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.
MET, also known as c-MET or HGFR (Hepatocyte growth factor receptor), is a transmembrane tyrosine kinase receptor that is encoded in humans by the MET gene. This receptor in charge of tyrosine-kinase activity is mapped at the chromosome 7q31.2 with 1408 amino acids. MET and its ligand HGF/SF (Hepatocyte growth factor/Scatter factor) are expressed in many tissues, principally in epithelial and mesenchymal origin cells, respectively. After binding to ligands, this tyrosine-protein kinase is rapidly internalized, polyubiquitinated and then degraded in a proteasome-dependent manner. MET is over-expressed in numerous types of neoplasms, such as tumors of the kidney, pancreas, thyroid and osteosarcoma. And it is reported that various mutations of MET gene are correlated with papillary renal carcinomas.