CSF2RB - colony stimulating factor 2 receptor subunit beta| Elisa - Clia - Antibody - Protein

Background

The Colony Stimulating Factor 2 Receptor Subunit Beta (CSF2RB), also known as common beta chain (βc), is an integral part of the receptor complex for several cytokines, notably granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5). These cytokines play essential roles in hematopoiesis, the immune system, and inflammatory processes by driving the proliferation, differentiation, and activation of various hematopoietic cells. CSF2RB is thus crucial for normal immune function and has also been implicated in inflammatory responses, tissue repair, and pathological conditions such as chronic inflammation and certain cancers.

Unlike its alpha counterparts (CSF2RA, IL3RA, and IL5RA), which are cytokine-specific, CSF2RB serves as a shared receptor subunit in these cytokine receptor complexes. This shared receptor structure allows it to transmit signals from multiple cytokines, although it does not bind cytokines directly. Instead, CSF2RB’s main function is to initiate downstream signaling cascades once the cytokine and alpha subunit have bound, forming a functional receptor complex. This receptor complex predominantly activates the JAK/STAT and MAPK signaling pathways, with substantial impact on immune responses, hematopoiesis, and cellular responses to stress.

Protein Structure

The CSF2RB protein is a type I transmembrane glycoprotein comprising 896 amino acids with a molecular weight of approximately 97 kDa. It consists of three major domains: an extracellular domain, a transmembrane domain, and an intracellular domain, each critical for its structural integrity and function.

Extracellular Domain (ECD):

• The ECD spans approximately 455 amino acids and contains two fibronectin type III-like (FNIII) domains that contribute to protein-protein interactions. These domains help CSF2RB associate with the cytokine-bound alpha subunits (CSF2RA, IL3RA, or IL5RA) to form the functional receptor complex.
• The FNIII domains are important for receptor dimerization and stabilization of the entire receptor complex, allowing effective downstream signaling.
• There are multiple N-linked glycosylation sites on the ECD that contribute to protein folding, stability, and receptor expression on the cell surface. These modifications are necessary to ensure proper receptor function and signaling efficiency.

Transmembrane Domain (TMD):

• The TMD of CSF2RB is a short hydrophobic region, anchoring the protein within the cellular membrane, providing stability, and ensuring orientation for optimal interaction between the extracellular and intracellular domains. It plays a minor role in signal transduction but is vital for structural integrity.

Intracellular Domain (ICD):

• The ICD of CSF2RB is essential for initiating and propagating downstream signaling events. It contains conserved tyrosine residues that become phosphorylated upon receptor activation. These phosphorylated tyrosines serve as docking sites for signaling proteins and facilitate the recruitment of Janus kinases (JAKs), particularly JAK2, which are pivotal for triggering the JAK/STAT signaling pathway.
• Additionally, the ICD interacts with proteins involved in the MAPK/ERK and PI3K/AKT pathways, allowing diverse cellular responses depending on the context and specific cytokine engagement. These pathways regulate various cellular processes, including survival, proliferation, differentiation, and apoptosis.

Classification and Subtypes

CSF2RB is classified within the hematopoietin receptor family and is a type I cytokine receptor. The receptor subunit does not have subtypes; however, it acts as a common signaling chain for the cytokine receptor complexes of GM-CSF, IL-3, and IL-5. This shared signaling component classifies CSF2RB as part of a receptor subfamily with essential roles in hematopoiesis and immune function. Each cytokine engages CSF2RB by first binding its unique alpha chain, which then forms a heterodimer with CSF2RB, initiating downstream signaling events.

Function and Biological Significance

The primary role of CSF2RB is to mediate cytokine-induced signal transduction as part of receptor complexes for GM-CSF, IL-3, and IL-5. These cytokines are crucial in various biological processes, primarily within the immune and hematopoietic systems:

Hematopoiesis:

• CSF2RB plays a central role in hematopoiesis, influencing the development, differentiation, and function of multiple blood cell lineages, including granulocytes, monocytes/macrophages, eosinophils, basophils, and certain lymphocyte subsets.
• By mediating signaling from GM-CSF, IL-3, and IL-5, CSF2RB helps regulate the production and function of white blood cells, particularly under conditions of infection or inflammation, where rapid immune cell mobilization is necessary.

Immune Responses:

• CSF2RB contributes significantly to immune cell activation and function. GM-CSF-mediated activation through CSF2RB enhances macrophage, dendritic cell, and neutrophil responses, supporting pathogen clearance and immune surveillance.
• IL-5 signaling through CSF2RB specifically promotes eosinophil activation and survival, playing a role in responses against parasitic infections and in allergic inflammation. CSF2RB also mediates IL-3 signaling, which supports mast cell and basophil function, impacting allergic and inflammatory responses.

Inflammatory and Allergic Responses:

• CSF2RB's role in transmitting IL-5 signals links it to eosinophil activation in allergic conditions like asthma. Elevated IL-5 levels can lead to increased eosinophil counts, contributing to the inflammation characteristic of allergic diseases.
• GM-CSF, through CSF2RB, is implicated in chronic inflammatory diseases, where it promotes the survival and activity of macrophages and neutrophils in inflamed tissues. This contributes to tissue damage and sustained inflammation seen in conditions such as rheumatoid arthritis.

Cell Proliferation, Survival, and Differentiation:

• CSF2RB engagement in the GM-CSF and IL-3 pathways promotes cell survival and proliferation through STAT5 and AKT signaling, which is particularly important during immune responses and recovery from cytotoxic treatments.
• The receptor also affects differentiation pathways, particularly for dendritic cells and macrophages, where it enhances the immune response capabilities of these cells.

Clinical Issues

CSF2RB dysregulation is associated with several pathological conditions due to its role in immune regulation, hematopoiesis, and inflammation:

Autoimmune and Inflammatory Diseases:

• Inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease, often involve increased GM-CSF levels, which, through CSF2RB, drive macrophage and neutrophil activation in inflamed tissues. Elevated CSF2RB signaling in these cases contributes to chronic inflammation and tissue damage, suggesting CSF2RB as a therapeutic target.
• Asthma and allergic disorders involving eosinophil activation often exhibit elevated IL-5 levels. Targeting the IL-5/CSF2RB axis, as with monoclonal antibodies like mepolizumab, can reduce eosinophil numbers, decreasing inflammation and allergic symptoms.

Cancer:

• Aberrant CSF2RB signaling, particularly through GM-CSF and IL-3, has been implicated in hematological malignancies such as leukemia. In some leukemias, abnormal activation of the JAK/STAT pathway through CSF2RB leads to unchecked cell proliferation and survival, contributing to tumor growth.
• Certain solid tumors also exploit the GM-CSF/CSF2RB pathway to promote an immunosuppressive microenvironment by recruiting tumor-associated macrophages, which aid in immune evasion and tumor progression. Inhibiting CSF2RB signaling in these contexts is being explored to enhance anti-tumor immunity.

Pulmonary and Infectious Diseases:

• GM-CSF, via CSF2RB, is essential for alveolar macrophage function and pulmonary homeostasis. Deficiencies in CSF2RB signaling can lead to pulmonary alveolar proteinosis (PAP), a rare disease where dysfunctional alveolar macrophages result in the accumulation of surfactant in the lungs, impairing gas exchange.
• During infections, particularly bacterial, GM-CSF signaling through CSF2RB enhances the antimicrobial functions of macrophages and neutrophils. This pathway is under investigation for potential therapies that can augment host defenses in immune-compromised individuals.

Summary

CSF2RB, the common beta chain receptor for GM-CSF, IL-3, and IL-5, is central to hematopoiesis, immune responses, and inflammation regulation. Structurally, it features an extracellular domain for receptor complex formation, a transmembrane domain for anchorage, and an intracellular domain critical for signaling activation, particularly through the JAK/STAT pathway. CSF2RB enables diverse cytokine-driven responses across different cell types, contributing to various physiological and pathological processes. Clinically, its dysregulation is linked to autoimmune disorders, inflammatory diseases, certain cancers, and pulmonary conditions, making it a significant therapeutic target for modulating immune and inflammatory responses.