Molecular regulation of cellular protrusions by Rac and Cdc42 subfamily GTPases

由肌动蛋白聚合驱动的细胞突起，如片状脂膜和/或丝状足，是细胞运动和细胞过程的基本前提，细菌病原体也利用这些过程来入侵宿主细胞。Rac和CDC42是Rho家族小GTP酶家族的重要成员，在这些结构的形成过程中扮演着关键的调控角色。这些GTP酶的激活，例如通过生长因子的刺激，使它们能够与所谓的“效应器”特异性地相互作用，最终导致肌动蛋白组装。然而，从GTP负载的活性RAC/CDC42到肌动蛋白聚合机制的联系还没有明确的定义。对于不同效应蛋白在片状脂膜和丝状伪足突起中的意义的详细分析仍然缺乏。突起的形成伴随着多个肌动蛋白相关蛋白组装成含有Abi(用于AB1相互作用的)蛋白等分子的大复合体，这些蛋白被认为参与了raci介导的肌动蛋白重组。ABI蛋白结合NAP1(NCK相关蛋白1)，NAP1可以与Sra1相互作用，Sra1是一种新的RAC效应和Profilin招募蛋白。因此，NAP1和Sra1可能能够在RAC-GTP和Abi蛋白之间提供直接联系。然而，这些相互作用的生理相关性尚不清楚。这个项目的主要目的是研究NAP1和Sra1在片状脂胞和丝足形成中的作用。这些分析有望显著提高我们对导致基于肌动蛋白的细胞过程的信号通路的理解。

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.