Arrays or single kringles of plasminogen (Pig), (eg; K1-4 K5) display anti-angiogenic activity. Proteolytic mechanisms for the generation of angiostatin (AS) implicate elastases, macrophage metalloproteinases and plasmin. These methods require incubation for at least Ih at 37 °C with protease. Since circulating inhibitors (a2antiplasmin) will inhibit plasmin rapidly, the autocatalysis of Pig to AS in solution phase is unlikely to be physiologically relevant. Here, we describe a mechanism for rapid processing of Pig to kringle fragments which requires lysinedependent binding and conformational changes on receptors, (e.g., aenolase)' or cancer cell surfaces with high pig and uPA binding capacity2. Cell-surface bound Pig was efficiently activated to plasmin and subsequently processed by plasmin into an array kringle containing fragments. The K1-4 domain was released from cells within 30 sec of addition of Pig, with complete auto-digestion within 5 min. Other proteases known to cleave Pig, such as porcine pancreatic elastase, also rapidly generated AS from receptor-bound Pig. We hypothesise that the rate-limiting step for the in vivo generation of AS is lysine-dependent Pig conformational changes induced by cellsurface binding.