urokinase plasminogen activator signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals initiated by urokinase plasminogen activator binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. [GOC:gap, PMID:9417082]

The urokinase plasminogen activator (uPA) signaling pathway is a complex cascade of events initiated by the binding of uPA to its receptor, uPAR (urokinase plasminogen activator receptor), on the cell surface. This interaction triggers a series of downstream events, ultimately leading to the activation of plasminogen, a zymogen, into its active form, plasmin. Plasmin, in turn, plays a critical role in various physiological and pathological processes, including fibrinolysis, cell migration, and tissue remodeling.

Here's a detailed description of the pathway:

1. **uPA Binding and Receptor Activation:** uPA, a serine protease, binds to uPAR, a glycosylphosphatidylinositol (GPI)-anchored protein residing on the cell surface. This binding event triggers conformational changes in uPAR, exposing its binding sites for other proteins, including vitronectin, a component of the extracellular matrix.

2. **Formation of the uPA-uPAR-Vitronectin Complex:** The uPA-uPAR interaction promotes the recruitment of vitronectin, a protein that binds to uPAR and stabilizes the uPA-uPAR complex. This complex further enhances uPA activity and facilitates its association with plasminogen.

3. **Plasminogen Activation:** uPA, bound to its receptor, efficiently converts plasminogen, a zymogen, into its active form, plasmin. Plasminogen activation occurs through the proteolytic cleavage of plasminogen, releasing active plasmin.

4. **Downstream Effects of Plasmin:** Plasmin, a broad-spectrum serine protease, exerts diverse physiological functions. It primarily acts as a fibrinolytic agent, breaking down fibrin clots and promoting tissue remodeling. Plasmin also activates other proteases, such as matrix metalloproteinases (MMPs), contributing to tissue degradation.

5. **Regulation of uPA Activity:** The uPA signaling pathway is tightly regulated by several mechanisms, including:
- **PAI-1 (plasminogen activator inhibitor-1):** PAI-1 is a potent inhibitor of uPA, directly binding to it and blocking its activity.
- **uPAR Degradation:** uPAR can be internalized and degraded via endocytosis, reducing the availability of the receptor for uPA binding.
- **Proteolytic Cleavage of uPA:** uPA can be cleaved by other proteases, leading to its inactivation.

6. **Implications in Disease:** Dysregulation of the uPA signaling pathway has been implicated in various disease states, including:
- **Cancer:** Increased uPA activity contributes to tumor invasion and metastasis by facilitating the degradation of the extracellular matrix.
- **Cardiovascular Disease:** Excessive uPA activity can contribute to thrombosis and atherogenesis by disrupting fibrinolysis.
- **Wound Healing:** Abnormal uPA activity can impair wound healing by affecting cell migration and tissue remodeling.

The uPA signaling pathway is a critical regulator of extracellular matrix remodeling and plays a pivotal role in various physiological and pathological processes. Its intricate regulation and diverse downstream effects make it an important target for therapeutic intervention in a range of diseases.'
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Proteins (1)

Compounds (50)