ID TNF11_HUMAN Reviewed; 317 AA. AC O14788; O14723; Q96Q17; Q9P2Q3; DT 24-JAN-2001, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 11-NOV-2015, entry version 147. DE RecName: Full=Tumor necrosis factor ligand superfamily member 11; DE AltName: Full=Osteoclast differentiation factor; DE Short=ODF; DE AltName: Full=Osteoprotegerin ligand; DE Short=OPGL; DE AltName: Full=Receptor activator of nuclear factor kappa-B ligand; DE Short=RANKL; DE AltName: Full=TNF-related activation-induced cytokine; DE Short=TRANCE; DE AltName: CD_antigen=CD254; DE Contains: DE RecName: Full=Tumor necrosis factor ligand superfamily member 11, membrane form; DE Contains: DE RecName: Full=Tumor necrosis factor ligand superfamily member 11, soluble form; GN Name=TNFSF11; Synonyms=OPGL, RANKL, TRANCE; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Bone marrow, and Peripheral blood; RX PubMed=9367155; DOI=10.1038/36593; RA Anderson D.M., Maraskovsky E., Billingsley W.L., Dougall W.C., RA Tometsko M.E., Roux E.R., Teepe M.C., DuBose R.F., Cosman D., RA Galibert L.; RT "A homologue of the TNF receptor and its ligand enhance T-cell growth RT and dendritic-cell function."; RL Nature 390:175-179(1997). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RC TISSUE=Lymph node; RX PubMed=9568710; DOI=10.1016/S0092-8674(00)81569-X; RA Lacey D.L., Timms E., Tan H.-L., Kelley M.J., Dunstan C.R., RA Burgess T., Elliott R., Colombero A., Elliott G., Scully S., Hsu H., RA Sullivan J., Hawkins N., Davy E., Capparelli C., Eli A., Qian Y.-X., RA Kaufman S., Sarosi I., Shalhoub V., Senaldi G., Guo J., Delaney J., RA Boyle W.J.; RT "Osteoprotegerin ligand is a cytokine that regulates osteoclast RT differentiation and activation."; RL Cell 93:165-176(1998). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 3). RA Ikeda T., Kuroyama H., Hirokawa K.; RT "Determination of human RANKL isoforms."; RL Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC TISSUE=Tongue; RX PubMed=10708588; DOI=10.1006/bbrc.2000.2314; RA Nagai M., Kyakumoto S., Sato N.; RT "Cancer cells responsible for humoral hypercalcemia express mRNA RT encoding a secreted form of ODF/TRANCE that induces osteoclast RT formation."; RL Biochem. Biophys. Res. Commun. 269:532-536(2000). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Lung; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 73-317. RC TISSUE=Thymocyte; RX PubMed=9312132; DOI=10.1074/jbc.272.40.25190; RA Wong B.R., Rho J., Arron J., Robinson E., Orlinick J., Chao M., RA Kalachikov S., Cayani E., Bartlett F.S. III, Frankel W.N., Lee S.Y., RA Choi Y.; RT "TRANCE is a novel ligand of the tumor necrosis factor receptor family RT that activates c-Jun N-terminal kinase in T cells."; RL J. Biol. Chem. 272:25190-25194(1997). RN [7] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 162-317 IN COMPLEX WITH RP TNFRSF11B, FUNCTION, MUTAGENESIS OF ARG-223 AND LYS-257, AND RP INTERACTION WITH TNFRSF11B. RX PubMed=22664871; DOI=10.4049/jimmunol.1103387; RA Luan X., Lu Q., Jiang Y., Zhang S., Wang Q., Yuan H., Zhao W., RA Wang J., Wang X.; RT "Crystal structure of human RANKL complexed with its decoy receptor RT osteoprotegerin."; RL J. Immunol. 189:245-252(2012). RN [8] RP VARIANT OPTB2 LYS-199. RX PubMed=17632511; DOI=10.1038/ng2076; RA Sobacchi C., Frattini A., Guerrini M.M., Abinun M., Pangrazio A., RA Susani L., Bredius R., Mancini G., Cant A., Bishop N., Grabowski P., RA Del Fattore A., Messina C., Errigo G., Coxon F.P., Scott D.I., RA Teti A., Rogers M.J., Vezzoni P., Villa A., Helfrich M.H.; RT "Osteoclast-poor human osteopetrosis due to mutations in the gene RT encoding RANKL."; RL Nat. Genet. 39:960-962(2007). CC -!- FUNCTION: Cytokine that binds to TNFRSF11B/OPG and to CC TNFRSF11A/RANK. Osteoclast differentiation and activation factor. CC Augments the ability of dendritic cells to stimulate naive T-cell CC proliferation. May be an important regulator of interactions CC between T-cells and dendritic cells and may play a role in the CC regulation of the T-cell-dependent immune response. May also play CC an important role in enhanced bone-resorption in humoral CC hypercalcemia of malignancy. {ECO:0000269|PubMed:22664871}. CC -!- SUBUNIT: Homotrimer (Probable). Interacts with TNFRSF11B. CC {ECO:0000269|PubMed:22664871, ECO:0000305}. CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type CC II membrane protein. CC -!- SUBCELLULAR LOCATION: Isoform 3: Cell membrane; Single-pass type CC II membrane protein. CC -!- SUBCELLULAR LOCATION: Isoform 2: Cytoplasm {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Tumor necrosis factor ligand superfamily CC member 11, soluble form: Secreted {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=O14788-1; Sequence=Displayed; CC Name=2; Synonyms=SODF; CC IsoId=O14788-2; Sequence=VSP_006447; CC Name=3; CC IsoId=O14788-3; Sequence=VSP_006446; CC -!- TISSUE SPECIFICITY: Highest in the peripheral lymph nodes, weak in CC spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, CC skeletal muscle, stomach and thyroid. CC -!- INDUCTION: Up-regulated by T-cell receptor stimulation. CC -!- PTM: The soluble form of isoform 1 derives from the membrane form CC by proteolytic processing (By similarity). The cleavage may be CC catalyzed by ADAM17. {ECO:0000250}. CC -!- DISEASE: Osteopetrosis, autosomal recessive 2 (OPTB2) CC [MIM:259710]: A rare genetic disease characterized by abnormally CC dense bone, due to defective resorption of immature bone. CC Osteopetrosis occurs in two forms: a severe autosomal recessive CC form occurring in utero, infancy, or childhood, and a benign CC autosomal dominant form occurring in adolescence or adulthood. CC Recessive osteopetrosis commonly manifests in early infancy with CC macrocephaly, feeding difficulties, evolving blindness and CC deafness, bone marrow failure, severe anemia, and CC hepatosplenomegaly. Deafness and blindness are generally thought CC to represent effects of pressure on nerves. OPTB2 is characterized CC by paucity of osteoclasts, suggesting a molecular defect in CC osteoclast development. {ECO:0000269|PubMed:17632511}. Note=The CC disease is caused by mutations affecting the gene represented in CC this entry. CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. CC {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF019047; AAB86811.1; -; mRNA. DR EMBL; AF053712; AAC39731.1; -; mRNA. DR EMBL; AB064269; BAB79694.1; -; mRNA. DR EMBL; AB061227; BAB71768.1; -; mRNA. DR EMBL; AB064270; BAB79695.1; -; mRNA. DR EMBL; AB037599; BAA90488.1; -; mRNA. DR EMBL; BC074823; AAH74823.1; -; mRNA. DR EMBL; BC074890; AAH74890.1; -; mRNA. DR EMBL; AF013171; AAC51762.1; -; mRNA. DR CCDS; CCDS9384.1; -. [O14788-1] DR CCDS; CCDS9385.1; -. [O14788-2] DR RefSeq; NP_003692.1; NM_003701.3. [O14788-1] DR RefSeq; NP_143026.1; NM_033012.3. [O14788-2] DR RefSeq; XP_011533582.1; XM_011535280.1. [O14788-2] DR UniGene; Hs.333791; -. DR PDB; 3URF; X-ray; 2.70 A; A=162-317. DR PDBsum; 3URF; -. DR ProteinModelPortal; O14788; -. DR SMR; O14788; 162-317. DR BioGrid; 114160; 26. DR IntAct; O14788; 16. DR MINT; MINT-8247611; -. DR STRING; 9606.ENSP00000239849; -. DR ChEMBL; CHEMBL2364162; -. DR DrugBank; DB06643; Denosumab. DR DrugBank; DB00480; Lenalidomide. DR PhosphoSite; O14788; -. DR BioMuta; TNFSF11; -. DR PaxDb; O14788; -. DR PRIDE; O14788; -. DR Ensembl; ENST00000239849; ENSP00000239849; ENSG00000120659. [O14788-3] DR Ensembl; ENST00000358545; ENSP00000351347; ENSG00000120659. [O14788-2] DR Ensembl; ENST00000398795; ENSP00000381775; ENSG00000120659. [O14788-1] DR Ensembl; ENST00000405262; ENSP00000384042; ENSG00000120659. [O14788-2] DR Ensembl; ENST00000544862; ENSP00000444913; ENSG00000120659. [O14788-2] DR GeneID; 8600; -. DR KEGG; hsa:8600; -. DR UCSC; uc001uyt.2; human. [O14788-1] DR CTD; 8600; -. DR GeneCards; TNFSF11; -. DR HGNC; HGNC:11926; TNFSF11. DR HPA; CAB009193; -. DR HPA; HPA045142; -. DR MIM; 259710; phenotype. DR MIM; 602642; gene. DR neXtProt; NX_O14788; -. DR Orphanet; 667; Autosomal recessive malignant osteopetrosis. DR PharmGKB; PA36619; -. DR eggNOG; ENOG410IEIS; Eukaryota. DR eggNOG; ENOG410YGCE; LUCA. DR GeneTree; ENSGT00530000063443; -. DR HOGENOM; HOG000132981; -. DR HOVERGEN; HBG054257; -. DR InParanoid; O14788; -. DR KO; K05473; -. DR OMA; DIPSGSH; -. DR OrthoDB; EOG7V4B0Q; -. DR PhylomeDB; O14788; -. DR TreeFam; TF332169; -. DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway. DR Reactome; R-HSA-5669034; TNFs bind their physiological receptors. DR Reactome; R-HSA-5676594; TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway. DR GeneWiki; RANKL; -. DR GenomeRNAi; 8600; -. DR NextBio; 32221; -. DR PMAP-CutDB; O14788; -. DR PRO; PR:O14788; -. DR Proteomes; UP000005640; Chromosome 13. DR Bgee; O14788; -. DR CleanEx; HS_TNFSF11; -. DR ExpressionAtlas; O14788; baseline and differential. DR Genevisible; O14788; HS. DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell. DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB. DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW. DR GO; GO:0005887; C:integral component of plasma membrane; NAS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0005125; F:cytokine activity; NAS:UniProtKB. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; NAS:UniProtKB. DR GO; GO:0032813; F:tumor necrosis factor receptor superfamily binding; IC:BHF-UCL. DR GO; GO:0007257; P:activation of JUN kinase activity; IEA:Ensembl. DR GO; GO:0045453; P:bone resorption; IEA:Ensembl. DR GO; GO:0055074; P:calcium ion homeostasis; IEA:Ensembl. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl. DR GO; GO:0006955; P:immune response; NAS:UniProtKB. DR GO; GO:0060749; P:mammary gland alveolus development; IEA:Ensembl. DR GO; GO:0033598; P:mammary gland epithelial cell proliferation; IEA:Ensembl. DR GO; GO:0002548; P:monocyte chemotaxis; IDA:BHF-UCL. DR GO; GO:0009887; P:organ morphogenesis; IEA:Ensembl. DR GO; GO:0001503; P:ossification; IEA:Ensembl. DR GO; GO:0030316; P:osteoclast differentiation; NAS:UniProtKB. DR GO; GO:0002158; P:osteoclast proliferation; IEA:Ensembl. DR GO; GO:0038001; P:paracrine signaling; IEA:Ensembl. DR GO; GO:0045780; P:positive regulation of bone resorption; IDA:UniProtKB. DR GO; GO:0051466; P:positive regulation of corticotropin-releasing hormone secretion; ISS:BHF-UCL. DR GO; GO:0071848; P:positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling; IDA:BHF-UCL. DR GO; GO:0071812; P:positive regulation of fever generation by positive regulation of prostaglandin secretion; ISS:BHF-UCL. DR GO; GO:0034112; P:positive regulation of homotypic cell-cell adhesion; IDA:BHF-UCL. DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl. DR GO; GO:1902533; P:positive regulation of intracellular signal transduction; IDA:BHF-UCL. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:BHF-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:BHF-UCL. DR GO; GO:2001206; P:positive regulation of osteoclast development; IEA:Ensembl. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IDA:UniProtKB. DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IEA:Ensembl. DR GO; GO:0051091; P:positive regulation of sequence-specific DNA binding transcription factor activity; ISS:BHF-UCL. DR GO; GO:0050870; P:positive regulation of T cell activation; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL. DR GO; GO:0051260; P:protein homooligomerization; IEA:Ensembl. DR GO; GO:0071847; P:TNFSF11-mediated signaling pathway; IDA:BHF-UCL. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; ISS:BHF-UCL. DR Gene3D; 2.60.120.40; -; 1. DR InterPro; IPR006052; TNF_dom. DR InterPro; IPR017355; TNF_ligand_10/11. DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom. DR Pfam; PF00229; TNF; 1. DR PIRSF; PIRSF038013; TNF10_TNF11; 1. DR SMART; SM00207; TNF; 1. DR SUPFAM; SSF49842; SSF49842; 1. DR PROSITE; PS50049; TNF_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; Complete proteome; KW Cytokine; Cytoplasm; Developmental protein; Differentiation; KW Disease mutation; Glycoprotein; Membrane; Osteopetrosis; Receptor; KW Reference proteome; Secreted; Signal-anchor; Transmembrane; KW Transmembrane helix. FT CHAIN 1 317 Tumor necrosis factor ligand superfamily FT member 11, membrane form. FT /FTId=PRO_0000034514. FT CHAIN 140 317 Tumor necrosis factor ligand superfamily FT member 11, soluble form. {ECO:0000250}. FT /FTId=PRO_0000034515. FT TOPO_DOM 1 47 Cytoplasmic. {ECO:0000255}. FT TRANSMEM 48 68 Helical; Signal-anchor for type II FT membrane protein. {ECO:0000255}. FT TOPO_DOM 69 317 Extracellular. {ECO:0000255}. FT SITE 139 140 Cleavage. {ECO:0000250}. FT CARBOHYD 171 171 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 198 198 N-linked (GlcNAc...). {ECO:0000255}. FT VAR_SEQ 1 73 Missing (in isoform 2). FT {ECO:0000303|PubMed:10708588, FT ECO:0000303|Ref.3}. FT /FTId=VSP_006447. FT VAR_SEQ 1 47 Missing (in isoform 3). FT {ECO:0000303|Ref.3}. FT /FTId=VSP_006446. FT VARIANT 199 199 M -> K (in OPTB2). FT {ECO:0000269|PubMed:17632511}. FT /FTId=VAR_037424. FT MUTAGEN 223 223 R->A: Reduces affinity for TNFRSF11B. FT {ECO:0000269|PubMed:22664871}. FT MUTAGEN 257 257 K->A: Reduces affinity for TNFRSF11B. FT {ECO:0000269|PubMed:22664871}. FT CONFLICT 194 194 A -> G (in Ref. 6; AAC51762). FT {ECO:0000305}. FT STRAND 165 170 {ECO:0000244|PDB:3URF}. FT STRAND 182 184 {ECO:0000244|PDB:3URF}. FT STRAND 187 191 {ECO:0000244|PDB:3URF}. FT STRAND 194 202 {ECO:0000244|PDB:3URF}. FT STRAND 205 208 {ECO:0000244|PDB:3URF}. FT STRAND 212 225 {ECO:0000244|PDB:3URF}. FT STRAND 227 229 {ECO:0000244|PDB:3URF}. FT STRAND 235 248 {ECO:0000244|PDB:3URF}. FT STRAND 253 263 {ECO:0000244|PDB:3URF}. FT STRAND 269 283 {ECO:0000244|PDB:3URF}. FT STRAND 287 294 {ECO:0000244|PDB:3URF}. FT HELIX 296 298 {ECO:0000244|PDB:3URF}. FT TURN 303 305 {ECO:0000244|PDB:3URF}. FT STRAND 306 314 {ECO:0000244|PDB:3URF}. SQ SEQUENCE 317 AA; 35478 MW; 766176446348097F CRC64; MRRASRDYTK YLRGSEEMGG GPGAPHEGPL HAPPPPAPHQ PPAASRSMFV ALLGLGLGQV VCSVALFFYF RAQMDPNRIS EDGTHCIYRI LRLHENADFQ DTTLESQDTK LIPDSCRRIK QAFQGAVQKE LQHIVGSQHI RAEKAMVDGS WLDLAKRSKL EAQPFAHLTI NATDIPSGSH KVSLSSWYHD RGWAKISNMT FSNGKLIVNQ DGFYYLYANI CFRHHETSGD LATEYLQLMV YVTKTSIKIP SSHTLMKGGS TKYWSGNSEF HFYSINVGGF FKLRSGEEIS IEVSNPSLLD PDQDATYFGA FKVRDID //