Ozaki Kei-ichi, Miyazaki Satsuki, Tanimura Susumu, Kohno Michiaki
Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-14, Bunkyo-machi, Nagasaki 852-8521, Japan.
J Cell Sci. 2005 Dec 15;118(Pt 24):5861-71. doi: 10.1242/jcs.02711.
Strict regulation of the receptor tyrosine kinase (RTK)/extracellular signal-regulated kinase (ERK) pathway is essential for maintaining balanced growth in multi-cellular organisms. Several negative regulators of the pathway have been identified which include Sprouty proteins. Mammalian cells express four Sprouty isoforms (Sprouty1-4) in an ERK-dependent manner. In this study, we have examined the molecular mechanisms by which Sprouty proteins elicit their inhibitory effects on the RTK/ERK pathway, with special focus on the co-operation among Sprouty isoforms. The four mammalian Sprouty isoforms interact with each other, most probably to form hetero- as well as homo-oligomers through their C-terminal domains. Sprouty1 specifically interacts with Grb2, whereas Sprouty4 interacts with Sos1. Although any of the Sprouty isoforms by itself inhibits the fibroblast growth factor-2 (FGF-2)-induced activation of the ERK pathway significantly, hetero-oligomers show a more pronounced inhibitory activity. The hetero-oligomer formed between Sprouty1 and Sprouty4 exhibits the most potent inhibitory effect on ERK activation through its highly effective ability to suppress the association of Grb2-Sos1 complex with FRS2. The cooperative interactions observed among Sprouty isoforms could represent an advanced system that functions to regulate strictly the activation state of the RTK/ERK pathway in mammalian cells.
严格调控受体酪氨酸激酶（RTK）/细胞外信号调节激酶（ERK）信号通路对于多细胞生物体维持平衡生长至关重要。已鉴定出该信号通路的几种负调控因子，其中包括Sprouty蛋白。哺乳动物细胞以ERK依赖的方式表达四种Sprouty异构体（Sprouty1 - 4）。在本研究中，我们研究了Sprouty蛋白对RTK/ERK信号通路产生抑制作用的分子机制，特别关注Sprouty异构体之间的协同作用。四种哺乳动物Sprouty异构体相互作用，很可能通过其C末端结构域形成异源和同源寡聚体。Sprouty1特异性地与Grb2相互作用，而Sprouty4与Sos1相互作用。尽管任何一种Sprouty异构体本身都能显著抑制成纤维细胞生长因子2（FGF - 2）诱导的ERK信号通路激活，但异源寡聚体表现出更明显的抑制活性。Sprouty1和Sprouty4之间形成的异源寡聚体通过其高度有效地抑制Grb2 - Sos1复合物与FRS2的结合，对ERK激活表现出最有效的抑制作用。在Sprouty异构体之间观察到的协同相互作用可能代表了一种先进的系统，其功能是严格调节哺乳动物细胞中RTK/ERK信号通路的激活状态。
