Coordination of Rho and Rap-type GTPases in cell morphodynamics

在定向迁移中，细胞通过细胞突起和回缩的动态循环来探索自己的环境。在生理迁移过程中，如伤口愈合过程中，这些细胞形状的变化必须在空间和时间上相互协调，并与细胞黏附相协调。在肿瘤细胞转移等病理过程中，这些过程没有得到正确的调控和协调，本研究旨在探讨细胞内信号网络是如何控制这些过程的。特别是，小的GTP酶被认为起着重要的作用。具体地说，Rap GTP酶控制细胞黏附，Rho GTP酶控制动态细胞突起和收缩。这些小的GTP酶的活性在亚细胞区域通过生化反应和扩散过程的组合被局部调节。正反馈和负反馈机制产生脉动和波状的活性模式，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酶的细胞内活性模式的反馈机制，以及这些活性模式是如何与Rho GTP酶和相关的细胞形状变化耦合的。为了研究这些问题，我们使用了我们开发的方法，这些方法能够将急性光遗传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。我们将把我们的实验研究和理论方法结合起来，以获得对这些复杂系统的定量了解。我们期待这些研究将揭示调控Rap和Rho GTP酶在细胞迁移中局部活性动态的新机制，并能够预测该系统的变化如何导致病理性迁移行为，例如在癌细胞的转移中。

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.