Molecular regulation of cellular protrusions by Rac and Cdc42 subfamily GTPases

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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.