Déry O, Corvera C U, Steinhoff M, Bunnett N W
Department of Surgery, University of California, San Francisco 94143-0660, USA.
Am J Physiol. 1998 Jun;274(6):C1429-52. doi: 10.1152/ajpcell.1998.274.6.C1429.
Although serine proteases are usually considered to act principally as degradative enzymes, certain proteases are signaling molecules that specifically regulate cells by cleaving and triggering members of a new family of proteinase-activated receptors (PARs). There are three members of this family, PAR-1 and PAR-3, which are receptors for thrombin, and PAR-2, a receptor for trypsin and mast cell tryptase. Proteases cleave within the extracellular NH2-terminus of their receptors to expose a new NH2-terminus. Specific residues within this tethered ligand domain interact with extracellular domains of the cleaved receptor, resulting in activation. In common with many G protein-coupled receptors, PARs couple to multiple G proteins and thereby activate many parallel mechanisms of signal transduction. PARs are expressed in multiple tissues by a wide variety of cells, where they are involved in several pathophysiological processes, including growth and development, mitogenesis, and inflammation. Because the cleaved receptor is physically coupled to its agonist, efficient mechanisms exist to terminate signaling and prevent uncontrolled stimulation. These include cleavage of the tethered ligand, receptor phosphorylation and uncoupling from G proteins, and endocytosis and lysosomal degradation of activated receptors.
尽管丝氨酸蛋白酶通常被认为主要作为降解酶起作用，但某些蛋白酶是信号分子，它们通过切割和激活蛋白酶激活受体（PARs）新家族的成员来特异性调节细胞。该家族有三个成员，PAR-1和PAR-3，它们是凝血酶的受体，还有PAR-2，它是胰蛋白酶和肥大细胞类胰蛋白酶的受体。蛋白酶在其受体的细胞外NH2末端内进行切割，以暴露出一个新的NH2末端。这个拴系配体结构域内的特定残基与切割后的受体的细胞外结构域相互作用，从而导致激活。与许多G蛋白偶联受体一样，PARs与多种G蛋白偶联，从而激活许多平行的信号转导机制。PARs在多种组织中的多种细胞中表达，它们参与多种病理生理过程，包括生长发育、有丝分裂和炎症。由于切割后的受体与其激动剂物理偶联，因此存在有效的机制来终止信号传导并防止不受控制的刺激。这些机制包括拴系配体的切割、受体磷酸化以及与G蛋白的解偶联，以及激活受体的内吞作用和溶酶体降解。
