FIGURE 7.

Working model for feedback regulation of endothelial cell surface plasmin generation. Endothelial cell surface (A2·p11)₂ tetramer promotes plasmin generation by local assembly of t-PA and plasminogen. Plasmin cleaves surface A2 within its N terminus at lysine 27, separating it from p11 and preventing further plasmin generation. A2 remains bound to membrane phospholipids through its C-terminal core domain. Association of modified A2 with TLR4 activates phosphatidylinositol-specific phospholipase C (PLC), leading to hydrolysis of phospholipids and generation of second messengers, inositol 1,4,5-trisphosphate (IP₃) and diacylglycerol (DAG). Inositol 1,4,5-trisphosphate triggers mobilization of intracellular Ca²⁺, whereas diacylglycerol serves as a cofactor for activation of cPKC. Activation of cPKC leads to dual serine phosphorylation of A2 at residues 11 and 25. Free p11 subsequently dissociates from serine phosphorylated A2, becomes ubiquitinated, and is degraded by the proteasome. In addition, tyrosine phosphorylation of A2 at residue 23 is inhibited, preventing translocation of A2 to the cell surface and inhibiting further plasmin generation. PIP₂, phosphatidylinositol 4,5-bisphosphate.