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.
HER2 (Human epidermal growth factor receptor 2), also known as ERBB2, CD340 (cluster of differentiation 340), proto-oncogene Neu, is a membrane tyrosine kinase and has strongest catalytic kinase activity in HER family. Among four HER family proteins, HER2 functions as the most active signaling complex after dimerization with other members. It is encoded by the oncogene ERBB2, which is located at the human chromosome 17q12. HER2 participates in normal cell growth and found on some types of cancer cells. Its amplification is the major pathway causing HER2 receptor overexpression. HER2 is amplified in approximately 15%-20% of breast cancers and functions as the primary driver in breast tumor development and progression. The overexpressed HER2 is regarded as a valuable target in clinic therapeutics.