Macrophage Colony-Stimulating Factor Receptor (M-CSF R), also known as Colony Stimulating Factor 1 Receptor (CSF1 R) and CD115, is a cell-surface protein that serves as a receptor for the cytokines M-CSF and IL-34. It is a member of the type III subfamily of receptor tyrosine kinases. Human M-CSF R/CD115 is 972 amino acids (aa) in length with a predicted molecular weight of approximately 108 kDa, and shares 60% and 64% aa sequence identity with the mouse and rat orthologs, respectively. It is a type I membrane protein with a 19 aa signal peptide, a 493 aa extracellular domain (ECD) containing the ligand-binding domain and five immunoglobulin-like domains, a 25 aa transmembrane region, and a 435 aa cytoplasmic domain (ICD). M-CSF R/CD115 undergoes proteolytic processing at at least two different sites. TACE/ADAM17 cleaves M-CSF R/CD115 in its ECD, resulting in the shedding of the functional ligand-binding ECD. M-CSF R/CD115 can also be cleaved in its transmembrane region. This processing releases the ICD into the cytosol, where it moves into the nucleus and regulates gene transcription.
Ligand binding to M-CSF R/CD115 induces receptor homodimerization and transphosphorylation. The phosphorylated intracellular domain then binds to a multitude of proteins that influence cell proliferation, survival, and differentiation, and cytoskeletal reorganization. M-CSF R/CD115 is expressed primarily on cells of the monocyte/macrophage lineage, including microglia, dendritic cells, stem cells, and cells in the developing placenta. It is required for macrophage survival and regulates lineage decisions and maturation of these cells. Overactivation of M-CSF R/CD115 has been shown to lead to a malignant phenotype in different cell types. Additionally, it has been suggested that activated M-CSF R/CD115 is a predictor of poor outcome in several cancers including breast and ovarian. M-CSF R/CD115 expression has also been shown to be increased in microglia in brains afflicted with Alzheimer's disease and following injury.
