958778193  28 CDSCEAGTF----CS-KYPPVCTSCPPSTYSST-GGQPNCDICR-VCQGYFRFKKPCSSTHNAECECVEGFHCLGPKCTR 100
Cdd:cd10581    36 CDQCPPGTYvkqhCSaSRKTVCAPCPDHHYADDwNSNDECQYCNtVCKELQYVKQECNSTHNRVCECVEGRYLELEFCLK 115

                          90       100       110
                  ....*....|....*....|....*....|...
gi 1958778193 101 cEKDCRPGQELTEQG-------CKNCGLGTFND 126
Cdd:cd10581   116 -HTECPPGFGVVQPGtpesdtvCERCPEGFFSN 147

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958778193  28 CDSCEAGTFCSK-----YPPVCTSCPPSTYSSTGGQPN-CDICRVCQGYFRFKK--PCSSTHNAECECVEGFH----Clg 95
Cdd:cd13411    15 CSKCEPGKYMSSkctvtSDSVCLPCGPDEYLDTWNEEDkCLLHKVCDAGKALVAvdPGNSTAPRRCACTAGYHwsedC-- 92

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1958778193  96 pKCTRCEKDCRPG-------QELTEQGCKNCGLGTFNDQDGA-GVCRPWTNCSLDGRSVLKNGTKEKDVVC 158
Cdd:cd13411    93 -DCCRRNTECAPGfgaqhpvQLNKDTVCEPCLVGYFSDVFSStDKCKPWTNCTILGLEEAVPGTNKSDVVC 162

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 1958778193  28 CDSCEAGTFCSKY-----PPVCTSCPPSTY-SSTGGQPNCDICRVCQGYF--RFKKPCSSTHNAECECVEGFHCLGPKCT 99
Cdd:cd13405    13 CPMCPPGSRVSRHctedtSTSCVPCPDGTYmDEPNGLEKCFPCTNCDPGFglRVKQGCTYTSDTVCEPLEGFYCIDSTKD 92

                          90
                  ....*....|....*
gi 1958778193 100 RCE-----KDCRPGQ 109
Cdd:cd13405    93 GCSaaqrhSSCKPGQ 107

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 1958778193   47 CPPSTYSSTGGQPNCDICRVCQGYFRFKKPCSSTHNAEC 85
Cdd:smart00208   1 CKEGTYCSDGNHSSCLRCRRCPPGLVVKQPCTATSDTVC 39

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 1958778193  28 CDSCEAG----TFCSKYP-PVCTSCPPSTYSSTGGQ-PNCDICRV-CQGYFRFKKPCSSTHNAECECVEGFHCLGPKCTR 100
Cdd:cd10577    16 CSKCPPGqhvkHSCTKTSdTVCAPCEESTYTQLWNWvPECLSCSSpCSSDQVETQACTRQQNRICSCKPGWYCVLKLQEG 95

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1958778193 101 CE-----KDCRPGQELTEQG-------CKNCGLGTFNDQDGA-GVCRPWTNCSldgrSVLKNGTKEKDVVC 158
Cdd:cd10577    96 CRqcrplKKCGPGFGVARPGtassdveCKPCAPGTFSDTTSStDTCRPHRICS----SVAIPGNASMDAVC 162

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958778193  28 CDSCEAGTFCSKYPPVCTSCPP-STYSS-TGGQPNCDICRVCQGYFRFKKPCSSTHNAECECVEGFHCL--GPK-CTRCE 102
Cdd:cd10580     2 CGLCPAGTYVSEDSGDCIPCKEgVDYTEhPNGLPSCLPCTVCKSDEEELSPCTTTRNTECQCKPGTFCDpdSPEvCQKCS 81

                  ....*...
gi 1958778193 103 KDCRPGQE 110
Cdd:cd10580    82 TRCPEGMV 89