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Thrombin-activated PAR1 membrane expression is regulated by Rab11a-RCP complex dissociation
Alejandro Alvarez-Arce1, Irene Lee-Rivera1, Edith López1
1Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Cellular Signalling
|August 30, 2020
Summary
Thrombin-activated Protease-Activated Receptor 1 (PAR1) signaling in eye disease requires its lysosomal degradation. This study reveals calcium and calpain activation disrupt the Rab11a/RCP complex, enabling PAR1 internalization and degradation.
Area of Science:
- Ophthalmology
- Cell Biology
- Molecular Biology
Background:
- Protease-Activated Receptor 1 (PAR1) activation by thrombin drives fibroproliferative eye diseases via RPE cell transformation, proliferation, and migration.
- PAR1 signaling is typically arrested through lysosomal transport and degradation following thrombin cleavage.
- The GTPase Rab11a and its effector RCP are implicated in directing PAR1 to lysosomes.
Purpose of the Study:
- To elucidate the mechanism regulating thrombin-induced PAR1 internalization and lysosomal degradation.
- To investigate the role of the Rab11a/RCP complex in PAR1 trafficking.
- To determine the involvement of intracellular calcium and calpain in PAR1 degradation.
Main Methods:
- Investigated thrombin-induced PAR1 trafficking in RPE cells.
- Utilized techniques to assess Rab11a/RCP complex disassembly.
- Examined the impact of calcium signaling and calpain activation on PAR1 internalization.
Main Results:
- Thrombin-induced PAR1 internalization and lysosomal targeting necessitate the disassembly of the Rab11a/RCP complex.
- Disassembly of the Rab11a/RCP complex is dependent on thrombin-induced intracellular calcium increase.
- Calpain activation, triggered by calcium, is crucial for this disassembly process.
Conclusions:
- A novel mechanism regulating thrombin-activated PAR1 internalization and degradation has been identified.
- Intracellular calcium increase and subsequent calpain activation are key regulators of PAR1 lysosomal trafficking.
- Understanding this pathway offers potential therapeutic targets for fibroproliferative eye diseases.
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