Signal regulatory protein alpha (SIRPα) is a transmembrane glycoprotein belonging to the immunoglobulin (Ig) superfamily. Its extracellular region comprises three Ig-like domains-a ligand-binding N-terminal V-type domain followed by two C1-type domains-that mediate interactions with CD47, a broadly expressed "don't eat me" ligand. The single-pass transmembrane domain anchors the protein, while the cytoplasmic tail contains two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and an ITSM motif. These motifs recruit SHP-1 and SHP-2 phosphatases upon tyrosine phosphorylation, enabling downstream inhibitory signaling.
Predominantly expressed on myeloid cells, including macrophages and dendritic cells, SIRPα functions as a critical immune checkpoint by transmitting inhibitory signals via CD47 engagement. This interaction suppresses phagocytic activity and maintains self-tolerance under physiological conditions. Recent studies reveal SIRPα's polymorphic nature in human populations, particularly in extracellular V-domain residues, though these variations do not alter CD47 binding affinity, suggesting evolutionary pressures unrelated to ligand interaction. Beyond myeloid cells, SIRPα exhibits context-dependent expression in neurons and endothelial cells. In thymic portal endothelial cells, SIRPα-CD47 signaling activates ITIM-SHP2-Src pathways, promoting VE-cadherin endocytosis to facilitate hematopoietic progenitor cell transmigration and subsequent T-cell development. Therapeutically, SIRPα blockade disrupts CD47 signaling, enhancing macrophage-mediated tumor phagocytosis and synergizing with adaptive immune responses.
MUC1 (Mucin 1, cell surface associated), also referred to tumor-associated epithelial membrane antigen, EMA, MCD or CD227, is a 122 kDa single-pass type I transmembrane protein mapping at the chromosome 1q22. It is generally expressed on glandular or luminal epithelial cells of the mammary gland, stomach, esophagus, duodenum, pancreas, prostate, uterus, and lungs, and lesser in hematopoietic cells, but absent in the skin epithelium and mesenchymal cells. MUC1 gene coding for a membrane-bound protein, a member of the mucin family, is an O-glycosylated protein that functions in forming protective mucous barriers on epithelial cell surfaces. And they also play a part in intracellular signaling. Abnormally glycosylated MUC1 is overexpressed in most human epithelial cancer cells and has been regarded as an oncogenic molecule.