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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

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003701 5 splicing 2216 NP_003692 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 NM_033012 7 splicing 2377 NP_143026 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)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive liver           stomach       lowly Endocrine pancreas           thyroid       lowly Lymphoid/Immune lymph node       predominantly Skeleton           Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Connective bone       Epithelial secretory glandular endocrine

cells

System Cell Pubmed Species Stage Rna symbol   chondrocyte Blood/Hematopoietic leukocyte Blood/Hematopoietic monocyte Homo sapiens Lymphoid/Immune lymphocyte Skeleton osteoblast 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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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
	System Type Disorder Pubmed 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 immunology autoimmune   . 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 osteoarticular bone others . early TNFSF11 administration, as soluble RANKL treatment in mice, increases osteoclast number and stimulates bone resorption cancer metastases   . central role of TNFRSF11A/TNFSF11 pathway as potential therapeutic target not only in bone metastasis management, but also in the adjuvant setting cancer reproductive prostate 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