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.
PSMA (Prostate-specific membrane antigen, also known as Glutamate carboxypeptidase II (GCPII) or N-acetyl-L-aspartyl-L-glutamate peptidase I (NAALADase I)), is a type II transmembrane zinc metallopeptidase and is encoded in humans by the folate hydrolase 1 (FOLH1) gene. Human PSMA contains 750 amino acids and weighs around 84 kDa. The PSMA protein has a 3-part structure involving a 19-amino-acid internal portion, a 24-amino-acid transmembrane portion and a 707-amino-acid external portion. PSMA is a unique transmembrane glycoprotein over-expressed manifold on prostate cancer and neovasculature of most of the solid tumors, but not in the vasculature of the normal tissues. This specific expression of PSMA thereby makes it an important biomarker in the majority of prostate cancers.