for the uPAR (urokinase receptor) binding domain; while the zfuPA-b lacks two cysteines of the epidermal growth factor-like domain. zfuPA-b also has no binding activity in fish white blood cells or fish cell lines. The uPAR binding in mammalian system is essential for the activity of urokinase and uPAR as it also functions as an adhesion receptor due to its affinity to vitronectin, integrins and other proteases like PAI-1. The lack of the uPAR binding region in zebrafish uPA, suggests that zebrafish uPA functions without uPAR binding. Interaction partners The most important inhibitors of urokinase are the serpins plasminogen activator inhibitor-1 (PAI-1) and plasminogen activator inhibitor-2 (PAI-2), which inhibit the protease activity irreversibly. In the extracellular matrix, urokinase is tethered to the cell membrane by its interaction to the urokinase receptor. uPa also interacts with protein C inhibitor. zfuPA-a and zfuPA-b are poor activators of human plasminogen, while human uPA is a poor activator of salmon plasminogen. With the primary difference between the zebrafish uPA and human uPA being in the EGF domain. Urokinase and cancer Elevated expression levels of urokinase and several other components of the plasminogen activation system are found to be correlated with tumor malignancy. It is believed that the tissue degradation following plasminogen activation facilitates tissue invasion and, thus, contributes to metastasis. Urokinase-type plasminogen activator (uPA) is more commonly associated with cancer progression than tissue plasminogen activator (tPA). This makes uPA an attractive drug target, and, so, inhibitors have been sought to be used as anticancer agents. However, incompatibilities between the human and murine systems hamper clinical evaluation of these agents. Moreover, urokinase is used by normal cells for tissue remodeling and vessel growth, which necessitates distinguishing cancer-associated urokinase features for specific targeting. uPA breakdown of the extracellular matrix is crucial for initiating the angiogenesis which is associated with cancer growth. uPA antigen is elevated in breast cancer tissue, which correlates with poor prognosis in breast cancer patients. For this reason, uPA can be used as a diagnostic biomarker in breast cancer. Through its interaction with the urokinase receptor, urokinase affects several other aspects of cancer biology such as cell adhesion, migration, and cellular mitotic pathways. As of December 7, 2012, Mesupron (upamostat), a small molecule serine protease inhibitor developed by the WILEX pharmaceutical company, has completed phase II trials. Mesupron appears to be safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival in