Figure 1: Regulation of cellular plasmin generation by S100A10. Normal cells and cancer cells utilize the plasminogen receptor, S100A10 (p11), for cell surface plasmin generation. The predominant form of S100A10 at the cell surface is as the heterotetramer, AIIt which consists of two copies of the annexin A2 (p36) and a S100A10 homodimer. The model shows one-half of this heterotetrameric complex. Annexin A2 acts as a regulatory subunit which utilizes its phospholipid-binding sites to anchor S100A10 to the cell surface. S100A10 binds tPA and plasminogen (Pg) at its carboxyl-terminal lysine residue. It is unclear if one molecule of AIIt can bind both tPA and plasminogen at each of the binding sites on the antiparallel S100A10 monomers or if each molecule of AIIt can only bind two molecules of tPA or two molecules of plasminogen at the S100A10 monomers. The localization of tPA and plasminogen in close proximity promotes the rapid conversion of plasminogen to plasmin (Pm) by tPA. Plasmin binds to both annexin A2 and S100A10 at sites distinct from the plasminogen-binding site. The protease, urokinase-type plasminogen activator (uPA), is secreted from cells in its inactive, zymogen form called pro-uPA. Pro-uPA is converted to uPA by several proteases including plasmin. The uPA/uPAR complex colocalizes with the AIIt where uPA cleaves the S100A10-bound plasminogen, generating plasmin. Plasmin cleaves and activates promatrix metalloproteases (MMPs), procathepsin B (pro-CB), and pro-uPA. Plasmin, MMPs, and cathepsin B degrade many extracellular matrix (ECM) proteins and both release and activate growth factors from the ECM via proteolysis. Increased cell surface concentration of uPA or pro-uPA (by binding to its receptor, uPAR) and plasmin or plasminogen (by binding to S100A10) accelerates their reciprocal activation and focuses plasmin proteolytic activity to the cell surface.