Role of Lbc GEFs in cellular morphodynamics

• Applicant: Privatdozent Dr. Leif Dehmelt
• Subject Area: Cell Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450137870

Dynamic shape changes play a central role in many cellular functions. One of these functions is the directional migration of cells to their target sites. During this process, cells have to coordinate dynamic cell protrusions and retractions in space and time to steer their movements.In the proposed research, we aim to study how these dynamic cell shape changes are controlled by intracellular signal networks. We will focus on the interplay between two signal proteins of the Rho GTPase family, which are thought to be master regulators of cell shape changes: The Rho family member Rac, which stimulates cell protrusion, and Rho, which stimulates cell contraction and cell retraction. We will particularly focus on a specific class of regulators of Rho GTPases: The Lbc GEFs. These regulators stimulate cell contraction by activating Rho. Interestingly, some family members are activated by Rac. Thereby, Lbc GEFs can mediate Rac/Rho activity crosstalk and link the generation of cell protrusions and cell retractions. This link can result in local protrusion/retraction cycles that are used by cells to explore the properties of their environment during directed migration.Lbc GEFs can also get activated by Rho. Via this mechanism, these regulators can participate in a positive feedback loop that amplifies Rho activity in cells. This positive feedback plays a central role in the generation of highly dynamic local cell contraction pulses. By generating these contraction pulses, cells acquire an active sense of touch, by which they can probe the mechanical properties of their environment. This mechanotransduction process is thought to play an important role in the function and development of organs and tissues. We will study the role of each individual Lbc GEF family member in Rac1/Rho GTPase crosstalk and Rho positive feedback amplification, and how these molecules contribute to cellular morphodynamics during cell migration and mechanotransduction. To address these questions we will capitalize on new tools that we developed, that enable optogenetic or photochemical perturbations and monitoring of Rho GTPase activity responses. The combination of these approaches will allow us to directly investigate spatio-temporal signal processing in Rho GTPase signal networks in living cells.We expect that these studies will uncover differences in the molecular properties of distinct Lbc GEF family members and how these properties translate into distinct cellular functions. By focusing on directed cell migration and mechanotransduction, we expect to gain a deeper insight into two fundamental functions of cells that play a central role in many physiological and pathophysiological processes.

• DFG Programme: Research Grants