Urokinase plasminogen activator

Urokinase plasminogen activator (uPA), also known as urokinase, is a serine protease involved in the degradation of the extracellular matrix and in the process of cell migration and tissue remodeling. It plays a critical role in the physiological and pathological fibrinolysis, the process that dissolves blood clots. Urokinase converts plasminogen to plasmin, a major enzyme responsible for clot breakdown. This enzyme is produced by the kidneys and found in the urine, but it is also present in several other tissues and body fluids.

Function

Urokinase plasminogen activator is part of the plasminogen activator system, which includes tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), and plasminogen activator inhibitor-2 (PAI-2). The primary function of uPA is to activate plasminogen to plasmin, leading to the degradation of fibrin, a key component of blood clots. Beyond its role in fibrinolysis, uPA is involved in wound healing, angiogenesis (the formation of new blood vessels), and the spread of cancer cells by breaking down the extracellular matrix, facilitating tumor invasion and metastasis.

Structure

Urokinase plasminogen activator is synthesized as a single-chain precursor (pro-uPA) which is then cleaved into an active two-chain form. The enzyme consists of an A-chain and a B-chain, connected by a disulfide bond. The A-chain contains the growth factor domain, which binds to the uPA receptor (uPAR), and the B-chain contains the serine protease domain, responsible for its enzymatic activity.

Clinical Significance

Urokinase has been used clinically as a thrombolytic agent to treat severe or life-threatening blood clots, including pulmonary embolism and myocardial infarction. However, its use has been somewhat overshadowed by tissue plasminogen activator (tPA) due to tPA's higher specificity for fibrin-bound plasminogen.

In cancer, high levels of uPA and its receptor uPAR have been associated with increased tumor aggressiveness and a poor prognosis in various types of cancer, including breast, lung, and colorectal cancers. This has led to the development of therapeutic strategies aimed at inhibiting the uPA system to prevent cancer progression.

Therapeutic Applications and Research

Research into uPA has focused on its potential therapeutic applications beyond thrombolysis. This includes its role in cancer therapy, either by targeting uPA directly to inhibit cancer cell invasion and metastasis or by using uPA inhibitors to prevent tumor growth and spread. Additionally, because of its role in wound healing and tissue remodeling, uPA has been studied for its potential in treating chronic wounds and fibrotic diseases.

See Also

• Plasminogen
• Fibrinolysis
• Serine protease
• Extracellular matrix
• Angiogenesis