Molecular regulation of cellular protrusions by Rac and Cdc42 subfamily GTPases

Rac 和 Cdc42 亚家族 GTPases 对细胞突起的分子调节

• 批准号: 5407752
• 负责人: Professorin Dr. Theresia Stradal
• 金额: --
• 依托单位: Helmholtz-Zentrum für Infektionsforschung (HZI)
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2003
• 资助国家: 德国
• 起止时间: 2002-12-31 至 2009-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/5407752?language=en
• 关键词: Molecular; regulation; cellular; protrusions; Rac

The projection of cellular protrusions such as lamellipodia and/or filopodia driven by actin polymerization is an essential prerequisite for cell motility and for cellular processes which are also exploited by bacterial pathogens in order to invade their host cells. Rac and Cdc42, well characterized members of the Rho-family of small GTPases, have emerged as key regulatory players in the formation of these structures. Activation of these GTPases e.g. by growth factor stimulation renders them capable to specifically interact with so-called "effectors" eventually leading to actin assembly. However, the link from GTP-loaded, active Rac/Cdc42 to the actin polymerisation machinery is poorly defined. Detailed analysis of the significance of different effector proteins for the protrusion of lamellipodia and filopodia is still missing. Protrusion formation is accompanied by the assembly of multiple actin-associated proteins into large complexes harbouring molecules such as Abi (for Ab1 interacting) proteins which are thought to be involved in Racmediated actin reorganisation. Abi proteins bind Nap1 (Nck associated protein 1) which can interact with Sra1, a novel Rac effector and profilin-recruiting protein. Nap1 and Sra1 might therefore be able to provide a direct link between Rac-GTP and Abi proteins. The physiological relevance of these interactions is however unknown. The main goal of this project is to investigate the role of Nap1 and Sra1 in the formation of lamellipodia and filopodia. These analyses are expected to significantly improve our understanding of the signalling pathways leading to actin-based cellular processes.

由肌动蛋白聚合驱动的细胞突起如片状伪足和/或丝状伪足的投射是细胞运动和细胞过程的必要先决条件，这些细胞过程也被细菌病原体利用以侵入其宿主细胞。Rac和Cdc 42是Rho家族的小GTP酶的特征性成员，已成为这些结构形成中的关键调控参与者。这些GTP酶的活化，例如通过生长因子刺激，使它们能够特异性地与所谓的“效应物”相互作用，最终导致肌动蛋白组装。然而，从GTP负载，活性Rac/Cdc 42的肌动蛋白聚合机制的链接是不明确的。不同的效应蛋白对板状伪足和丝状伪足突出的意义的详细分析仍然缺失。蛋白质的形成伴随着多个肌动蛋白相关蛋白组装成大的复合物，所述复合物含有分子如Abi（用于Ab 1相互作用）蛋白，其被认为参与Rac介导的肌动蛋白重组。Abi蛋白结合Nap 1（Nck相关蛋白1），Nap 1可以与新的Rac效应子和profilin募集蛋白Sra 1相互作用。因此，Nap 1和Sra 1可能能够提供Rac-GTP和Abi蛋白之间的直接联系。然而，这些相互作用的生理相关性是未知的。本项目的主要目的是研究Nap 1和Sra 1在板状伪足和丝状伪足形成中的作用。这些分析预计将显着提高我们的理解，导致肌动蛋白为基础的细胞过程的信号通路。