# CSF2RB

## Overview
The CSF2RB gene encodes the colony stimulating factor 2 receptor subunit beta, a critical component of the receptor complexes for cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5). This protein, also known as the beta common chain (βc), is a transmembrane receptor subunit that plays a pivotal role in hematopoiesis and immune cell signaling. The CSF2RB protein forms part of a heterodimeric receptor complex with specific alpha subunits, facilitating high-affinity cytokine binding and subsequent signal transduction. It is involved in activating key signaling pathways, including JAK/STAT, MAPK, and PI3K/Akt, which are essential for cell proliferation, differentiation, and survival (Hercus2017Role; Hercus2012The). Mutations in CSF2RB have been implicated in various diseases, highlighting its clinical significance in immune regulation and disease pathogenesis (Chuang2016A; Tanaka2010Adult-onset).

## Structure
The CSF2RB protein, also known as the beta common chain (bc), is a critical component of the receptor complexes for cytokines such as GM-CSF, IL-3, and IL-5. It is involved in forming a heterodimeric complex with an alpha subunit, such as GMRa, to facilitate high-affinity cytokine binding and signal transduction (Hercus2012The). The protein structure includes an extracellular domain that interacts with cytokines, a transmembrane domain, and a cytoplasmic domain essential for signal transduction (Hercus2012The).

The quaternary structure of the CSF2RB protein involves forming a hexameric complex, where two binary complexes of GM-CSF and GMRa are bound to a single bc homodimer. This homodimer forms an arch connecting the two binary complexes (Hercus2012The). The dodecameric structure of the receptor complex is stabilized by interactions at multiple sites, including Site 4 between GMRa and bc, and Site 5 between GM-CSF molecules (Hercus2012The).

Post-translational modifications, such as phosphorylation, play a crucial role in the signaling function of CSF2RB. Phosphorylation of tyrosine residues in the cytoplasmic domain is essential for activating downstream signaling pathways, including JAK/STAT, MAPK, and PI3K/Akt (Hercus2012The).

## Function
The CSF2RB gene encodes the beta subunit of the receptor for colony-stimulating factors, which is crucial for hematopoiesis and immune cell signaling. This protein forms part of the receptor complex for cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5), facilitating signal transduction for cell proliferation, differentiation, and survival (Broughton2012The; Hercus2017Role).

In healthy human cells, CSF2RB is involved in the activation of several key signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K) pathways. These pathways are essential for the proper functioning of immune cells, such as monocytes and macrophages, and are activated upon stimulation by GM-CSF (Chuang2016A; Hercus2017Role). The CSF2RB protein is active in immune cells, influencing immune response and inflammation, and plays a critical role in mediating immune responses through its interaction with GM-CSF and associated signaling pathways (Chuang2016A).

The β common (βc) subunit, encoded by CSF2RB, is a key component of the GM-CSF, IL-3, and IL-5 receptors, and is crucial for receptor activation and signaling diversity (Hercus2017Role).

## Clinical Significance
Mutations in the CSF2RB gene have been linked to several diseases, primarily due to their impact on cytokine signaling pathways. A frameshift mutation in CSF2RB is associated with an increased risk of Crohn's disease, particularly among Ashkenazi Jews. This mutation leads to impaired GM-CSF signaling in monocytes, which is crucial for immune responses, and results in decreased STAT5 phosphorylation, contributing to the pathogenesis of Crohn's disease (Chuang2016A). 

In the context of autoimmune diseases, CSF2RB expression is upregulated in regulatory T cells (Tregs) of patients with multiple sclerosis (MS) and systemic lupus erythematosus (SLE), suggesting its potential as a biomarker for these conditions. However, the specific functional role of CSF2RB in Tregs remains unclear (Côrte-Real2022Dissecting).

CSF2RB mutations are also implicated in pulmonary alveolar proteinosis (PAP), a rare lung disease. A single-base deletion in CSF2RB can lead to defective GM-CSF signaling, resulting in impaired surfactant catabolism and the accumulation of lipoproteinaceous material in the alveoli (Tanaka2010Adult-onset; Li2024Case). 

Additionally, a germline mutation in CSF2RB, specifically the R461C mutation, has been identified in a leukemia patient, leading to ligand-independent activation of the receptor and contributing to leukemia development (WatanabeSmith2016Discovery).

## Interactions
CSF2RB, also known as the beta common receptor, is a critical component of the receptor complexes for cytokines such as GM-CSF, IL-3, and IL-5. It forms high-affinity ternary complexes with specific alpha subunits, including GMRa, IL3Ra, and IL5Ra, to mediate cytokine signaling (Broughton2015The). The interaction between CSF2RB and these alpha subunits is essential for the activation of signaling pathways like JAK-STAT, MAPK, and PI3-kinase/Akt, which are crucial for immune responses and hematopoiesis (Hercus2013Signalling).

In the context of FLT3-ITD-positive acute myeloid leukemia (AML), CSF2RB interacts with the FLT3 receptor. This interaction leads to the phosphorylation of CSF2RB, which is necessary for the activation of STAT5, a key mediator of oncogenic signaling in these cells (Charlet2021The). The phosphorylation of CSF2RB by FLT3-ITD does not require complex formation with IL3RA, indicating a direct interaction between CSF2RB and FLT3 (Charlet2021The).

CSF2RB also participates in the formation of higher-order signaling complexes, such as hexameric and dodecameric structures, which are important for the function of the GM-CSF receptor complex (Broughton2015The). These complexes involve specific interaction sites, such as Site 2, where GM-CSF interacts with aromatic residues in CSF2RB, highlighting the structural complexity of these interactions (Broughton2015The).


## References


[1. (Tanaka2010Adult-onset) T. Tanaka, N. Motoi, Y. Tsuchihashi, R. Tazawa, C. Kaneko, T. Nei, T. Yamamoto, T. Hayashi, T. Tagawa, T. Nagayasu, F. Kuribayashi, K. Ariyoshi, K. Nakata, and K. Morimoto. Adult-onset hereditary pulmonary alveolar proteinosis caused by a single-base deletion in csf2rb. Journal of Medical Genetics, 48(3):205–209, November 2010. URL: http://dx.doi.org/10.1136/jmg.2010.082586, doi:10.1136/jmg.2010.082586. This article has 111 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1136/jmg.2010.082586)

[2. (Côrte-Real2022Dissecting) Beatriz F. Côrte-Real, Rebeca Arroyo Hornero, Aleksandra Dyczko, Ibrahim Hamad, and Markus Kleinewietfeld. Dissecting the role of csf2rb expression in human regulatory t cells. Frontiers in Immunology, December 2022. URL: http://dx.doi.org/10.3389/fimmu.2022.1005965, doi:10.3389/fimmu.2022.1005965. This article has 3 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fimmu.2022.1005965)

[3. (Chuang2016A) Ling-Shiang Chuang, Nicole Villaverde, Ken Y. Hui, Arthur Mortha, Adeeb Rahman, Adam P. Levine, Talin Haritunians, Sok Meng Evelyn Ng, Wei Zhang, Nai-Yun Hsu, Jody-Ann Facey, Tramy Luong, Heriberto Fernandez-Hernandez, Dalin Li, Manuel Rivas, Elena R. Schiff, Alexander Gusev, L. Phillip Schumm, Beatrice M. Bowen, Yashoda Sharma, Kaida Ning, Romain Remark, Sacha Gnjatic, Peter Legnani, James George, Bruce E. Sands, Joanne M. Stempak, Lisa W. Datta, Seth Lipka, Seymour Katz, Adam S. Cheifetz, Nir Barzilai, Nikolas Pontikos, Clara Abraham, Marla J. Dubinsky, Stephan Targan, Kent Taylor, Jerome I. Rotter, Ellen J. Scherl, Robert J. Desnick, Maria T. Abreu, Hongyu Zhao, Gil Atzmon, Itsik Pe’er, Subra Kugathasan, Hakon Hakonarson, Jacob L. McCauley, Todd Lencz, Ariel Darvasi, Vincent Plagnol, Mark S. Silverberg, Aleixo M. Muise, Steven R. Brant, Mark J. Daly, Anthony W. Segal, Richard H. Duerr, Miriam Merad, Dermot P.B. McGovern, Inga Peter, and Judy H. Cho. A frameshift in csf2rb predominant among ashkenazi jews increases risk for crohn’s disease and reduces monocyte signaling via gm-csf. Gastroenterology, 151(4):710-723.e2, October 2016. URL: http://dx.doi.org/10.1053/j.gastro.2016.06.045, doi:10.1053/j.gastro.2016.06.045. This article has 51 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1053/j.gastro.2016.06.045)

[4. (Li2024Case) Qiuhong Li, Huikang Xie, Manhui Li, and Kebin Cheng. Case report: fibrotic interstitial lung disease as the initial manifestation of hereditary pulmonary alveolar proteinosis caused by csf2rb mutation. Frontiers in Pharmacology, January 2024. URL: http://dx.doi.org/10.3389/fphar.2023.1252193, doi:10.3389/fphar.2023.1252193. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fphar.2023.1252193)

[5. (Charlet2021The) Anne Charlet, Max Kappenstein, Philip Keye, Kathrin Kläsener, Cornelia Endres, Teresa Poggio, Sivahari P. Gorantla, Stefanie Kreutmair, Jana Sänger, Anna L. Illert, Cornelius Miething, Michael Reth, Justus Duyster, Christoph Rummelt, and Nikolas von Bubnoff. The il-3, il-5, and gm-csf common receptor beta chain mediates oncogenic activity of flt3-itd-positive aml. Leukemia, 36(3):701–711, November 2021. URL: http://dx.doi.org/10.1038/s41375-021-01462-4, doi:10.1038/s41375-021-01462-4. This article has 15 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/s41375-021-01462-4)

[6. (Hercus2012The) Timothy R. Hercus, Sophie E. Broughton, Paul G. Ekert, Hayley S. Ramshaw, Michelle Perugini, Michele Grimbaldeston, Joanna M. Woodcock, Daniel Thomas, Stuart Pitson, Timothy Hughes, Richard J. D’Andrea, Michael W. Parker, and Angel F. Lopez. The gm-csf receptor family: mechanism of activation and implications for disease. Growth Factors, 30(2):63–75, January 2012. URL: http://dx.doi.org/10.3109/08977194.2011.649919, doi:10.3109/08977194.2011.649919. This article has 85 citations and is from a peer-reviewed journal.](https://doi.org/10.3109/08977194.2011.649919)

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[9. (Broughton2015The) Sophie E. Broughton, Tracy L. Nero, Urmi Dhagat, Winnie L. Kan, Timothy R. Hercus, Denis Tvorogov, Angel F. Lopez, and Michael W. Parker. The βc receptor family – structural insights and their functional implications. Cytokine, 74(2):247–258, August 2015. URL: http://dx.doi.org/10.1016/j.cyto.2015.02.005, doi:10.1016/j.cyto.2015.02.005. This article has 61 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.cyto.2015.02.005)

[10. (Broughton2012The) Sophie E. Broughton, Urmi Dhagat, Timothy R. Hercus, Tracy L. Nero, Michele A. Grimbaldeston, Claudine S. Bonder, Angel F. Lopez, and Michael W. Parker. The <scp>gm</scp>–<scp>csf</scp>/<scp>il‐3</scp>/<scp>il‐5</scp> cytokine receptor family: from ligand recognition to initiation of signaling. Immunological Reviews, 250(1):277–302, October 2012. URL: http://dx.doi.org/10.1111/j.1600-065x.2012.01164.x, doi:10.1111/j.1600-065x.2012.01164.x. This article has 2 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1111/j.1600-065x.2012.01164.x)

[11. (WatanabeSmith2016Discovery) K Watanabe-Smith, C Tognon, J W Tyner, J P P Meijerink, B J Druker, and A Agarwal. Discovery and functional characterization of a germline, csf2rb-activating mutation in leukemia. Leukemia, 30(9):1950–1953, April 2016. URL: http://dx.doi.org/10.1038/leu.2016.95, doi:10.1038/leu.2016.95. This article has 18 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/leu.2016.95)