RANKL, Soluble (RANKL) Human Active Protein

This gene encodes 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. This protein was shown to be a dentritic 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 (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. 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. Two alternatively spliced transcript variants have been found. [provided by RefSeq, Jul 2008]

Function: Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Ref.7

Subunit structure: Homotrimer

Probable. Interacts with TNFRSF11B. Ref.7

Subcellular location: Isoform 1: Cell membrane; Single-pass type II membrane protein. Isoform 3: Cell membrane; Single-pass type II membrane protein. Isoform 2: Cytoplasm

By similarity. Tumor necrosis factor ligand superfamily member 11, soluble form: Secreted

By similarity.

Tissue specificity: Highest in the peripheral lymph nodes, weak in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid.

Induction: Up-regulated by T-cell receptor stimulation.

Post-translational modification: The soluble form of isoform 1 derives from the membrane form by proteolytic processing

By similarity. The cleavage may be catalyzed by ADAM17.

Involvement in disease: Osteopetrosis, autosomal recessive 2 (OPTB2) [MIM:259710]: A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8

Sequence similarities: Belongs to the tumor necrosis factor family.