Colony-stimulating factor 1 receptor (CSF1R) Y969C mutant (CSF1R Y969C)

The Colony-stimulating factor 1 receptor (CSF1R), also known as FMS, is a type III receptor tyrosine kinase that plays a pivotal role in the survival, proliferation, and differentiation of the mononuclear phagocyte lineage, including macrophages and osteoclasts (UniProt: P07333). The Y969C mutation is a specific amino acid substitution located in the C-terminal regulatory tail of the receptor. In the wild-type protein, Tyrosine 969 serves as a docking site for the E3 ubiquitin ligase c-Cbl upon phosphorylation; this interaction facilitates receptor ubiquitination and subsequent lysosomal degradation, acting as a critical negative feedback loop (PubMed: 8144878). The Y969C mutation abolishes this regulatory site, preventing c-Cbl recruitment and leading to impaired receptor turnover and prolonged activation of oncogenic signaling cascades like the MAPK and PI3K pathways (PubMed: 1561438). This mutation is associated with increased transforming potential in myeloid cells and has been implicated in the pathogenesis of various malignancies. Therapeutic strategies targeting this mutant involve small-molecule tyrosine kinase inhibitors, such as pexidartinib, which block the ATP-binding site of the receptor to inhibit its catalytic activity and downstream signaling (PubMed: 31361488). Clinical management of patients with CSF1R-driven diseases requires monitoring for specific toxicities, most notably hepatotoxicity, which is a known risk of potent CSF1R inhibitors.

Other names

FMSMacrophage colony-stimulating factor receptorM-CSFRCD115Proto-oncogene c-Fms

Tyrosine kinase inhibition