Arora Puneeta, Ricks Tiffany K, Trejo JoAnn
Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
J Cell Sci. 2007 Mar 15;120(Pt 6):921-8. doi: 10.1242/jcs.03409.
Protease-activated receptors (PARs) are G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. PARs play crucial roles in hemostasis and thrombosis, as well as in inflammation and vascular development. Coagulant proteases, which are generated at sites of vascular injury, act mainly through PARs to elicit signalling in a variety of cell types. Since PARs are irreversibly activated signalling must be tightly regulated. Desensitization and trafficking of proteolytically activated PARs control the magnitude, duration and spatial aspects of receptor signalling. Recent studies have revealed novel endocytic sorting mechanisms that regulate PAR signalling. PARs have also been implicated in tumor progression. PARs are overexpressed in several types of malignant cancer, transmit signals in response to tumor-generated proteases and promote tumor growth, invasion and metastasis. Recent work also indicates that matrix metalloprotease 1 (MMP-1) signals through PAR1 to promote tumor growth and invasion. In addition to PAR overexpression, tumor cells display aberrant PAR1 trafficking, which causes persistent signalling and cellular invasion. Thus, a novel type of gain-of-function in GPCR signalling in cancer can be acquired through dysregulation of receptor trafficking.
蛋白酶激活受体（PARs）是通过独特的蛋白水解机制被激活的G蛋白偶联受体（GPCRs）。PARs在止血和血栓形成以及炎症和血管发育中发挥关键作用。在血管损伤部位产生的凝血蛋白酶主要通过PARs在多种细胞类型中引发信号传导。由于PARs被不可逆地激活，因此信号传导必须受到严格调控。蛋白水解激活的PARs的脱敏和转运控制着受体信号传导的强度、持续时间和空间方面。最近的研究揭示了调节PAR信号传导的新型内吞分选机制。PARs也与肿瘤进展有关。PARs在几种类型的恶性癌症中过度表达，响应肿瘤产生的蛋白酶传递信号并促进肿瘤生长、侵袭和转移。最近的研究还表明，基质金属蛋白酶1（MMP-1）通过PAR1发出信号以促进肿瘤生长和侵袭。除了PAR过度表达外，肿瘤细胞还表现出异常的PAR1转运，这会导致持续的信号传导和细胞侵袭。因此，癌症中GPCR信号传导的一种新型功能获得可以通过受体转运失调来实现。
