CSF2RA - colony stimulating factor 2 receptor subunit alpha | Elisa - Clia - Antibody - Protein

Background

The Colony Stimulating Factor 2 Receptor Subunit Alpha (CSF2RA) is a component of the receptor complex for granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that plays an essential role in immune and hematopoietic functions. CSF2RA, encoded by the CSF2RA gene, is part of a multi-subunit receptor complex essential for binding GM-CSF, which in turn regulates the survival, proliferation, and differentiation of granulocyte and macrophage lineages. This cytokine-receptor signaling pathway is crucial for innate immune functions, including the inflammatory response, infection control, and tissue repair.

The CSF2RA gene is located on the pseudoautosomal region (PAR) of the X and Y chromosomes and encodes the alpha chain of the GM-CSF receptor complex. Dysfunctional signaling through CSF2RA can lead to immune-related pathologies, hematopoietic disorders, and severe congenital diseases such as pulmonary alveolar proteinosis (PAP). CSF2RA signaling is clinically relevant due to its involvement in immune function and its potential as a therapeutic target in inflammatory and autoimmune diseases, as well as certain cancers.

Protein Structure

CSF2RA is a transmembrane protein that serves as the ligand-binding subunit in the heterodimeric GM-CSF receptor complex. The protein can be structurally categorized into three main domains, each contributing to its unique functional properties:

Extracellular Domain:

• The extracellular domain of CSF2RA is composed of approximately 300 amino acids and features distinct subregions involved in cytokine binding and receptor dimerization. The N-terminal segment contains an immunoglobulin-like (Ig-like) domain, which is crucial for binding GM-CSF.
• This Ig-like domain is followed by two fibronectin type III-like (FNIII-like) domains that provide structural integrity and additional interaction sites for the beta subunit of the receptor complex.
• Several N-linked glycosylation sites in the extracellular domain facilitate proper folding, receptor stability, and increased affinity for GM-CSF.

Transmembrane Domain:

• CSF2RA has a single hydrophobic transmembrane region of approximately 20–25 amino acids that anchors the receptor in the cell membrane. This domain plays a structural role, stabilizing the receptor complex within the lipid bilayer and facilitating the juxtaposition of the extracellular and intracellular domains.

Intracellular Domain:

• The intracellular domain of CSF2RA is relatively short, consisting of around 50 amino acids and lacking intrinsic enzymatic activity. However, it contains phosphorylation sites that interact with downstream signaling molecules.
• Upon ligand binding and receptor dimerization, this domain initiates intracellular signaling cascades through association with Janus kinases (JAKs) and signal transducers and activators of transcription (STATs).
• While the alpha subunit (CSF2RA) binds the ligand, the signal transduction is carried out by the beta subunit (CSF2RB), which has a larger intracellular domain with tyrosine kinase activity.

Classification and Subtypes

CSF2RA belongs to the type I cytokine receptor family, which includes receptors for other hematopoietic cytokines such as interleukins and granulocyte colony-stimulating factor (G-CSF). Specifically, it is classified under the hematopoietin receptor family, known for its conserved cytokine-binding motifs.

CSF2RA does not have distinct subtypes; however, its function is context-dependent, with its effects modulated by its heterodimerization with the beta common (βc) subunit (CSF2RB). The βc subunit is shared with other receptors in the cytokine receptor family, including those for interleukin-3 (IL-3) and interleukin-5 (IL-5), providing functional flexibility and diversity in cellular responses.

Function and Biological Significance

CSF2RA, as part of the GM-CSF receptor complex, has critical roles in the immune response, hematopoiesis, and cellular differentiation:

Role in Hematopoiesis:

• CSF2RA mediates the effects of GM-CSF on myeloid progenitor cells in the bone marrow, promoting the differentiation of granulocytes and macrophages. This signaling pathway ensures the proper development of key components of the innate immune system.
• GM-CSF signaling also influences erythroid and megakaryocyte lineages under certain physiological conditions, contributing to erythropoiesis and platelet formation, especially in states of inflammation or infection.

Immune Function:

• In immune responses, CSF2RA activation stimulates granulocyte and macrophage activity, enhancing their phagocytic, antimicrobial, and antigen-presenting functions. This is crucial for the immune system’s ability to control infections and respond to pathogens.
• Macrophages activated via CSF2RA participate in inflammatory processes and tissue remodeling, essential for healing and recovery from injury.

Tissue Homeostasis and Repair:

• GM-CSF and CSF2RA signaling contribute to tissue repair and homeostasis by regulating macrophage polarization and promoting pro-inflammatory phenotypes. This is especially significant in the lungs, liver, and skin, where macrophages play a major role in tissue integrity and defense.
• In the lungs, alveolar macrophages regulated by CSF2RA signaling maintain surfactant homeostasis, preventing pulmonary disorders such as alveolar proteinosis.

Cancer Biology:

• CSF2RA signaling is involved in the tumor microenvironment, particularly in cancers where GM-CSF is overexpressed, such as some hematologic malignancies and solid tumors. High levels of GM-CSF can lead to an immunosuppressive environment by promoting regulatory myeloid cells, which suppress anti-tumor immune responses.

Clinical Issues

Abnormal CSF2RA signaling or genetic mutations in CSF2RA can lead to clinical disorders:

Pulmonary Alveolar Proteinosis (PAP):

• Genetic mutations or deficiencies in CSF2RA can result in primary alveolar proteinosis, a rare lung disorder characterized by the accumulation of surfactant proteins in the alveoli. This accumulation impairs gas exchange and results in respiratory difficulties.
• In PAP, dysfunctional GM-CSF signaling impairs the ability of alveolar macrophages to clear surfactant, leading to alveolar filling with lipoproteinaceous material. Treatment often includes therapies aimed at enhancing GM-CSF signaling or lung lavage procedures.

Immunodeficiency and Myeloid Disorders:

• Defective CSF2RA signaling is associated with various immunodeficiencies due to impaired macrophage and granulocyte function, resulting in increased susceptibility to infections and inflammatory disorders.
• Certain mutations in the CSF2RA gene have also been linked to hematologic malignancies like myelodysplastic syndromes and leukemias, where dysfunctional receptor signaling alters normal hematopoiesis.

Inflammatory and Autoimmune Diseases:

• Enhanced CSF2RA signaling is associated with chronic inflammatory diseases, including rheumatoid arthritis, where elevated GM-CSF levels drive macrophage activation and inflammation.
• Targeting CSF2RA in inflammatory diseases has gained interest, with CSF2RA inhibitors and GM-CSF antagonists showing potential as therapeutic agents for diseases like rheumatoid arthritis and other autoimmune conditions.

Cancer Therapy:

• Given its role in immune cell function and macrophage regulation, CSF2RA is being explored as a therapeutic target in cancer. By modulating CSF2RA signaling, it may be possible to reduce tumor-associated macrophages or enhance anti-tumor immunity.

Summary

CSF2RA is an integral part of the GM-CSF receptor complex and plays an essential role in immune and hematopoietic functions. Structurally, CSF2RA consists of an extracellular domain with Ig-like and FNIII-like regions for ligand binding, a single transmembrane domain, and a short intracellular domain that interacts with signaling proteins. In combination with the beta subunit (CSF2RB), CSF2RA transduces GM-CSF signals that regulate granulocyte and macrophage survival, proliferation, and differentiation.

CSF2RA’s significance extends to immune response, inflammation, tissue homeostasis, and cancer biology. Its dysfunction is associated with diseases like pulmonary alveolar proteinosis, immune deficiencies, chronic inflammatory diseases, and cancer. CSF2RA is of clinical interest due to its potential as a therapeutic target in autoimmune diseases, hematologic disorders, and cancer, highlighting its critical role in both health and disease.