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.
FAP (Fibroblast activation protein), previously known as F19 cell surface antigen, is a cell surface serine protease with an extracellular catalytic domain. This type II membrane protease belongs to a prolyl-cleaving peptidase family. It is an endopeptidase with weak dipeptidase activity and the physiological substrate of FAP is α2-antiplasmin (α2-AP). FAP is expressed at sites of tissue remodeling during embryonic development and selectively produced in the stromal fibroblasts related to epithelial cancer. And FAP just has low or undetectable expression in the resting fibroblasts of the normal tissue in adults. Diseases linked to FAP include infiltrative basal cell carcinoma, hemophagocytic lymphohistiocytosis, and so on. It is reported that FAP support the tumor growth and proliferation, which makes it a novel target for anticancer therapies.