Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

Figure 4

Integrins. Integrins are transmembrane glycoprotein adhesion receptor complexes consisting of α and β subunits. The α subunit contains a seven-bladed β-propeller head domain connected to a leg support structure made of a thigh, a calf-1, a calf-2, a transmembrane, and a cytoplasmic domain that mediates ligand specificity. The β subunit contains an N-terminal plexin-semaphorin-integrin (PSI) domain, a hybrid domain, a β-I domain, four cysteine-rich epidermal growth factor (EGF) repeats, a transmembrane, and a cytoplasmic domain that interacts with the cell cytoskeleton. The N-terminal β-I domain of a β subunit inserts into the β-propeller domain of an α subunit forming a headpiece complex. The formation of integrin receptor complexes depends on divalent cation (i.e., Ca²⁺, Mn²⁺, Mg²⁺) that bind to metal-ion-dependent adhesion site (MIDAS) motifs in the α subunits and adjacent to MIDAS (ADMIDAS) motifs in β subunits. Three conformation states exist for α and β subunit complexes. (1) The unliganded conformation has a closed headpiece and a bent receptor structure with the EGF domains of the β-subunit touching the calf-1-calf-2 domains of the α-subunit. (2) The headpiece remains closed, but structural changes in the β-subunit EGF domains cause a separation from the calf-1-calf-2 domains of the α-subunits causing an extended structure. (3) Conformational changes in the β ₆-α ₇ loops expose the ligand-binding site along with a complete separation of the β-subunit from the calf-1-calf-2 domains in the α-subunit. These conformational changes engage the specific integrin headpiece with its ligand.