Regulated localization confers multiple functions on the protease urokinase plasminogen activator

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• The plasminogen activation cascade is crucial in various physiological processes.
• Its specific role in skeletal muscle differentiation, particularly concerning myoblast migration and fusion, remains incompletely understood.
• Urokinase plasminogen activator (uPA) and its receptor (uPAR) are key components of this cascade.

Purpose of the Study:

• To investigate the function of the plasminogen activation cascade in skeletal muscle differentiation.
• To elucidate the distinct roles of cell-surface versus soluble urokinase plasminogen activator (uPA) in myogenesis.

Main Methods:

• Studied myoblast cultures during differentiation.
• Utilized non-catalytic uPA (NC-uPA) to block uPA-uPAR interaction.
• Employed protease inhibitors (aprotinin, alpha2-antiplasmin, PAI-1) to inhibit soluble uPA/plasmin activity.
• Assessed effects on myoblast migration and differentiation.

Main Results:

• Migrating myoblasts express cell-surface uPA/uPAR, and blocking this interaction inhibits migration and differentiation.
• During differentiation, uPAR is downregulated, and uPA redistributes to the extracellular space.
• Inhibition of soluble uPA/plasmin by protease inhibitors stimulates myoblast differentiation.
• Aprotinin's ability to inhibit latent TGF-beta activation suggests a mechanism for differentiation stimulation.

Conclusions:

• Regulation of urokinase plasminogen activator (uPA) localization dictates its dual role in skeletal muscle development.
• Cell-associated uPA hinders myoblast differentiation, while soluble uPA promotes it.
• The plasminogen activation cascade is a critical regulator of myogenesis through spatial control of uPA activity.