RANKL

Tumor necrosis factor (ligand) superfamily, member 11
PDB rendering based on 1s55.
Available structures PDB 1s55
Identifiers
Symbols	TNFSF11; CD254; ODF; OPGL; OPTB2; RANKL; TRANCE; hRANKL2; sOdf
External IDs	OMIM: 602642 MGI: 1100089 HomoloGene: 2744 GeneCards: TNFSF11 Gene
Gene Ontology Molecular function • receptor activity • cytokine activity • cytokine activity • tumor necrosis factor receptor binding • tumor necrosis factor receptor superfamily binding Cellular component • extracellular region • extracellular space • intracellular • cytoplasm • plasma membrane • integral to plasma membrane Biological process • ossification • monocyte chemotaxis • response to stress • immune response • multicellular organismal development • response to radiation • organ morphogenesis • positive regulation of intracellular protein kinase cascade • cytokine-mediated signaling pathway • cell differentiation • osteoclast differentiation • osteoclast differentiation • osteoclast differentiation • tumor necrosis factor-mediated signaling pathway • mammary gland epithelial cell proliferation • positive regulation of homotypic cell-cell adhesion • positive regulation of I-kappaB kinase/NF-kappaB cascade • positive regulation of osteoclast differentiation • positive regulation of bone resorption • positive regulation of T cell activation • positive regulation of sequence-specific DNA binding transcription factor activity • positive regulation of NF-kappaB transcription factor activity • protein homooligomerization • positive regulation of corticotropin-releasing hormone secretion • positive regulation of protein kinase B signaling cascade • mammary gland alveolus development • positive regulation of fever generation by positive regulation of prostaglandin secretion • TNFSF11-mediated signaling pathway • positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	8600	21943
Ensembl	ENSG00000120659	ENSMUSG00000022015
UniProt	O14788	Q059M3
RefSeq (mRNA)	NM_003701.3	NM_011613.3
RefSeq (protein)	NP_003692.1	NP_035743.2
Location (UCSC)	Chr 13: 43.14 – 43.18 Mb	Chr 14: 78.68 – 78.71 Mb
PubMed search	[1]	[2]

Receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.^[1][2]

RANKL is important in bone metabolism. This natural and necessary surface-bound molecule (also known as CD254) found on osteoblasts serves to activate osteoclasts, which are the cells involved in bone resorption.

Function

RANKL is a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. RANKL also has a function in the immune system, where it is expressed by T helper cells and is thought to be involved in dendritic cell maturation. This protein was shown to be a dendritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor 6 (TRAF6), which indicated this protein may have a role in the regulation of cell apoptosis.^[3]

Animal models

Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy.^[3]

Clinical significance

Bone

Overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and psoriatic arthritis. The first FDA-approved RANK ligand inhibitor was denosumab (to prevent osteoporosis in post menopausal women).

Breast cancer

Treatment with medroxyprogesterone acetate (MPA), a synthetic progestin that is used in birth control pills and hormone replacement therapy, is associated with an increased risk of developing breast cancer. MPA causes a substantial induction of RANKL in mammary-gland epithelial cells while deletion of RANKL decreases the incidence MPA-induced breast cancer. Hence inhibition of RANKL has potential for the prevention and treatment of breast cancer.^[4][5]

See also

• Cluster of differentiation
• RANK
• Osteoprotegerin
• Osteoimmunology

References

1. ^ Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y (October 1997). "TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells". J. Biol. Chem. 272 (40): 25190–4. doi:10.1074/jbc.272.40.25190. PMID 9312132. 
2. ^ Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (November 1997). "A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function". Nature 390 (6656): 175–9. doi:10.1038/36593. PMID 9367155. 
3. ^ ^{a b} "Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8600. 
4. ^ Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ, Widschwendter M, Schett G, Penninger JM (November 2010). "Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer". Nature 468 (7320): 98–102. doi:10.1038/nature09387. PMID 20881962. 
5. ^ Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC (November 2010). "RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis". Nature 468 (7320): 103–7. doi:10.1038/nature09495. PMID 20881963. 

Further reading

• Whyte M (2006). "The long and the short of bone therapy". N Engl J Med 354 (8): 860–3. doi:10.1056/NEJMe068003. PMID 16495400.  link
• Buckley KA, Fraser WD (2003). "Receptor activator for nuclear factor kappaB ligand and osteoprotegerin: regulators of bone physiology and immune responses/potential therapeutic agents and biochemical markers.". Ann. Clin. Biochem. 39 (Pt 6): 551–6. doi:10.1258/000456302760413324. PMID 12564836. 
• Jeffcoate W (2005). "Vascular calcification and osteolysis in diabetic neuropathy-is RANK-L the missing link?". Diabetologia 47 (9): 1488–92. doi:10.1007/s00125-004-1477-5. PMID 15322748. 
• Collin-Osdoby P (2005). "Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.". Circ. Res. 95 (11): 1046–57. doi:10.1161/01.RES.0000149165.99974.12. PMID 15564564. 
• Whyte MP, Mumm S (2005). "Heritable disorders of the RANKL/OPG/RANK signaling pathway.". Journal of musculoskeletal & neuronal interactions 4 (3): 254–67. PMID 15615493. 
• Clohisy DR, Mantyh PW (2005). "Bone cancer pain and the role of RANKL/OPG.". Journal of musculoskeletal & neuronal interactions 4 (3): 293–300. PMID 15615497. 
• Anandarajah AP, Schwarz EM (2006). "Anti-RANKL therapy for inflammatory bone disorders: Mechanisms and potential clinical applications.". J. Cell. Biochem. 97 (2): 226–32. doi:10.1002/jcb.20674. PMID 16240334. 
• Baud'huin M, Duplomb L, Ruiz Velasco C, et al. (2007). "Key roles of the OPG-RANK-RANKL system in bone oncology.". Expert Rev Anticancer Ther 7 (2): 221–32. doi:10.1586/14737140.7.2.221. PMID 17288531. 
• Yogo K, Ishida-Kitagawa N, Takeya T (2007). "Negative autoregulation of RANKL and c-Src signaling in osteoclasts.". J. Bone Miner. Metab. 25 (4): 205–10. doi:10.1007/s00774-007-0751-2. PMID 17593489. 
• Boyce BF, Xing L (2007). "Biology of RANK, RANKL, and osteoprotegerin.". Arthritis Res. Ther. 9 Suppl 1: S1. doi:10.1186/ar2165. PMC 1924516. PMID 17634140. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1924516. 
• McClung M (2007). "Role of RANKL inhibition in osteoporosis.". Arthritis Res. Ther. 9 Suppl 1: S3. doi:10.1186/ar2167. PMC 1924518. PMID 17634142. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1924518. 

External links

• RANKL Signaling Pathway
• MeSH RANKL+Protein

This article incorporates text from the United States National Library of Medicine, which is in the public domain.