# TNFRSF11A

## Overview
The TNFRSF11A gene encodes the tumor necrosis factor receptor superfamily member 11a (RANK), a type I transmembrane receptor that plays a pivotal role in bone metabolism and immune system regulation. As a member of the tumor necrosis factor (TNF) receptor superfamily, RANK is integral to the development and activation of osteoclasts, cells responsible for bone resorption, thereby maintaining bone homeostasis. The receptor is also involved in immune responses, influencing T-cell and dendritic cell functions. Structurally, RANK comprises an extracellular domain with cysteine-rich motifs, a transmembrane domain, and an intracellular domain that interacts with tumor necrosis factor receptor-associated factors (TRAFs) to activate signaling pathways such as NF-κB, JNK, and others. These pathways are crucial for various cellular processes, including osteoclastogenesis and immune regulation. Mutations in TNFRSF11A are linked to bone disorders such as autosomal-recessive osteopetrosis and Paget's disease of bone, highlighting its clinical significance (Rao2018RANKL; Guerrini2008Human; Dougall1999RANK).

## Structure
The TNFRSF11A gene encodes the RANK protein, a type I transmembrane receptor crucial for bone metabolism and immune system regulation. The molecular structure of RANK includes an extracellular N-terminal domain, a transmembrane domain, and an intracellular C-terminal domain. The extracellular domain features four cysteine-rich repeat motifs that facilitate receptor trimerization and interaction with the RANKL ligand (Xue2020The; Sirinian2013Alternative). The intracellular domain contains three tumor necrosis factor receptor-associated factors (TRAFs)-binding motifs, which activate several signaling pathways, including NF-кB, JNK, ERK, p38, NFATc1, and Akt, to mediate osteoclastogenesis (Xue2020The).

Alternative splicing of TNFRSF11A can produce multiple isoforms, such as the RANK-e5a variant, which lacks 42 nucleotides from exon 5. This results in a truncation of thirteen amino acids in the extracellular domain, affecting the third and fourth TNFR motifs and reducing the receptor's affinity for RANKL (Sirinian2013Alternative). The RANK protein is composed of 616 amino acids, with a signal secretion peptide, a transmembrane domain, and a long cytoplasmic domain (Sirinian2013Alternative). The protein can form homotrimers, which is essential for its function in signaling pathways (Dougall1999RANK).

## Function
The TNFRSF11A gene encodes the receptor RANK, a member of the tumor necrosis factor (TNF) receptor superfamily, which plays a crucial role in various physiological processes in healthy human cells. RANK is primarily involved in bone metabolism, where it regulates osteoclast development and activity, essential for bone remodeling and maintaining bone density (Rao2018RANKL; Hughes2000Mutations). The RANK/RANKL signaling pathway is vital for balancing the activities of bone-building osteoblasts and bone-resorbing osteoclasts, ensuring healthy bone tissue (Rao2018RANKL).

In the immune system, RANK is expressed on dendritic cells and certain T cells, where it enhances T-cell growth and dendritic-cell function. This interaction is important for immune regulation and T-cell tolerance (Anderson1997A; Darnay1998Characterization). RANK signaling is also involved in the development of lymph nodes and the regulation of B and T cell development (Rao2018RANKL).

RANK is active in the regulation of mammary gland physiology, particularly in response to the hormone progesterone, and is implicated in the development of lactating mammary glands during pregnancy (Rao2018RANKL). The receptor's activity is mediated through the activation of the nuclear factor kappa B (NF-κB) signaling pathway, which is crucial for various cellular processes, including cell survival and proliferation (Darnay1998Characterization).

## Clinical Significance
Mutations in the TNFRSF11A gene, which encodes the receptor activator of nuclear factor kappa-B (RANK), are associated with several bone disorders. Autosomal-recessive osteopetrosis (ARO) is characterized by a lack of mature osteoclasts due to TNFRSF11A mutations, leading to osteoclast-intrinsic defects and preventing monocytes from differentiating into osteoclasts. This condition is also linked with hypogammaglobulinemia, marked by low levels of immunoglobulins, and can be treated with hematopoietic stem cell transplantation (HSCT) (Guerrini2008Human).

Paget's disease of bone (PDB) is another condition associated with TNFRSF11A. Specific polymorphisms, such as T575C, are linked to increased NFκB activity and disease severity, particularly in patients with concurrent SQSTM1 mutations (Gianfrancesco2011A).

Dysosteosclerosis (DOS) is caused by TNFRSF11A mutations leading to elongated proteins and aberrant splicing, resulting in a distinct clinical presentation from osteopetrosis. DOS is characterized by osteosclerosis and platyspondyly, with specific mutations causing truncated or elongated RANK proteins that maintain partial activity (Xue2020The).

## Interactions
The TNFRSF11A gene encodes the receptor activator of NF-κB (RANK), which is involved in various protein interactions crucial for its function. RANK interacts with tumor necrosis factor receptor-associated factors (TRAFs), specifically TRAF2, TRAF5, and TRAF6, through its C-terminal domain. These interactions are essential for the activation of NF-κB and the c-Jun N-terminal kinase (JNK) pathways, although JNK activation can occur independently of direct TRAF binding (Darnay1998Characterization).

RANK also contains a novel cytoplasmic motif, IVVY, which is critical for osteoclastogenesis. This motif does not activate known TRAF-dependent pathways, indicating the presence of alternative signaling mechanisms (Xu2006A). The IVVY motif cooperates with TRAF-binding sites to induce the expression of nuclear factor of activated T-cells c1 (NFATc1) and osteoclast-specific genes, playing a significant role in osteoclast lineage commitment (Jules2015The).

In the context of breast cancer, RANK forms dimers with ERBB2, a member of the ERBB family, which influences NF-κB signaling and is associated with tumor growth and drug resistance (Zoi2019Combining). These interactions highlight the diverse roles of RANK in cellular signaling and disease processes.


## References


[1. (Dougall1999RANK) W. C. Dougall, M. Glaccum, K. Charrier, K. Rohrbach, K. Brasel, T. De Smedt, E. Daro, J. Smith, M. E. Tometsko, C. R. Maliszewski, A. Armstrong, V. Shen, S. Bain, D. Cosman, D. Anderson, P. J. Morrissey, J. J. Peschon, and J. Schuh. Rank is essential for osteoclast and lymph node development. Genes & Development, 13(18):2412–2424, September 1999. URL: http://dx.doi.org/10.1101/gad.13.18.2412, doi:10.1101/gad.13.18.2412. This article has 1157 citations.](https://doi.org/10.1101/gad.13.18.2412)

[2. (Sirinian2013Alternative) Chaido Sirinian, Anastasios D. Papanastasiou, Ioannis K. Zarkadis, and Haralabos P. Kalofonos. Alternative splicing generates a truncated isoform of human tnfrsf11a (rank) with an altered capacity to activate nf-κb. Gene, 525(1):124–129, August 2013. URL: http://dx.doi.org/10.1016/j.gene.2013.04.075, doi:10.1016/j.gene.2013.04.075. This article has 10 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2013.04.075)

[3. (Zoi2019Combining) Ilianna Zoi, Michalis V. Karamouzis, Evangelia Xingi, Panagiotis Sarantis, Dimitra Thomaidou, Panayiotis Lembessis, Stamatios Theocharis, and Athanasios G. Papavassiliou. Combining rank/rankl and erbb-2 targeting as a novel strategy in erbb-2-positive breast carcinomas. Breast Cancer Research, December 2019. URL: http://dx.doi.org/10.1186/s13058-019-1226-9, doi:10.1186/s13058-019-1226-9. This article has 8 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/s13058-019-1226-9)

[4. (Darnay1998Characterization) Bryant G. Darnay, Valsala Haridas, Jian Ni, Paul A. Moore, and Bharat B. Aggarwal. Characterization of the intracellular domain of receptor activator of nf-κb (rank). Journal of Biological Chemistry, 273(32):20551–20555, August 1998. URL: http://dx.doi.org/10.1074/jbc.273.32.20551, doi:10.1074/jbc.273.32.20551. This article has 342 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.273.32.20551)

[5. (Jules2015The) Joel Jules, Shunqing Wang, Zhenqi Shi, Jianzhong Liu, Shi Wei, and Xu Feng. The ivvy motif and tumor necrosis factor receptor-associated factor (traf) sites in the cytoplasmic domain of the receptor activator of nuclear factor κb (rank) cooperate to induce osteoclastogenesis. Journal of Biological Chemistry, 290(39):23738–23750, September 2015. URL: http://dx.doi.org/10.1074/jbc.M115.667535, doi:10.1074/jbc.m115.667535. This article has 21 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.M115.667535)

[6. (Xu2006A) Duorong Xu, Shunqing Wang, Wei Liu, Jianzhong Liu, and Xu Feng. A novel receptor activator of nf-κb (rank) cytoplasmic motif plays an essential role in osteoclastogenesis by committing macrophages to the osteoclast lineage. Journal of Biological Chemistry, 281(8):4678–4690, February 2006. URL: http://dx.doi.org/10.1074/jbc.m510383200, doi:10.1074/jbc.m510383200. This article has 38 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m510383200)

[7. (Anderson1997A) Dirk M. Anderson, Eugene Maraskovsky, William L. Billingsley, William C. Dougall, Mark E. Tometsko, Eileen R. Roux, Mark C. Teepe, Robert F. DuBose, David Cosman, and Laurent Galibert. A homologue of the tnf receptor and its ligand enhance t-cell growth and dendritic-cell function. Nature, 390(6656):175–179, November 1997. URL: http://dx.doi.org/10.1038/36593, doi:10.1038/36593. This article has 1783 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/36593)

[8. (Rao2018RANKL) Shuan Rao, Shane J.F. Cronin, Verena Sigl, and Josef M. Penninger. Rankl and rank: from mammalian physiology to cancer treatment. Trends in Cell Biology, 28(3):213–223, March 2018. URL: http://dx.doi.org/10.1016/j.tcb.2017.11.001, doi:10.1016/j.tcb.2017.11.001. This article has 73 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.tcb.2017.11.001)

[9. (Guerrini2008Human) Matteo M. Guerrini, Cristina Sobacchi, Barbara Cassani, Mario Abinun, Sara S. Kilic, Alessandra Pangrazio, Daniele Moratto, Evelina Mazzolari, Jill Clayton-Smith, Paul Orchard, Fraser P. Coxon, Miep H. Helfrich, Julie C. Crockett, David Mellis, Ashok Vellodi, Ilhan Tezcan, Luigi D. Notarangelo, Michael J. Rogers, Paolo Vezzoni, Anna Villa, and Annalisa Frattini. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to tnfrsf11a (rank) mutations. The American Journal of Human Genetics, 83(1):64–76, July 2008. URL: http://dx.doi.org/10.1016/j.ajhg.2008.06.015, doi:10.1016/j.ajhg.2008.06.015. This article has 246 citations.](https://doi.org/10.1016/j.ajhg.2008.06.015)

[10. (Xue2020The) Jing-Yi Xue, Zheng Wang, Sarah F. Smithson, Christine P. Burren, Naomichi Matsumoto, Gen Nishimura, Shiro Ikegawa, and Long Guo. The third case of tnfrsf11a-associated dysosteosclerosis with a mutation producing elongating proteins. Journal of Human Genetics, 66(4):371–377, October 2020. URL: http://dx.doi.org/10.1038/s10038-020-00831-8, doi:10.1038/s10038-020-00831-8. This article has 7 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s10038-020-00831-8)

[11. (Gianfrancesco2011A) Fernando Gianfrancesco, Domenico Rendina, Marco Di Stefano, Alessandra Mingione, Teresa Esposito, Daniela Merlotti, Salvatore Gallone, Sara Magliocca, Alice Goode, Daniela Formicola, Giovanna Morello, Robert Layfield, Annalisa Frattini, Gianpaolo De Filippo, Ranuccio Nuti, Mark Searle, Pasquale Strazzullo, Giancarlo Isaia, Giuseppe Mossetti, and Luigi Gennari. A nonsynonymous tnfrsf11a variation increases nfκb activity and the severity of paget’s disease. Journal of Bone and Mineral Research, 27(2):443–452, October 2011. URL: http://dx.doi.org/10.1002/jbmr.542, doi:10.1002/jbmr.542. This article has 34 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1002/jbmr.542)

[12. (Hughes2000Mutations) Anne E. Hughes, Stuart H. Ralston, John Marken, Christine Bell, Heather MacPherson, Richard G.H. Wallace, Wim van Hul, Michael P. Whyte, Kyoshi Nakatsuka, Louis Hovy, and Dirk M. Anderson. Mutations in tnfrsf11a, affecting the signal peptide of rank, cause familial expansile osteolysis. Nature Genetics, 24(1):45–48, January 2000. URL: http://dx.doi.org/10.1038/71667, doi:10.1038/71667. This article has 579 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/71667)