PAR1 activation by thrombin promotes intracellular signaling leading to RPE cell transformation, proliferation, and migration, characteristic of fibroproliferative eye diseases. Due to the cleavage of PAR1 N-terminal domain, carried by thrombin, the arrest of PAR1 signaling is achieved by transport into lysosomes and degradation. Recent findings suggest that the GTPase Rab11a in conjunction with its effector RCP may direct PAR1 to lysosomes. Hereby we demonstrate that thrombin-induced PAR1 internalization and lysosomal targeting requires the disassembly of the Rab11a/RCP complex, and that this process depends on thrombin-induced intracellular calcium increase and calpain activation. These findings unveil a novel mechanism that regulates thrombin activated PAR1 internalization and degradation.

凝血酶激活 PAR1 促进细胞内信号传导，导致 RPE 细胞转化、增殖和迁移，这是纤维增殖性眼病的特征。由于由凝血酶携带的 PAR1 N 端结构域的切割，PAR1 信号的阻滞是通过运输到溶酶体和降解来实现的。最近的研究结果表明 GTPase Rab11a 与其效应子 RCP 可能将 PAR1 引导至溶酶体。在此我们证明凝血酶诱导的 PAR1 内化和溶酶体靶向需要 Rab11a/RCP 复合物的分解，并且该过程取决于凝血酶诱导的细胞内钙增加和钙蛋白酶激活。这些发现揭示了一种调节凝血酶激活的 PAR1 内化和降解的新机制。