PROJECT A12
Integrin Subtype-specific Organization and Force Transduction
The ability of cells to firmly adhere to the extracellular environment and, at the same time, sense and respond to mechanical cues is crucial for a wide range of developmental and homeostatic processes, but also relevant for numerous human disorders. It has been recognized that integrin- and cadherin-based complexes are crucial not only for mediating cell adhesion but also for transmitting mechanical signals into the cell. However, it remains largely unclear how these physical signals, that originate at the plasma membrane, alter transcriptional and epigenetic profiles in the nucleus to enable cell adaptation. In this project, we will address this long-standing question by combining the expertise of two research groups that have established unique approaches to quantify and modulate molecular force transduction processes in cells and to evaluate nuclear mechanosignaling. We propose to apply distinct mechanically stimuli onto cells and apply a range of recently developed technologies to monitor molecular force transmission from the extracellular side of cell-matrix and cell-cell adhesion complexes (i.e., integrins and cadherins), across intracellular force transmitting molecules (e.g., talin-1) to LINC complex proteins at the nuclear envelope. In parallel, we will investigate how the distinct force transduction pathways modulate the mechanical properties of the nucleus using atomic force microscopy-based measurements and quantitative imaging of nuclear envelope fluctuations, but also how cells adapt their transcriptional profile using spatial transcriptomic analyses. Together, these experiments will provide unique insights into the biochemical and biophysical communication principles between cell adhesion interfaces at the plasma membrane and the nucleus and assess the impact of this communication on cell state regulation.
