Exploring the Mechanics of Focal Adhesion Kinase in Cells

• Applicant: Professor Dr. Carsten Grashoff
• Subject Area: Cell Biology ; Biophysics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539434708

Cell-matrix adhesion is key to a wide range of cell biological processes including cell migration, differentiation and cell survival, and thus central to development, tissue homeostasis but also pathology. It is mediated by integrin receptors that assemble complex, macromolecular structures called focal adhesions (FAs), which act as mechano-chemical signal processors and comprise hundreds of different molecules. While not all of these proteins appear to be critical, it is clear that a set of core proteins is indispensable for FA function and essential in virtually all adherent cell types. One of these central molecules is called focal adhesion kinase (FAK). FAK is a ubiquitously expressed, non-receptor tyrosine kinase that is constitutively associated with FAs. Since FAK activity is modulated by numerous signaling cascades and because FAK is highly sensitive to mechanical stimuli, it is considered a central coordinator of mechano-chemical signaling in FAs. In addition, FAK is implicated in numerous pathologies, most notably fibrosis and cancer, where it is frequently upregulated promoting cell proliferation or cell invasion. Given the undisputed relevance of FAK in physiology and disease, it is surprising that fundamental aspects of FAK regulation are still poorly understood. For instance, FAK is central for sensing and translating mechanical signals in cell adhesion sites, but the underlying mechanisms are still unclear. Existing models based on in-silico and in-vitro studies hypothesized that mechanical loads directly act upon the FAK molecule to modulate its kinase activity, yet direct evidence that the molecule is indeed exposed to mechanical stresses in cells is missing. Where and when such a mechanical loading occurs in cells and which molecular interactions are required for it, is of course also unknown. Moreover, the nanoscale organization of the molecule and how this is related to its mechano-chemical function is largely unclear. How individual FAK molecules, which undergo dimerization, laterally assemble in cell adhesions sites, where and when the interactions with known binding partners and modulators of cell signaling occur, and how this organization is modulated by mechanical stimuli has remained unknown. These examples illustrate that it is indeed not well understood how the FAK molecule operates on the molecular level. An obvious reason is that approaches to investigate FAK at the relevant (i.e., molecular) force and length scales are lacking. Therefore, we have developed new techniques to enable the quantitative investigation of FAK in cells. We propose to apply these tools to unravel the molecular-scale biology of this central cell adhesion regulator that is so fundamental to mammalian cell biology.

• DFG Programme: Research Grants