RANK

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Nuclear Factor Receptor Activator? B ( RANK ), also known as TRANCE Receptor or TNFRSF11A , is a member of the tumor necrosis factor receptor (TNFR) sub- molecular families. RANK is a receptor for RANK-Ligand (RANKL) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and development of mammary glands. Osteoprotegerin (OPG) is a feed receptor for RANK, and regulates the stimulation of RANK signaling pathways by competing for RANKL. The RANK cytoplasmic domain binds TRAFs 1, 2, 3, 5, and 6 that send signals to downstream targets such as NF-? B and JNK.

RANK is constitutively expressed in skeletal muscle, thymus, liver, large intestine, small intestine, adrenal gland, osteoclasts, mammary epithelial cells, prostate, vascular cells, and pancreas. Most commonly, NF- activation? B is mediated by RANKL, but the excessive RANK expression is enough to activate the NF- pathway? B.

RANKL (Receptor Activator for Nuclear Factor? B Ligand) is found on the surface of stromal cells, osteoblasts, and T cells.

Video RANK

Structure

RANK is a 616 protein type of transmembrane amino acids. The extracellular domain consists of 184 amino acids, its transmembrane domain has 21 amino acids, and its cytoplasmic domain consists of 383 amino acids. Like other members of the TNFR family, it has four rich, cysteine-rich pseudo-repeat (CRD) domains. It shares the 40% amino acid identity with CD40. RANK is encoded on human chromosome 18q22.1. This shows 85% homology between homologous rats and humans.

There are two RANK monomers associated with 2-times noncrystallographic symmetry that is perpendicular to the long axis of the molecule in the asymmetric unit. RANK contains four CRDs that cover the length of 100 Angstrom which makes it the longest member of the TNFR family to date.

The binding of RANKL to RANK modeled the receptor and activated the signaling pathway. The RANK-RANKL complex forms a heterohexameric complex. Only two of the four CRD RANK are in direct contact with RANKL. The majority of the complex residues are hydrophilic. Unlike other TNFSF members, every surface interaction within RANK-RANKL is sustainable.

Maps RANK

Function

Osteoclastogenesis

TRAF6 has been shown to be very important for the associated RANK osteoclastogenesis pathway. RANKL binds RANK, which then binds to TRAF6. TRAF6 stimulates the activation of the n-terminal kinase c-jun (JNK) pathway and kappa-b nuclear pathway (NF-kB) which triggers osteoclast differentiation and activation. This system is offset by OPG's relative expression to RANKL, which is highly regulated by many factors including hormones, immune signals, and growth factors. Excessive RANKL expression can lead to overproduction and osteoclast activation, which destroys bone. The balance between RANKL and OPG is a target for therapy in many diseases including osteoporosis associated with estrogen deficiency, rheumatoid arthritis, Paget's disease, periodontal disease, and bone tumor and malignancy.

Thermoregulation

RANK has also been shown to be key in female thermoregulation signals, which seem to be regulated by ovarian sex hormones. RANK is expressed in the brain's key areas associated with thermoregulation. RANK inactivation in these areas leads to a loss of febrile response to an increase in RANKL levels. It has also been shown to be a critical mediator of the febrile response to the lipopolysaccharide-induced fevers and proinflammatory cytokines IL-1B and TNFa. The key role of this RANK-RANKL system can link osteoporosis and hot flashes that are seen as symptoms of hormonal changes in postmenopausal women.

Development of mammary glands

RANK is constitutively expressed in the mammary epithelial tissue. Calcium is transferred from the mother to the fetus and the neonate is provided by the degradation of the female bone by an increase in osteoblastic activity, which is governed by the RANK/RANKL axis. RANKL also works through RANK to provide proliferative and survival signals to promote the final stage of breastfeeding mammary gland development. Dysfunctional RANKL or RANKL leads to the capture of differentiation and alveolar group expansion into the adult lobulo-alveolar mammary structure, thereby shutting off milk production.

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Clinical interests

Cancer

RANK and RANKL have been reportedly expressed in several pathways of breast cancer and prostate cancer cells. RANKL expression in T cells that infiltrate in mammary carcinoma activates neoplastic breast epithelial cells expressing RANK that stimulates metastasis. The RANKL expression in these cells and the expression of RANK in bone cells may be the biological presentation of Paget seeds and the idea of ​​soil. The affinity for RANK from RANKL may be the reason why this cancer tends to metastasize to the bone. Once the tumor is favored in the bone, tumor cells stimulate bone resorption by secreting factors such as RANKL or encouraging the surrounding stroma to express growth factors. These growth factors then increase RANKL production leading to osteoclastogenesis and bone destruction. Bone damage releases more growth factors and RANKL induces more osteoclastogenesis, which triggers a vicious cycle of bone destruction seen in metastatic bone tumors.

Targeted therapies

Most therapies targeting the RANK/RANKL/OPG axis aim to decrease RANKL expression or increase expression of OPG feed receptors. For example, denosumab is a fully human monoclonal antibody directed against RANKL. In phase I and II trials, denosumab causes decreased bone resorption in multiple myeloma, prostate cancer and breast cancer patients. Other studies look into developing small mimeticism based on OPG structures that bind RANK as well as RANKL and cause coupling damage between the two.

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Interactions

RANK has been shown to interact with:

• TRAF1,
• TRAF2,
• TRAF3,
• TRAF5, and
• TRAF6.

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See also

• RANKL
• Osteoprotegerin
• Osteoimmunology

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References

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Further reading

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External links

• RANK Protein at US National Library of Medicine's Medical Subject Headings (MeSH)

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

Source of the article : Wikipedia