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.
PSCA (Prostate stem cell antigen) is a cell surface protein of Thy-1/Ly-6 family anchored by a glycosylphosphatidylinositol (GPI) linkage. It is located on chromosome 8q24.2 and encodes a 123-aa glycoprotein with an N-terminal signal sequence, a C-terminal GPI-anchoring sequence, and multiple N-glycosylation sites. PSCA shares 30% homology with a surface marker of immature lymphocytes, called stem cell antigen type 2 (SCA-2). Just as SCA-2, PSCA is attached to the cell membrane that can be separated by a GPI-specific phospholipase. In humans, PSCA is highly expressed in the basal and secretory epithelial cells of the normal prostate and also detected in placenta, bladder, stomach, colon, and weakly in the kidney. It is up-regulated in some cancers and is found in more than 80% of prostate carcinomas.