About Colony-Stimulating Factor Receptors G-CSFR, M-CSFR, and GM-CSFR
Granulocyte Colony-Stimulating Factor Receptor, Macrophage Colony-Stimulating Factor Receptor, and Granulocyte Macrophage Colony-Stimulating Factor Receptor are members of a family of transmembrane receptors that play a key role in immune regulation and myeloid cell function making them attractive targets for drug discovery. In this post, we will look at their function, role in various disease states, and implications for targeting these receptors for drug discovery and development.
Colony Stimulating Factor Receptors G-CSFR, M-CSFR, and GM-CSFR are expressed primarily in myeloid cells and induce cell differentiation, proliferation, survival, and mobilization of these cells into the blood. Upon ligand binding, G-CSFR and M-CSFR form a homodimer, whereas GM-CSFR forms a heterodimer with ligand-specific alpha and beta subunits. G-CSFR and GM-CSFR rely upon adaptor proteins, Janus Kinases (JAKs), and Signal Transducer and Activators of Transcription (STATs) for downstream activation, whereas M-CSFR relies on signaling cascades that include the RAS-MAPK pathways. Myeloid cells are important because they are the precursors to a variety of innate immune cell types (e.g., monocytes, basophils, eosinophils, neutrophils, dendritic cells, or macrophages). Together through these three CSFR’s it becomes possible to exert potential control over the entire landscape of phagocytes. This makes the CSF family of receptors of particular interest in a variety of cancers and immune-related disorders.
Colony-Stimulating Factor Receptor Roles in Disease
Colony Stimulating Factor Receptors G-CSFR, M-CSFR, and GM-CSFR are implicated in a wide variety of disease states related to cancer and inflammation. In cancer, for example, mutations of G-CSFR are associated with acute myeloid leukemia and atypical chronic myelogenous leukemia.1 In cancer progression, GM-CSFR and M-CSFR act as a double-edged sword since they stimulate the production and maturation of macrophages and dendritic cells that mediate the host response to cancer.2 Too little of this activity, and not enough immune cells are produced. However, too much activity may lead to immune exhaustion and promote cancer progression.
In disorders related to inflammation, antibody blockage of G-CSFR is shown to protect against rheumatoid arthritis in animal models, with G-CSF/G-CSFR deficient mice having been shown to be profoundly protected from the disease.3 In addition, G-CSFR is associated with hidradenitis suppurativa, a chronic inflammatory skin condition.4 M-CSFR inhibition has been shown to reduce inflammation associated with rheumatoid arthritis, while GM-CSF stimulates the activation and subsequent migration of myeloid cells to sites of inflammation. In the brain, M-CSF is secreted primarily by microglia, the resident immune cells of the brain known to eliminate toxic elements. Low level M-CSF/M-CSFR expression or receptor inhibition in microglia has been associated with pre-symptomatic Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS) and frontotemporal dementia.5,6,7. In addition, an imbalance in GM-CSF production and signaling has been associated with autoimmune diseases like multiple sclerosis (MS), rheumatoid arthritis (RA), myasthenia gravis (MG), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE).8,9
Colony-Stimulating Factor Receptors in Drug Discovery
Colony Stimulating Factor Receptors G-CSFR, M-CSFR, and GM-CSFR are targets for a wide variety of drug discovery therapies for cancer and inflammation-related disorders. For example, G-CSF is often used after chemotherapy treatments to help protect a patient from post-treatment infections or for patients receiving stem cell treatments. M-CSF has shown promise in tissue repair and is used after bone marrow transplantation or chemotherapies to stimulate white blood cell regeneration. M-CSF treatment is also a therapeutic target for neurological disorders such as Alzheimer’s Disease (AD). GM-CSF plays a role in therapies that speed white blood cell recovery following bone marrow transplants. GM-CSF is known to be associated with autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS). It may also contribute to lung inflammation in severe cases of COVID-19 pneumonia.
INDIGO’s Colony-Stimulating Factor Receptor Assays
INDIGO Biosciences offers cell-based luciferase reporter assays for the human Colony-Stimulating Factor Receptors G-CSFR, GM-CSFR, and M-CSFR, allowing scientists to screen compound candidates that may be used to treat diseases related to these receptors. INDIGO assays use firefly luciferase reporter gene technology. Since the receptor binding controls the expression of the luciferase reporter gene, luciferase activity in the cells can be correlated directly with the activity of the receptor. These assays allow researchers to examine compounds for their ability to activate or inhibit CSFR activity, and INDIGO’s extensive catalog of receptor assays allow for screening of potential off-target effects such as drug-drug/drug-nutrient interactions and cellular toxicity.
INDIGO’s all-inclusive assay kits eliminate weeks of cell-culture work while providing superior sensitivity and reproducible results and contain all supplies and reagents needed to perform the assay including cryo-preserved reporter cells, optimized media for use during cell culture and in diluting the test samples, a reference agonist, luciferase detection reagent, and a cell culture-ready assay plate. We can also run the assays in our own lab as a screening service for researchers.
Contact us today to learn more about our CSFR assay kits and screening capabilities!
