TNF-alpha-receptor-like protein; Provisional

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1034582395  22 PAPKSCPERHYwAQGKLCCQMCEPGTFLVKDCDQhRKAAQCDPCIPGVSFSPDHHTrPHCESC 84
Cdd:PHA02637   27 PSDGKCKDNEY-KRHNLCCLSCPPGTYASRLCDI-KTNTQCTPCGSGTFTSHNNHL-PACLSC 86

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 1034582395  39 CCQMCEPGTFLVKDCDQHRKaAQCDPCIPGvSFSPDHHTRPHCESCRHCNSGLLV--RNCTITANAECACRNGWQC-RDK 115
Cdd:cd00185     1 CCQRCPPGEYLSSDCTATTD-TVCSPCPPG-TYSESWNSLSKCLPCTTCGGGNQVekTPCTATDNRCCTCKPGFYCdEGT 78

                  ....*..
gi 1034582395 116 ECTECDP 122
Cdd:cd00185    79 NVEECKP 85

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 1034582395  31 HYWAQGKLCCQMCEPGTFLVKDCDQHRKAAqCDPCIPGvSFSPDHHTRPHCESCRHCN--SGLL-VRNCTITANAECACR 107
Cdd:cd15835    12 YYNDGSNLCCSKCRPGTRLKTKCSETSDTV-CEPCPSG-QYSENWNYYPNCFSCPKCKerKGLQyAQNCSSTTNAVCVCK 89

                          90
                  ....*....|....*..
gi 1034582395 108 NGWQC----RDKECTEC 120
Cdd:cd15835    90 PGMYCimgfDHPSCSEC 106

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 1034582395  27 CPERHYWAQGKlCCQMCEPGTFLVKDCDQHRKAaQCDPCIPGvSFSpDHHTRP-HCESCRHC--NSGLLV-RNCTITANA 102
Cdd:cd13407     1 CREKQYLHNGR-CCSLCPPGQKLVSDCTEATDT-ECLPCEEG-EFQ-DTWNRErHCHQHRYCdpNLGLRVqTEGTAETDT 76

                          90       100
                  ....*....|....*....|
gi 1034582395 103 ECACRNGWQCRDKECTECDP 122
Cdd:cd13407    77 TCTCQEGQHCTSEACETCAL 96

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 1034582395  25 KSCPERHYWAQGKlCCQMCEPGTFLVKDCDQHRkaAQCDPCIPGVSFSPD-HHTRPhCESCRHCNSGLLVRN-CTITANA 102
Cdd:cd13416     1 EACPSGQYTSSGE-CCEQCPPGEGVARPCGDNQ--TVCEPCLDGVTFSDVvSHTEP-CQPCTRCPGLMSMRApCTATHDT 76

                          90       100
                  ....*....|....*....|....*..
gi 1034582395 103 ECACRNGW-------QCrdKECTECDP 122
Cdd:cd13416    77 VCECAYGYyldedsgTC--EPCTVCPP 101

Tumor necrosis factor receptor superfamily member 26 (TNFRSF26), also known as tumor necrosis factor receptor homolog 3 (TNFRH3); TNFRSF26 (also known as tumor necrosis factor receptor homolog 3 (TNFRH3) or TNFRSF24) is predominantly expressed in embryos and lymphoid cell types, along with its closely related TNFRSF22 and TNFRSF23 orthologs, and is developmentally regulated. Unlike TNFRSF22/23, TNFRSF26 does not serve as a TRAIL decoy receptor; it remains an orphan receptor.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  27 CPERHYWAQGkLCCQMCEPGTFLVKDCDQHRKAAQCDPCIPGvSFSPDHHTRPHCESCRHCNSGL-LVRNCTITANAECA 105
Cdd:cd15837     1 CGPGEYKSAN-LCCQLCPAGHYVSEPCQENHGVGECAPCEPG-TFTAHPNGETSCFPCSQCRDDQeVVAECSATSDRQCQ 78

                          90
                  ....*....|....
gi 1034582395 106 CRNGWQCRDKECTE 119
Cdd:cd15837    79 CKQGHFYCDENCLE 92

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 1034582395  39 CCQMCEPGTFLVKDcdqhrkAAQCDPCIPGVSFSPDHHTRPHCESCRHCNSG-LLVRNCTITANAECACRNGWQCRDKEC 117
Cdd:cd10580     1 SCGLCPAGTYVSED------SGDCIPCKEGVDYTEHPNGLPSCLPCTVCKSDeEELSPCTTTRNTECQCKPGTFCDPDSP 74

                  ...
gi 1034582395 118 TEC 120
Cdd:cd10580    75 EVC 77

Tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in teleosts; also known as TNFR1; This subfamily of TNFRSF1 ((also known as type I TNFR, TNFR1, DR1, TNFRSF1A, CD120a, p55) is found in teleosts. It 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. Serum levels of TNFRSF1A are elevated in schizophrenia and bipolar disorder, and high levels are also associated with cognitive impairment and dementia. 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-kappaB in endothelial cells. Thus, this apoptotic pathway seems to be evolutionarily conserved, as TNFalpha promotes apoptosis of human endothelial cells and triggers caspase-2 and P53 activation in these cells via TNFRSF1A.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  27 CPERHYWAQGKLCCQMCEPGTFLVKDCDQHRKAAQCDPCIPGvSFSPDHHTRPHCESCRHCNSGL--LVRNCTITANAEC 104
Cdd:cd15834     1 CLDSEYLSENGICCNKCHPGYKLKEECTAPGERSQCTPCPEG-TYLEQINYSPNCRRCTLCKVKNeeEVSPCKKSSNTVC 79

                          90       100
                  ....*....|....*....|....*...
gi 1034582395 105 ACRNG----------WQCRdkECTECDP 122
Cdd:cd15834    80 RCKKGyyksridsetRECL--KCKTCGP 105

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  26 SCPERHYWAQGKlCCQMCEPGTFLVKDCDQhRKAAQCDPCIPGvSFSPDHHTRPHCESCRHCNSG---LLVRNCTITANA 102
Cdd:cd15836     3 TCNQTQYLKDGK-CCRKCEPGSFVFAHCSG-SSDTICRDCGRN-EYQPDWTSEMKCIPQKFCDEGkgfNRTRPHNPTALE 79

                          90       100
                  ....*....|....*....|..
gi 1034582395 103 ECACRNGWQCRDKECTECDPLP 124
Cdd:cd15836    80 PCQCKPGFQCSPLNCEFCEKIP 101

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  36 GKLCCQMCEPGTFLVKDCDQHRKAAqCDPCIPGVSFS-PDHHTRphCESCRHC--NSGLLV-RNCTITANAECACRNGWQ 111
Cdd:cd13405     9 NGECCPMCPPGSRVSRHCTEDTSTS-CVPCPDGTYMDePNGLEK--CFPCTNCdpGFGLRVkQGCTYTSDTVCEPLEGFY 85

                  ....*....
gi 1034582395 112 CRDKECTEC 120
Cdd:cd13405    86 CIDSTKDGC 94

Tumor necrosis factor receptor superfamily member 14 (TNFRSF14), also known as herpes virus entry mediator (HVEM); TNFRSF14 (also known as herpes virus entry mediator or HVEM, ATAR, CD270, HVEA, LIGHTR, TR2) 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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  36 GKLCCQMCEPGTFLVKDCDQHRKAAqCDPCIPGVSFSpDHHTRPHCESCRHCNSGLL---VRNCTITANAECACRNGWQC 112
Cdd:cd10582     9 GSECCPKCSPGYRVKKACGELTGTV-CEPCPPGTYTA-HLNGLSKCLQCRVCDPAMGlvtRRNCSSTENTVCGCIPGHFC 86

                          90
                  ....*....|....
gi 1034582395 113 RDK---ECTECDPL 123
Cdd:cd10582    87 SAQdgdHCVECVPH 100

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 1034582395  28 PERHYWAQGKlCCQMCEPGTFLVKD--CDQhrkaAQCDPCIPGvSFSPDHHTRPHCESCRHCNSGL---LVRNCTITANA 102
Cdd:cd13422     3 PETQYEKDGE-CCKMCGPGTRMSSDsgCLD----PQCQPCGED-EYQDKYTKENKCKRQPYCDPNKnfeISVNKSKTSRS 76

                          90       100
                  ....*....|....*....|
gi 1034582395 103 ECACRNGWQCRDKECTECDP 122
Cdd:cd13422    77 VCKCKPGFHCSSEECLTCVP 96

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  38 LCCQMCEPGTFLVKDCDQHRKaAQCDPCiPGVSFSPDHHTRPHCESCRH-CNSGLLVRN-CTITANAECACRNGWQCRDK 115
Cdd:cd10581    34 LMCDQCPPGTYVKQHCSASRK-TVCAPC-PDHHYADDWNSNDECQYCNTvCKELQYVKQeCNSTHNRVCECVEGRYLELE 111

                          90
                  ....*....|
gi 1034582395 116 EC---TECDP 122
Cdd:cd10581   112 FClkhTECPP 121

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.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1034582395  27 CPERHY-WAQGKLC--CQMCEPGTFLVKDCdQHRKAAQCDPCIPGvSFSPDHHTRPHCESCRHC-NSGLLVRNCTITANA 102
Cdd:cd13416    80 CAYGYYlDEDSGTCepCTVCPPGQGVVQSC-GPNQDTVCEACPEG-TYSDEDSSTDPCLPCTVCeDGEVELRECTPVSDT 157

                  ..
gi 1034582395 103 EC 104
Cdd:cd13416   158 VC 159