Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms
Efficient suppression of FGF-2-induced ERK activation by the cooperative interaction among mammalian Sprouty isoforms
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DOI：
10.1242/jcs.02711
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发表时间：
2005-12-15
影响因子：
4
通讯作者：
Kohno, M
中科院分区：
文献类型：
--
作者：
Ozaki, K;Miyazaki, S;Kohno, M
受体酪氨酸激酶(RTK)/细胞外信号调节激酶（ERK）通路的严格调控对于维持多细胞生物的平衡生长至关重要。已经确定了该途径的几个负调节因子，其中包括Sprouty蛋白。哺乳动物细胞以erk依赖的方式表达四种Sproutyl-4亚型。在这项研究中，我们研究了Sprouty蛋白对RTK/ERK通路的抑制作用的分子机制，特别关注了Sprouty亚型之间的合作。这四种哺乳动物的芽胞异构体相互作用，很可能通过它们的c端结构域形成异聚物和同聚物。Sprouty1专门与Grb2相互作用，而Sprouty4与Sos1相互作用。尽管任何一种Sprouty亚型本身都能显著抑制成纤维细胞生长因子-2 （FGF-2）诱导的ERK通路的激活，但异聚物寡聚物表现出更明显的抑制活性。Sproutyl和Sprouty4之间形成的异聚物通过其高效抑制Grb2-Sos1复合物与FRS2结合的能力，对ERK活化表现出最有效的抑制作用。在Sprouty亚型之间观察到的合作相互作用可能代表了一个高级系统，该系统在哺乳动物细胞中严格调节RTK/ERK通路的激活状态。
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 (Sproutyl-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 Sproutyl 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.