Drug targets for Cancer: SIRPα

Drug Targets for Cancer: SIRPα and Cancer

Signal regulatory protein alpha (SIRPα) is a transmembrane receptor composed of 3 immunoglobulin-like domains in its extracellular region and an intracellular domain containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) which recruit and activate SHP-1 and SHP-2. SIRPα is predominantly expressed on myeloid and neuronal cells and its activation has been implicated in regulation of different cellular functions such as adhesion, migration, growth and differentiation. Despite restricted expression of SIRPα, CD47, the natural ligand for SIRPα, is ubiquitously expressed and interacts with the SIRPα extracellular region. This interaction results in inhibition of phagocytosis by macrophages through tyrosine phosphatase activation and inhibition of myosin accumulation. CD47 functions as a "don't eat me" signal and plays a key role in the programmed cell removal of abberant versus normal cells. Indeed, it was recently shown that CD47 is overexpressed on AML leukemic stem cells as compared to their normal counterparts (hematopoietic stem cells) and this contributes to inhibition of phagocytosis and clearance of LSCs. In addition, blocking antibodies directed against CD47 promoted phagocytosis as suggested through disruption of CD47-SIRPα interaction and this enhanced tumor clearance in vivo. These findings are in line with several studies, which reported elimination of cancer cells by employment of CD47 blocking antibodies.

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Drug Targets for Cancer: SIRPα Related Reference

Irandoust M, Alvarez Zarate J, Hubeek I, et al. Engagement of SIRPα Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells. Roberts DD, ed. PLoS ONE. 2013;8(1):e52143.

Drug Targets for Cancer: SIRPα Related Information