Coordination of Rho and Rap-type GTPases in cell morphodynamics

在定向迁移中，细胞通过细胞伸出和缩回的动态循环探索它们的环境。在生理迁移过程中，例如在伤口愈合中，这些细胞形状变化必须在空间和时间上彼此协调并与细胞粘附协调。在癌细胞的转移等病理过程中，这些过程没有得到正确的调节和协调。本研究项目旨在研究细胞内信号网络如何控制这些过程。特别是，小GTP酶被认为发挥重要作用。具体而言，Rap GTP酶控制细胞粘附，Rho GTP酶控制动态细胞突起和缩回。这些小GTPases的活性通过生化反应与扩散过程的结合在亚细胞区域局部调节。正反馈和负反馈机制产生脉动和波浪状的活动模式，这些模式驱动细胞突起和细胞收缩的动态局部循环。我们将研究Rap GTP酶的细胞内活动模式产生的反馈机制，以及这些活动模式如何与Rho GTP酶和相关的细胞形状变化耦合。为了研究这些问题，我们使用我们开发的方法，该方法能够将急性光遗传学或光化学信号网络扰动与多个信号网络响应的并行读出相结合。我们将联合收割机的实验研究与理论研究相结合，对这些复杂系统进行定量研究，希望通过这些研究，能够对细胞迁移中Rap和Rho GTPases的局部活性动态调节机制有新的认识，并预测该系统的变化如何导致癌细胞转移等病理性迁移行为。

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.