Kobilka Institute of Innovative Drug Discovery, School of Life and Health Sciences, The Chinese University of Hong Kong, Shenzhen, Shenzhen, 518172, China.
Pharmacol Res. 2020 Mar;153:104676. doi: 10.1016/j.phrs.2020.104676. Epub 2020 Jan 30.
Phosphatidylinositol 3,4,5-trisphosphate (PIP)-dependent Rac exchanger 1 (P-Rex1) is a guanine nucleotide exchange factor (GEF) for Rac small GTPases and the Rac-related GTPase RhoG. P-Rex1 plays an important role in cell migration and relays intracellular signals generated through activation of G protein-coupled receptors and receptor tyrosine kinases. Studies of mouse models have found that P-Rex1 expression and activation is associated with tumor cell migration, brain development and pathological changes such as lung edema. Since its initial discovery, P-Rex1 has been known for its large size and multiple activation mechanisms that involve not only PIP but also the βγ subunits of heterotrimeric G proteins and a regulatory subunit of cyclic AMP-dependent kinase, PKA RIα. At the core of the GEF activity is the tandem Dbl homology domain and the pleckstrin homology domain (DH/PH domains) that are masked until activation signals unwind the P-Rex1 structure. Understanding the activation mechanisms will help designing therapeutics that target P-Rex1 for cancer and other diseases.
磷脂酰肌醇 3,4,5-三磷酸（PIP）依赖性 Rac 交换因子 1（P-Rex1）是 Rac 小分子 GTP 酶和 Rac 相关 GTP 酶 RhoG 的鸟嘌呤核苷酸交换因子（GEF）。P-Rex1 在细胞迁移中发挥重要作用，并传递通过 G 蛋白偶联受体和受体酪氨酸激酶激活产生的细胞内信号。对小鼠模型的研究发现，P-Rex1 的表达和激活与肿瘤细胞迁移、脑发育以及肺水肿等病理变化有关。自最初发现以来，P-Rex1 因其大尺寸和多种激活机制而闻名，这些机制不仅涉及 PIP，还涉及异三聚体 G 蛋白的βγ亚基和环 AMP 依赖性激酶的调节亚基，PKA RIα。GEF 活性的核心是串联 Dbl 同源结构域和磷酯酶结构域（DH/PH 结构域），直到激活信号解开 P-Rex1 结构，这些结构才会被掩盖。了解激活机制将有助于设计针对癌症和其他疾病的 P-Rex1 的治疗方法。
