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FLASH GENE

Symbol

TNFRSF11A

contributors: mct - updated : 22-05-2018

HGNC name	tumor necrosis factor receptor superfamily, member 11a, NFKB activator
HGNC id	11908

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	DOSCO2 dysosteosclerosis 2 HEPOD polyostotic osteolytic dysplasia, hereditary expansile OPTIGD osteopetrosis with immunoglobulin defect PDB2 Paget bone disease 2
Location	18q21.33      Physical location : 59.992.547 - 60.053.502
Synonym name	tumor necrosis factor receptor superfamily, member 11a, activator of NFKB
	CD265 antigen
	osteoclast differentiation factor receptor
	loss of heterozygosity, 18, chromosomal region 1
	receptor activator of NF-KB
Synonym symbol(s)	RANK, EVI36, ODGR, TRANCER, CD265, FEO, LOH18CR1, ODFR, OFE, OPTB7, OSTS

DNA

TYPE	functioning gene
STRUCTURE	62.81 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003839 10 - 3133 NP_003830 63.6 616 - 2008 18606301 NM_001270949 9 - 3809 NP_001257878 - 263 - 2008 18606301 isoform delta9 NM_001270951 7 - 3642 NP_001257880 - 299 - 2008 18606301 isoform delta7,8,9 NM_001270950 8 - 3756 NP_001257879 - 337 - 2008 18606301 isoform delta8,9 NM_001278268 10 splicing 4551 NP_001265197 - 602 normal brain 2013 23664977 TNFRSF11A_e5a lacks 42 nucleotides from exon 5, giving rise to a novel shorter form of exon 5, named exon 5a truncation of thirteen amino acids of the third and fourth TNFR motifs of the extracellular part of the receptor

EXPRESSION

Type	ubiquitous

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 Cardiovascular heart         Digestive intestine large intestine colon       intestine small intestine       Endocrine adrenal gland         Lymphoid/Immune lymph node         Respiratory respiratory tract larynx

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Epithelial secretory glandular endocrine   Muscular striatum skeletal

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune dendritic cell Skeleton osteoclast Homo sapiens

cell lineage	osteoclast precursors
cell lines
fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two extracellular cysteine-rich pseudo repeats typical for TNFR superfamily
	a preligand assembly domain (PLAD) in CRD1 mediating ligand-independent receptor assembly and signaling
	a cytoplasmic tail lacking the DEATH domain
	a TRAF-independent motif (IVVY(535-538), which is dispensable for the activation of TRAF-induced signaling pathways but essential for osteoclast lineage commitment

mono polymer

homomer , trimer

HOMOLOGY

interspecies

homolog to murine Tnfrsf11a

Homologene

FAMILY

tumor necrosis factor receptor superfamily

CATEGORY

receptor

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,cytosolic

basic FUNCTION	intrinsic hematopoietic cell surface receptor
	receptor activator of NFKB, involved in RANKL/RANK signaling
	stimulator of JUN kinase
	adaptor of TRAFs TNFR-associated factors,mediating osteoprotegerin ligand (TNFSF11) ligand effects for osteoclastogenesis and regulating bone mass and calcium metabolism
	TNFRSF11A signaling pathway plays an important role in bone remodeling
	role for TNFRSF11A/ERK-mediated signaling in normal osteoblasts chemotactic migration during bone remodeling that is altered or lost during osteosarcoma tumorigenesis
	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
	potential role for TNFRSF11A, the corresponding gene of which is a direct binding target of KLF5, in tumour cell proliferation and invasiveness
	may have different roles in skeletal development and metabolism

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

metal

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	forms a complex with LYN, the tyrosine phosphatase, PTPN6, and the adapter protein, Grb2-associated binder 2 (GAB2)
	involvement of the TNFRSF11A/TNFSF11/TNFRSF11B axis in osteosarcoma biology

INTERACTION

DNA

RNA

small molecule

protein	interacting with TRAF6 at different sites and leading to NF-kappa B activation,via MAP3K14
	interacting with TRAF2 and leading to JNK activation
	interacting with TRAF5
	expression of retro-viral receptor, XPR1, is regulated by TNFSF11-TNFRSF11A signaling
	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
	SIGLEC15 links TNFSF11-TNFSFR11-NFATC1 signaling with ITAM-mediated intracellular signaling cascades during functional osteoclast development
	FAM102A is a novel TNFRSF11A signaling component controlling TNFRSF11A-mediated osteoclast formation
	TNFSF11, TNFRSF11A signalling pathway can be inhibited by cleavage of TNFRSF11A instead of targeting TNFSF11
	interaction of TNFRSF11A, a member of the tumour necrosis factor receptor superfamily, with TNFSF11 is crucial for the formation, function and survival of osteoclasts
	TNFRSF11A is also known as TNFSF11 receptor, and its signaling plays a critical role in osteoclastogenesis
	interaction between TNFSF11 and its receptor TNFRSF11A is essential for the differentiation and bone resorbing capacity of the osteoclast
	OSCAR-collagen interaction stimulates TNFRSF11A-dependent osteoclastogenesis
	RELB is necessary for the effective production of downstream TNFRSF11A(+) mTEC (medullary Thymic epithelial cells) progenitors
	role for TNFRSF11A as a key regulator of Ca(2+)storage and ATP2A1 activity, ultimately affecting denervated skeletal muscle function
	TNFRSF11A recruits TRAF6 to TRAF6-binding sites (T6BSs) in the TNFRSF11A cytoplasmic tail (RANKcyto) to trigger downstream osteoclastogenic signaling cascades
	VAV3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between TRAF6-binding sites (T6BSs) and the IVVY motif in the TNFRSF11A signaling complex

cell & other

REGULATION

induced by

insulin that induces TNFRSF11A expression via ERK1/2, which contributes to the enhancement of osteoclast differentiation

ASSOCIATED DISORDERS

corresponding disease(s)

HEPOD , PDB2 , OPTIGD , DOSCO2

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

Susceptibility

to osteoporosis to Paget disease to breast cancer (BC) and bone metastasis (BM)

Variant & Polymorphism other	rs3018362 strongly associated with Paget disease
	TNFRSF11A SNP rs34945627 has a high allelic frequency in patients with breast cancer (BC) and bone metastasis (BM), and is associated with decreased disease-free survival (DFS) and overall survival (OS)

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 osteoarticular bone   generation of TNFRSF11A-antagonists is a promising strategy for the exploration of new therapeutics against osteoporosis

ANIMAL & CELL MODELS

persistence of bone erosion and synovial osteoclasts in Rank-deficient mice, but bone erosion and osteoclast formation were reduced