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tumor necrosis factor ligand superfamily member 11; osteoclast differentiation factor; ODF; osteoprotegerin ligand; OPGL; receptor activator of nuclear factor kappa-B ligand; RANKL; TNF-related activation-induced cytokine; TRANCE; CD254; contains: tumor necrosis factor ligand superfamily member 11, membrane form; contains: tumor necrosis factor ligand superfamily member 11, soluble form (TNFSF11, OPGL, RANKL, TRANCE)

Function: - cytokine that regulates: a) bone remodelling & resorption b) lymph node organogenesis c) lymphocyte development d) interactions between T-cells & dendritic cells - binds to TNFRSF11B/OPG & to TNFRSF11A/RANK - osteoclast differentiation & activation factor - OPGL stimulates osteoclast activity - both forms of OPGL stimulate osteoclast activity - augments the ability of dendritic cells to stimulate naive T-cell proliferation - may regulate interactions between T-cells & dendritic cells & may play a role in regulation of the T-cell-dependent immune response - the soluble form of isoform 1 derives from the membrane form by proteolytic processing (putative) - the cleavage may be catalyzed by ADAM17 - activation of T-cells via protein kinase C, phosphoinositide 3-kinase & calcineurin-mediated signalling pathways increases OPGL expression - systemic activation of T-cells results in an OPLG-mediated increase is osteoclast activity & bone loss blocked by osteoprotegerin - TGF-beta inhibits OPGL * see figure Structure: - homotrimer (putative) - belongs to the tumor necrosis factor family Compartment: - tumor necrosis factor ligand superfamily member 11, soluble form: secreted (putative) - isoform 1: cell membrane - isoform 2: cytoplasm (putative) - isoform 3: cell membrane - OPGL is found on the surface of activated T-cells & is secreted as well Alternative splicing: named isoforms=3 Expression: - highest expression in the peripheral lymph nodes - weak expression in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach & thyroid - up-regulated by T-cell receptor stimulation - the OPGL receptor, RANK, is expressed on: a) chondrocytes b) osteoclast precursors & mature osteoclasts Pathology: - defects in TNFSF11 are the cause of osteopetrosis autosomal recessive type 2, characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development - it has been suggested that OPLG may be involved in the pathogenesis of rheumatoid arthritis - may also play a role in enhanced bone-resorption in humoral hypercalcemia of malignancy Pharmacology: - inhibited by monoclonal antibody denosumab (Prolia, Xgeva) Comparative biology: - in mice, progestins stimulate production of RANKL, which in turn induces proliferation of mammary epithelial cells [4]

Related

denosumab (Prolia, Xgeva) tumor necrosis factor receptor superfamily member 11A; receptor activator of NF-KB; osteoclast differentiation factor receptor; ODFR; CD265 (TNFRSF11A, RANK) tumor necrosis factor receptor superfamily member 11B; osteoprotegerin; osteoclastogenesis inhibitory factor (TNFRSF11B OCIF OPG)

General

cluster-of-differentiation antigen; cluster designation antigen; CD antigen tumor necrosis factor (TNF) family protein

Properties

SIZE: entity length = 317 aa MW = 35 kD COMPARTMENT: cytoplasm MOTIF: transmembrane domain {48-68} proteolytic site {139-140} N-glycosylation site {N171} N-glycosylation site {N198}

Database Correlations

OMIM correlations MORBIDMAP 602642 UniProt O14788 Pfam PF00229 Entrez Gene 8600 Kegg hsa:8600

References

  1. Journal Watch vol 19, #24, pg 192-93 Dec 15, 1999
  2. Kong YY et al Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402:304, 1999 PMID: 10580503
  3. Yasuda H et al Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. PNAS 95:3597-3602, 1998 PMID: 9520411
  4. Schramek D et al. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer. Nature 2010 Nov 4; 468:98 PMID: 20881962 - Gonzalez-Suarez E et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010 Nov 4; 468:103 PMID: 20881963
  5. Entrez Gene :accession 8600