Self-organization of spatio-temporal Rho GTPase activity patterns
Biophysics
Final Report Abstract
In order to fulfill their diverse functions, cells developed mechanisms that allow them to change their shape in a highly dynamic way. These shape changes are based on filamentous cell structures that produce mechanical forces. Basically, cells generate two opposing shape changes: Protrusions and contractions, which enable a local expansion of the cell or a local retraction. The spatial and temporal coordination of these processes allows cells to change their position. This process of directed cell migration plays a central role in many physiological and pathophysiological processes, such as wound healing, the immune response, embryonic development and cancer metastasis. How cells coordinate their shape changes in space and time is not yet sufficiently understood. Previous studies have shown that the signaling molecules Rac1, Cdc42 and RhoA play a central role in this process. Classically, Rac1 and Cdc42 promote cell protrusions, while RhoA stimulates cell contractions. In this DFG-funded project, we investigated their regulation in space and time within individual cells. The project focused on two systems in particular. On the one hand, the dynamics of local cell contraction pulses, which play a role in mechanotransduction, were investigated. Secondly, the coordination of protrusions and contractions during cell migration was studied. Previous investigations from our lab in collaboration with the group of Perihan Nalbant (University of Duisburg-Essen) showed that non-migrating cells can generate local cell contraction pulses and that these pulses are modulated by the elasticity of the cell environment. Here, the underlying mechanism was investigated in more detail. The cell contraction regulator RhoA plays a central role in this system and is controlled by a signaling network via positive and negative feedback, leading to pulsatile dynamics. On this basis, we developed quantitative differential equation models that enabled testable predictions, which were confirmed experimentally using an optogenetic approach. Furthermore, based on this model, we predicted that low positive feedback enables optimal mechanotransduction of elasticity signals from the cell environment into biochemical signals within the cell. Directional migration of cells requires spatial separation of cell protrusion and cell contraction in anterior and posterior cell regions, respectively. Previous models hypothesized that this polarization of the cell is achieved by mutual inhibition between the regulators Rac1/Cdc42 and RhoA. However, by combining an induced perturbation and measurement of the system response, we were not able to confirm this mutual inhibition. Surprisingly, we found instead that Rac1 activates RhoA. More detailed studies showed that two Rho activators: Arhgef11 and Arhgef12, mediate this coupling and that their overactivation causes dynamic cycles of protrusion and retraction and less directional cell migration. These findings revealed an important mechanism that can control cell migration: By promoting less directional cell migration, the Rac1 induced RhoA activation may play a role in cancer metastasis. Taken together, these studies provide new insights into the spatiotemporal organization of cell shape and form the basis for a deeper understanding of how cells use these processes to carry out their functions.
Publications
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Optogenetic Tuning Reveals Rho Amplification-Dependent Dynamics of a Cell Contraction Signal Network. Cell Reports, 33(9), 108467.
Kamps, Dominic; Koch, Johannes; Juma, Victor O.; Campillo-Funollet, Eduard; Graessl, Melanie; Banerjee, Soumya; Mazel, Tomáš; Chen, Xi; Wu, Yao-Wen; Portet, Stephanie; Madzvamuse, Anotida; Nalbant, Perihan & Dehmelt, Leif
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Monitoring the Response of Multiple Signal Network Components to Acute Chemo‐Optogenetic Perturbations in Living Cells. ChemBioChem, 23(4).
Kowalczyk, Manuela; Kamps, Dominic; Wu, Yaowen; Dehmelt, Leif & Nalbant, Perihan
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Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles. Nature Communications, 14(1).
Nanda, Suchet; Calderon, Abram; Sachan, Arya; Duong, Thanh-Thuy; Koch, Johannes; Xin, Xiaoyi; Solouk-Stahlberg, Djamschid; Wu, Yao-Wen; Nalbant, Perihan & Dehmelt, Leif
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Cdc42 activity in the trailing edge is required for persistent directional migration of keratinocytes. Molecular Biology of the Cell, 35(1).
Patwardhan, Rutuja; Nanda, Suchet; Wagner, Jessica; Stockter, Tom; Dehmelt, Leif & Nalbant, Perihan
