d/kiko2011/anatomíapatológica san juan preparación clases/patología general 2014 1/clases-teoría/quinta clase

Urokinase

plasminogen activator, urokinase

Locus Chr. 10 q24

Urokinase, also called urokinase-type plasminogen activator (uPA), is a serine

protease (EC 3.4.21.73). It was discovered in 1947 by McFarlane.[1] Urokinase was
originally isolated from human urine, but is present in several physiological locations,
such as blood stream and the extracellular matrix. The primary physiological substrate
is plasminogen, which is an inactive form (zymogen) of the serine protease plasmin.
Activation of plasmin triggers a proteolysis cascade that, depending on the physiological
environment, participates in thrombolysis or extracellular matrix degradation. This links
urokinase to vascular diseases and cancer.
Molecular characteristics
Urokinase is a 411-residue protein, consisting of three domains: the serine protease
domain, the kringle domain, and the growth factor domain. Urokinase is synthesized as
a zymogen form (prourokinase or single-chain urokinase), and is activated by proteolytic
cleavage between Lys158 and Ile159. The two resulting chains are kept together by a
disulfide bond.
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.

1
Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.
The molecular weight of (high molecular weight) urokinase is about 54000 Daltons. Only
the Abbokinase = low molecular weight urokinase has a molecular weight of about
31000 Daltons.
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. This makes urokinase an attractive drug target, and, so, inhibitors have been sought
to be used as anticancer agents.[2][3] However, incompatibilities between the human and murine
systems hamper clinical evaluation of these agents. Through its interaction with the urokinase
receptor, urokinase affects several other aspects of cancer biology such as cells adhesion,
migration, and cellular mitotic pathways.
As of December 7, 2012 Mesupron®, a small molecule serine protease inhibitor developed by
the WILEX pharmaceutical company, has completed phase II trials.[4] Mesupron appears to be
safe when combined with chemotherapeutic drug Capecitabine for the progression-free survival
in human breast cancer.[5]
Clinical applications
Urokinase is used clinically as a thrombolytic agent in the treatment of severe or massive deep
venous thrombosis, pulmonary embolism, myocardial infarction, and occluded intravenous or
dialysis cannulas. It is also administered intrapleurally to improve the drainage of complicated
pleural effusions and empyemas. Urokinase is presently marketed as KinlyticTM, and competes
with AlteplaseTM as a thrombolytic drug in infarction. It is the most effective drug in myocardial
infarction. In contrast to TPA tissue plasminogen activator it immediately removes the clot. Its
injection is very costly.