CSF3R - colony stimulating factor 3 receptor | Elisa - Clia - Antibody - Protein

Background

The Colony-Stimulating Factor 3 Receptor (CSF3R), also known as the granulocyte colony-stimulating factor receptor (G-CSFR), is a transmembrane protein that plays a crucial role in the regulation of granulopoiesis—the process by which granulocytes, a type of white blood cell, are produced in the bone marrow. CSF3R is the receptor for colony-stimulating factor 3 (CSF3 or G-CSF), a cytokine that promotes the proliferation, differentiation, and activation of granulocytic progenitors and mature neutrophils. It is a member of the cytokine receptor family and shares structural and functional similarities with other receptors in this family.

The CSF3R gene is located on chromosome 1 (1p34.3) and encodes the G-CSFR protein. CSF3R is essential for neutrophil production and function and is involved in the immune response against infections, particularly bacterial infections. Dysregulation or mutations in the CSF3R gene have been implicated in a variety of hematological disorders, including severe congenital neutropenia and certain types of acute myeloid leukemia (AML), where it often plays a role in leukemic transformation.

Protein Structure

CSF3R is a single-pass transmembrane receptor composed of 836 amino acids. It has distinct extracellular, transmembrane, and intracellular domains, each contributing to ligand binding, receptor dimerization, and signaling.

Extracellular Domain:

• The extracellular domain of CSF3R consists of around 603 amino acids and is responsible for binding to G-CSF. It contains a cytokine-binding module with two cytokine receptor homology domains (CRHDs) that facilitate high-affinity binding with G-CSF.
• The receptor binding is characterized by its cytokine receptor-like domains which are essential for the stable attachment of CSF3, leading to receptor dimerization and subsequent signaling.
• This region also contains a fibronectin type III domain and is further stabilized by conserved cysteine residues.

Transmembrane Domain:

• The transmembrane domain spans the cell membrane and consists of approximately 20 hydrophobic amino acids. It anchors the receptor in the cell membrane and facilitates receptor dimerization upon ligand binding.
• This domain is critical for the proper positioning of the intracellular domain for effective downstream signaling.

Intracellular Domain:

• The intracellular or cytoplasmic domain of CSF3R is around 180 amino acids long and lacks intrinsic kinase activity. Instead, it serves as a docking site for signal transduction proteins, including Janus kinase 2 (JAK2).
• Upon ligand binding and receptor dimerization, JAK2 associates with the intracellular domain of CSF3R, leading to receptor phosphorylation and activation of multiple signaling pathways, including JAK-STAT, MAPK/ERK, and PI3K-AKT. These pathways regulate granulocyte differentiation, proliferation, and survival.
• Specific tyrosine residues within the intracellular domain act as docking sites for signaling molecules and adaptor proteins. Phosphorylation of these residues upon ligand binding triggers the recruitment of proteins such as STAT3 and STAT5, which mediate gene expression changes necessary for granulopoiesis.

Glycosylation Sites:

• The extracellular domain has multiple N-linked glycosylation sites which aid in protein folding, stability, and ligand-binding efficiency. Glycosylation is important for efficient receptor expression on the cell surface and proper interaction with G-CSF.

Classification and Subtypes

CSF3R is part of the Type I cytokine receptor family, specifically within the class I hematopoietic cytokine receptor superfamily. It is closely related to other cytokine receptors, such as the receptors for erythropoietin (EPO) and thrombopoietin (TPO).

In terms of variations, CSF3R can exist in different forms due to alternative splicing and post-translational modifications. Additionally, mutations in the CSF3R gene, particularly truncating and point mutations, have been observed in hematologic diseases, contributing to altered receptor signaling:

• Membrane-bound CSF3R: The primary form, typically located on cell surfaces, binds G-CSF and transmits signals that promote granulocyte production.
• Truncated Mutants: Mutations leading to truncated forms of CSF3R can cause constitutive activation of signaling pathways and are often observed in myeloid malignancies.

Function and Biological Significance

The main function of CSF3R is to mediate the effects of G-CSF on myeloid progenitor cells, driving the production, differentiation, and function of neutrophils and granulocytes. Key roles include:

Regulation of Granulocyte Production:

• The G-CSF-CSF3R signaling axis is central to granulopoiesis. Binding of G-CSF to CSF3R triggers receptor dimerization, leading to activation of downstream signaling cascades that promote the survival, proliferation, and differentiation of granulocyte progenitors.
• This process is critical for maintaining appropriate neutrophil counts and ensuring an effective immune response to bacterial infections.

Activation of Signaling Pathways:

• Binding of G-CSF to CSF3R activates JAK2, which phosphorylates specific tyrosine residues on the intracellular domain, creating docking sites for STAT3 and STAT5. Phosphorylated STAT proteins translocate to the nucleus to induce the expression of genes necessary for granulocyte differentiation and survival.
• Additional pathways activated include PI3K-AKT, which supports cell survival, and MAPK/ERK, which influences cell proliferation and maturation.

Response to Infection and Inflammation:

• G-CSF and CSF3R expression can be upregulated during infection or inflammation, leading to increased granulocyte production. This response ensures a rapid and effective immune response by mobilizing neutrophils to combat pathogens.

Stem Cell Mobilization:

• G-CSF-CSF3R signaling is involved in the mobilization of hematopoietic stem cells (HSCs) from the bone marrow to the peripheral blood. This effect is harnessed clinically to collect stem cells for transplantation.

Clinical Issues

Mutations and dysregulation of CSF3R are linked to a range of hematological disorders:

Severe Congenital Neutropenia (SCN):

• Mutations in CSF3R, often truncating mutations, are common in patients with SCN, a disorder characterized by an inability to produce adequate neutrophils. SCN patients are prone to recurrent infections and, over time, some may develop leukemia.
• CSF3R mutations contribute to neutropenia by impairing normal receptor function or causing abnormal signaling patterns that disrupt granulocyte production.

Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML):

• Gain-of-function mutations in CSF3R have been observed in certain cases of MDS and AML, where they drive abnormal myeloid cell proliferation. In AML, CSF3R mutations lead to constitutive signaling that promotes leukemic cell survival and proliferation.
• CSF3R mutations are particularly common in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML), where they often represent driver mutations that can contribute to leukemic transformation.

Cytokine Receptor-Like Factor 3 (CRLF3) Syndrome:

• CSF3R mutations in combination with mutations in other cytokine receptors may predispose individuals to multi-lineage hematological disorders and immune dysregulation syndromes. These mutations can lead to aberrant hematopoiesis, resulting in disorders that impact multiple blood cell lineages.

Therapeutic Resistance:

• CSF3R mutations in AML and other myeloid malignancies can confer resistance to standard therapies, complicating treatment strategies. For instance, mutations in CSF3R that lead to activation of alternative signaling pathways, such as the RAS-MAPK pathway, can result in resistance to JAK inhibitors, which are otherwise effective in JAK-STAT-driven diseases.
• Understanding CSF3R mutation status can therefore be crucial for selecting effective treatment regimens and for the development of targeted therapies.

Use in G-CSF Therapy:

• Recombinant G-CSF is used clinically to treat neutropenia, particularly in cancer patients undergoing chemotherapy. Patients receiving G-CSF therapy require intact CSF3R signaling for optimal response. Understanding the receptor’s structure and function is critical for assessing patient response to G-CSF therapy and for managing conditions like SCN.

Summary

CSF3R, or the granulocyte colony-stimulating factor receptor, is a cytokine receptor critical to neutrophil production and the immune response. Structurally, CSF3R is a transmembrane receptor with extracellular domains for G-CSF binding, a transmembrane domain anchoring it in the membrane, and an intracellular domain for signaling. CSF3R activates the JAK-STAT, PI3K-AKT, and MAPK/ERK pathways, promoting granulocyte differentiation and function.

Mutations in CSF3R are implicated in severe congenital neutropenia, certain leukemias, and myeloid malignancies, where they drive abnormal cell proliferation and survival. CSF3R is also central to G-CSF therapy in neutropenic patients and plays a key role in hematopoietic stem cell mobilization. Understanding CSF3R structure, function, and associated mutations is crucial for managing hematological disorders and optimizing therapeutic strategies.