Complement receptor 3 (CR3) is a heterodimer of α (CD11b) and β (CD18) transmembrane glycoproteins. While the α-chain is unique to CR3, the β subunit is shared by LFA1, CR4, and αdβ2, all belonging to the β2 integrin leukocyte receptor family. CR3 is mainly expressed on macrophages, monocytes, granulocytes, and NK cells, playing a role in cell-cell and cell-matrix interactions. It enables the establishment of leukocyte adherence to the endothelium and facilitates movement of leukocytes through the endothelial intercellular junctions. CR3 is also involved in phagocytosis, cellular killing by oxidative burst, and it regulates homeostasis of inflammation by mediating apoptosis of extravasated neutrophils. The multiple activities of CR3 depend upon its ability to interact with a wide variety of ligands, such as iC3b, fibrinogen, ICAM-1, ICAM-2, zymosan, LPS, factor X, haptoglobin, and oligodeoxynucleotides.
A dynamic regulation of CR3 function allows rapid on and off switches of receptor adherence to some of its ligands. Such modifications in CR3 occur following activation of other cell surface molecules, such as selectins and receptors for chemoatractants and cytokines. These receptors transmit signals into the cell, leading to conformational changes in CR3 that convert it to an active adhesive form (“inside-out” signaling). In its active form, CR3 can bind specific ligands, which, in turn, induce a cascade of “outside-in” signaling events. Recent data suggest that CR3 can also transmit signals emanating at glycosylphosphatidylinositol (GPI)-linked proteins such as FcγRIIIB, CD14 (receptor for LPS), and urokinase plasminogen activator receptor (uPAR). It was speculated that these GPI-anchored proteins, which are devoid of a transmembrane domain, trap the ligand while floating in the membrane lipid bilayer and transmit inflammation signals via coassociated CR3 molecules. Accordingly, CR3 has been termed a public transducer.
Even though complement receptor 3 (CR3) is a bidirectional signaling molecule, its α- and β-chains possess short cytoplasmic domains (22 and 46 amino acids, respectively) devoid of an intrinsic catalytic activity. Cumulative evidence suggests that CR3 signaling is mediated either via other cell surface receptors, such as FcγRII, or through intracellular molecules, such as cytoskeleton-associated proteins, acting as initiators of the signaling cascade.
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