Regulation of G-proteins during chemotaxis in space and time

The coordinated movement of cells in a gradient of a chemical substance (chemo-attractant) is called chemotaxis. The gradient is translated to cell movement towards the chemo-attractant by a signal transduction pathway inside the cell. Chemotaxis is important for several processes within the human body, including wound healing and embryonic development, but is also involved in some diseases like metastasis of cancer cells and asthma. The signal transduction pathway begins with activation of a receptor on the outside of the cell, after which G-proteins are activated. First the heterotrimeric G proteins Gα and Gβγ are activated, the activation is directly proportional to the steepness of the gradient. Subsequently the monomeric G proteins Ras, Rap and Rac are activated, however these show a much stronger activation at the front of the cell. In my thesis I describe a newly discovered protein LrrA which connects these heterotrimeric and monomeric G proteins and regulates the timing and localization of several components in the signal transduction pathway. Furthermore, the activation mechanism of the monomeric G-protein Rap1 is described in detail. Lastly my thesis describes how Rap1 induces the cytoskeleton and how in turn the cytoskeleton inhibits Rap1 activity. As a whole my thesis demonstrates that chemotaxis is strongly regulated at all levels of the signal transduction pathway. The many layers of regulation result in a robust but flexible system that functions in both low and high concentrations of chemo-attractant