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FLASH GENE
Symbol TNFSF11 contributors: mct/shn - updated : 19-09-2019
HGNC name tumor necrosis factor (ligand) superfamily, member 11
HGNC id 11926
Corresponding disease
OPTB2 osteopetrosis type B2
Location 13q14.11      Physical location : 43.136.871 - 43.182.149
Synonym name
  • TNFRSF11A (RANK) ligand and OPG (osteprogerin) ligand
  • receptor activator of NF-kappaB ligand
  • receptor activator of nuclear factor-KB ligand
  • osteoclast differentiation factor
  • osteoprotegerin ligand
  • TNF-related activation-induced cytokine2
  • CD254 antigen
  • Tumor necrosis factor (TNF)-related activation-induced cytokine
    • Synonym symbol(s) RANKL, ODF, TRANCE, OPGL, CD254, RANKL2, TRANCE, RP11-86N24.2, OPTB2, hRANKL2, sOdf
    DNA
    TYPE functioning gene
    STRUCTURE 45.28 kb     7 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure a putative E2F1 binding site within this 72 bp region in the promoter
    MAPPING cloned Y linked N status provisional
    Map cen - D13S263 - D13S1247 - TNFSF11 - D13S1297 - D13S1270 - qter
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 splicing 2216 35.3 317 - 1997 9367155
  • type II transmembrane protein
  • 5 exons (first exon being different from the variant 2)
  • including a distinct 5' end region, which introduces an upstream in-frame translation start codon compared to variant 2
    • 7 splicing 2377 27.6 244 - 2000 10708588
  • including an unique 5' end region lacking the translation start codon used by variant1
  • translation begining at a downstream in frame start codon
  • secreted
  • 5 exons (first exon being different from the variant 1)
    		•
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver    
     stomach   lowly
    Endocrinepancreas    
     thyroid   lowly
    Lymphoid/Immunelymph node   predominantly
    Skeleton      Homo sapiens
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / Hematopoieticbone marrow   
    Connectivebone   
    Epithelialsecretoryglandularendocrine 
    cells
    SystemCellPubmedSpeciesStageRna symbol
     chondrocyte
    Blood/Hematopoieticleukocyte
    Blood/Hematopoieticmonocyte Homo sapiens
    Lymphoid/Immunelymphocyte
    Skeletonosteoblast Homo sapiens
    cell lineage
    cell lines expressed within normal, pre-malignant and neoplastic mammary epithelium
    fluid/secretion
    at STAGE
    physiological period pregnancy
    Text placenta lowly
    PROTEIN
    PHYSICAL PROPERTIES globular
    STRUCTURE
    motifs/domains
  • an extracellular C terminus
    • conjugated GlycoP
    isoforms Precursor cleaved into a soluble form by ectodomain shedding
    HOMOLOGY
    interspecies ortholog to Tnfsf11, Mus musculus
    ortholog to TNFSF11, Pan troglodytes
    ortholog to Tnfsf11, Rattus norvegicus
    Homologene
    FAMILY
  • tumor necrosis factor cytokine family
    • CATEGORY regulatory , signaling cytokine
    SUBCELLULAR LOCALIZATION     plasma membrane
    text type II transmembrane protein
    basic FUNCTION
  • mediating osteoclastogenesis and bone loss through systemic activation of T cells
  • activating the antiapoptotic serine threonine kinase AKT/PKB through a signal complex involving TRAF6 and SRC
  • regulating lymph node organogenesis lymphocyte development and interactions between T cells and dendritic cells
  • key osteoclast differentiation/activation factor through induction of FOSL1
  • a dentritic cell survival factor, maintaining bone homeostasis through C-FOS-dependent induction of IFNB
  • regulating the differentiation of bone-resorbing cells, osteoclasts, in the presence of macrophage-colony stimulating factor(CSF1), but other costimulatory signals ITAM-dependent cooperate for bone homeostasis
  • playing an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells
  • inducing the expression of NFATC1, but not of NFKB subunits during osteoclast formation
  • key regulator of bone remodeling, mammary gland formation, lymph node development and T-cell/dendritic cell communication (cooperating with TNFRSF11A)
  • playing a role during heart valve development
  • stimulating osteoclasts and their precursors to release VEGF-C through an NF-kappaB-dependent mechanism
  • an important role in cell migration and the tissue-specific metastatic behaviour of cancer cells
  • controls regulatory T-cell numbers via activation of dendritic cells
  • a key role in female thermoregulation and the central fever response in inflammation
  • controls the incidence and onset of progestin-driven breast cancer
  • a potential role for TNFSF11 inhibition in the management of proliferative breast disease
  • up-regulated CKB mRNA expression and protein production during osteoclastogenesis
  • play a key role in osteoclastogenesis and tumor metastasis
  • induces histone acetyltransferases-mediated NFATC1 acetylation and stability, and subsequently increases the transcriptional activity of NFATC1 during osteoclast differentiation
  • key factor linking bone formation to resorption during bone remodeling
  • expression of TNFRSF11B, TNFRSF11A and TNFSF11 genes exert a crucial role in the progression of Femoral head avascular necrosis (AVN), suggesting their roles in mediating bone homeostasis and potential effects on bone destruction
    • CELLULAR PROCESS cell life, proliferation/growth
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS development , immunity/defense , ossification
    text
  • a key factor for osteoclast differentiation and activation
  • skeletal development and maintenance
  • positive control of cell proliferation
    • PATHWAY
    metabolism
    signaling signal transduction
    TNFSF11/TNFRSF11A signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover
    a component
  • involvement of the TNFRSF11A/TNFSF11/TNFRSF11B axis in osteosarcoma biology
  • crucial role for the TNFSF11/NFATC1 signaling pathway in promoting invasion of epicardium-derived cells into the myocardium by induction of extracellular matrix-degrading enzyme gene expression
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • c-Src and TRAF6
  • cooperating with RANK (TNFRSF11A) prostaglandin receptor activator of NF kappa B
  • ZNF347 in osteoclastogenesis
  • ligand of osteoprotegerin
  • delta- CAPRI-Ras-MMP14 axis plays an important role in the TNFSF11 shedding
  • intreacting with CTSK and NFATC1 (valve leaflet morphogenesis involves NFATC1-dependent expression of remodeling enzymes including CTSK)
  • TNFSF11 induces the formation of receptors for calcitonin (CALCRL) and CALCA in the bone marrow macrophages (BMM)3)
  • expression of retro-viral receptor, XPR1, is regulated by TNFSF11-TNFRSF11A signaling
  • RAB27A and RAB27B are involved in the stimulation-dependent TNFSF11 release pathway in osteoblastic cells
  • TNFSF11 and TNFRSF11A interaction acts through MEK/ERK, which in turn activates NFKB, resulting in the activation of ICAM1 and contributing to the migration of human lung cancer cells
  • IL4 inhibits osteoclast formation by inhibiting TNFSF11 induction of NFATC1 via STAT6 as an early event, in addition to its suppression of other signaling pathways
  • important role of adenosine, through ADORA1 in TNFSF11-induced osteoclastogenesis
  • LAT acts as a positive regulator of TNFSF11-induced osteoclastogenesis
  • accessory subunit of vacuolar-type H(+)-ATPases (V-ATPases), highly induced by receptor activator for nuclear factor kappa B ligand (TNFSF11) in osteoclast differentiation
  • SIGLEC15 links TNFSF11-TNFSFR11-NFATC1 signaling with ITAM-mediated intracellular signaling cascades during functional osteoclast development
  • EGR2 is an important modulator of TNFSF11-induced osteoclast differentiation, providing the link between TNFSF11, EGR2 and ID proteins in osteoclast-lineage cells
  • CXCR6 was down-regulated during TNFSF11-mediated osteoclastogenesis through JAK2/STAT3 pathway
  • TNFSF11 disrupts CXCL16-mediated kinase signal activation
  • MAP3K7 is indispensable to TNFSF11-induced osteoclastogenesis
  • upon TNFSF11 activation, HDAC7 suppresses NFATC1 and prevents CTNNB1 down-regulation, thereby blocking osteoclast differentiation
  • SIGLEC15 plays an important role in physiologic bone remodeling by modulating TNFSF11 signaling, especially in the secondary spongiosa
  • TNFSF11, TNFRSF11A signalling pathway can be inhibited by cleavage of TNFRSF11A instead of targeting TNFSF11
  • TNFSF11 is a direct PGR target gene and STAT5A has a novel role as a cofactor in PGR-mediated transcriptional signaling in the mammary gland
  • interaction of TNFRSF11A, a member of the tumour necrosis factor receptor superfamily, with TNFSF11 is crucial for the formation, function and survival of osteoclasts
  • CTGF significantly bound to TNFRSF11B, which is a decoy receptor of TNFSF11
  • TNFSF11-expression by osteoblasts in an acidic environment was mediated by cAMP/PRKACA signaling resulting from GPR4 activation 0)
  • interaction between TNFSF11 and its receptor TNFRSF11A is essential for the differentiation and bone resorbing capacity of the osteoclast
  • ARL6IP5 was an anti-catabolic factor by binding with TNFSF11 and disturbing its subcellular trafficking in osteoblast
  • NRROS is a novel negative regulator of TNFSF11-induced osteoclastogenesis
  • PTH can stimulate a novel negative feedback of its anabolic actions by stimulating TNFSF1l and PTGS2 expression
  • MPO and EPX, may play a fundamental role in inhibiting TNFSF11-induced osteoclast differentiation at inflammatory sites of bone fracture and injury
  • TRAF6 promotes TNFSF11-induced osteoclastogenesis by regulating novel non-canonical NFKB signaling via BCL3 deubiquitination
  • ESRRG functions as a negative regulator in receptor activator of TNFSF11-induced osteoclast differentiation
    • cell & other
    REGULATION
    induced by T cell activation
    E2F1
    in vivo administration of medroxyprogesterone acetate triggers massive induction of the key osteoclast differentiation factor RANKL in mammary-gland epithelial cells
    TNFSF11 (induces NFATC1 expression during osteoclastogenesis at a transcriptional level)
    inhibited by TCR stimulation
    calcineurin-regulated transcription factors
    IL1B and TNFRSF11B
    IFNG through rapid degradation of TRAF6
    multiple hormones and cytokines including vitamin D3,IL1,IL11,PGE2,CALCA,TNF
    Other solubilized by MMP-7
    ASSOCIATED DISORDERS
    corresponding disease(s) OPTB2
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    associated with bone mineral density at different skeletal sites in adult men, but not in women
    constitutional     --over  
    in keratinocytes of the inflamed skin (resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4(+)CD25(+) T cells)
    constitutional     --over  
    significantly elevated in non-cirrhotic, chronic liver disease, which could modulate bone loss
    constitutional     --over  
    in rheumatoid arthritis subchondral bone tissue biopsies
    Susceptibility
  • to modification of Camurati-engelmann disease (CED)
  • to Crohn disease
    • Variant & Polymorphism other
  • TNFSF11 variant associated with unique phenotype of CED
  • increasing the risk of Crohn disease
    • Candidate gene
    Marker
  • expression of TNFRSF11A, TNFSF11 and TNFRSF11B may be used as diagnostic markers to identify patients at high risk for aggressive Prostate carcinoma 6)
    • Therapy target
    SystemTypeDisorderPubmed
    allergy  
    . local induction of TNFSF11/TNFRSF11A in the skin could be used as a therapeutic approach for allergies as well for systemic autoimmunity through increasing regulatory T cells
    immunologyautoimmune 
    . local induction of TNFSF11/TNFRSF11A in the skin could be used as a therapeutic approach for allergies as well for systemic autoimmunity through increasing regulatory T cells
    osteoarticularboneothers
    . early TNFSF11 administration, as soluble RANKL treatment in mice, increases osteoclast number and stimulates bone resorption
    cancermetastases 
    . central role of TNFRSF11A/TNFSF11 pathway as potential therapeutic target not only in bone metastasis management, but also in the adjuvant setting
    cancerreproductiveprostate
    effective suppression of Prostate carcinoma cell migration by TNFRSF11B via the blockage of TNFSF11 activity represents a potential therapeutic strategy for interfering with prostate tumor metastasis and progression to bone
    ANIMAL & CELL MODELS
  • TRANCE-deficient mice showed severe osteopetrosis, with no osteoclasts, marrow spaces, or tooth eruption, and exhibited profound growth retardation at several skeletal sites, including the limbs, skull, and vertebrae
  • mice lacking RANK fail to form lobulo-alveolar mammary structures during pregnancy, resulting in death of newborns
  • RANKL overexpression in keratinocytes resulted in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4(+)CD25(+) T cells
  • Transgenic overexpression of TRANCE in lymphocytes of TRANCE-deficient mice rescued osteoclast development
  • deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of medroxyprogesterone acetate-driven mammary cancer
  • severe osteopetrotic phenotype observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling