Hollenberg Morley D, Oikonomopoulou Katerina, Hansen Kristina K, Saifeddine Mahmoud, Ramachandran Rithwik, Diamandis Eleftherios P
Proteinases and Inflammation Network, Department of Pharmacology and Therapeutics, University of Calgary Faculty of Medicine, Calgary T2N 4N1, AB, Canada.
Biol Chem. 2008 Jun;389(6):643-51. doi: 10.1515/BC.2008.077.
Proteinases such as thrombin and trypsin can affect tissues by activating a novel family of G protein-coupled proteinase-activated receptors (PARs 1-4) by exposing a 'tethered' receptor-triggering ligand (TL). Work with synthetic TL-derived PAR peptide sequences (PAR-APs) that stimulate PARs 1, 2 and 4 has shown that PAR activation can play a role in many tissues, including the gastrointestinal tract, kidney, muscle, nerve, lung and the central and peripheral nervous systems, and can promote tumor growth and invasion. PARs may play roles in many settings, including cancer, arthritis, asthma, inflammatory bowel disease, neurodegeneration and cardiovascular disease, as well as in pathogen-induced inflammation. In addition to activating or disarming PARs, proteinases can also cause hormone-like effects via PAR-independent mechanisms, such as activation of the insulin receptor. In addition to proteinases of the coagulation cascade, recent data suggest that members of the family of kallikrein-related peptidases (KLKs) represent endogenous PAR regulators. In summary: (1) proteinases are like hormones, signaling in a paracrine and endocrine manner via PARs or other mechanisms; (2) KLKs must now be seen as potential hormone-like PAR regulators in vivo; and (3) PAR-regulating proteinases, their target PARs, and their associated signaling pathways appear to be novel therapeutic targets.
诸如凝血酶和胰蛋白酶之类的蛋白酶可通过暴露“拴系”的受体触发配体（TL）来激活一类新的G蛋白偶联蛋白酶激活受体（PARs 1-4），从而影响组织。对刺激PARs 1、2和4的合成TL衍生PAR肽序列（PAR-APs）的研究表明，PAR激活可在许多组织中发挥作用，包括胃肠道、肾脏、肌肉、神经、肺以及中枢和外周神经系统，并且可促进肿瘤生长和侵袭。PARs可能在许多情况下发挥作用，包括癌症、关节炎、哮喘、炎症性肠病、神经退行性变和心血管疾病，以及病原体诱导的炎症。除了激活或使PARs失活外，蛋白酶还可通过PAR非依赖性机制产生类似激素的作用，如激活胰岛素受体。除了凝血级联反应中的蛋白酶外，最近的数据表明激肽释放酶相关肽酶（KLKs）家族成员是内源性PAR调节剂。总之：（1）蛋白酶类似于激素，通过PARs或其他机制以旁分泌和内分泌方式发出信号；（2）现在必须将KLKs视为体内潜在的类似激素的PAR调节剂；（3）PAR调节蛋白酶、其靶PARs及其相关信号通路似乎是新的治疗靶点。
