Coordination of Rho and Rap-type GTPases in cell morphodynamics

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In directional migration, cells explore their environment through dynamic cycles of cell protrusion and retraction. In physiological migration processes such as in wound healing, these cell shape changes must be coordinated spatially and temporally with one another and with cell adhesion. In pathological processes such as in the metastasis of cancer cells, these processes are not correctly regulated and coordinated.This research project aims to investigate how intracellular signal networks control these processes. In particular, small GTPases are thought to play an important role. Specifically, Rap GTPases control cell adhesion and Rho GTPases control dynamic cell protrusions and retractions. The activity of these small GTPases is regulated locally in sub-cellular areas by a combination of biochemical reactions with diffusion processes. Positive and negative feedback mechanisms generate pulsatile and wave-like activity patterns, which drive the dynamic, local cycles of cell protrusions and cell retractions.We will investigate the feedback mechanisms by which intracellular activity patterns of Rap GTPases are generated and how these activity patterns are coupled with Rho GTPases and associated cell shape changes. In order to investigate these questions, we use methods developed by us, which enable a combination of acute optogenetic or photochemical signal network perturbations with the parallel readout of multiple signal network responses. We will combine our experimental investigations with theoretical approaches to gain a quantitative understanding of these complex systems.We expect that these studies will uncover new insights into the mechanisms that regulate the local activity dynamics of Rap and Rho GTPases in cell migration, and that we will be able to make predictions about how changes in this system lead to pathological migration behavior, such as in the metastasis of cancer cells.