Dissecting the mechanisms shaping focal adhesion dynamics and cell migration

• Applicant: Professorin Dr. Tanja Maritzen
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516983053

Cells adhere to the substratum via highly complex multiprotein assemblies. These focal adhesions serve not only as traction points during cell migration, but also as important signalling hubs. Hence, focal adhesions play crucial roles in numerous physiological processes including developmental morphogenesis and wound healing as well as immune defense. In addition, altered focal adhesion dynamics contribute to the pathology of various diseases ranging from chronic inflammation to cancer. In spite of the well-established importance of focal adhesions, our knowledge regarding their disassembly is still largely fragmentary. While endocytic factors, trafficking proteins and proteases all have been implicated in focal adhesion turnover, it is still entirely unclear how different mechanisms act concertedly in a spatiotemporally controlled manner to bring about focal adhesion dissolution. Furthermore, key players were likely missed by the previous candidate-based approaches. My group has started to fill this critical gap by successfully performing a systematic and unbiased microscopy-based genome-wide siRNA screen to functionally identify essential mediators and regulators of focal adhesion disassembly. The aim of the proposed project is to follow-up on the hits we have obtained in our screen and to dissect their molecular role in focal adhesion dynamics and cell migration focusing on two lines of reseach. Firstly, our screen revealed an intimate link between cellular metabolism and focal adhesions by pinpointing the glycolytic enzyme aldolase A as focal adhesion regulator. Since the integration of cellular metabolism with cellular activities such as focal adhesion dynamics and cell migration is a fundamental question in cell biology with strong implications for cancer metastasis, we aim to decipher by which molecular mechanism aldolase A shapes focal adhesion dynamics and cell migration. Secondly, our screen strongly implicated RNA binding and splicing proteins in the regulation of focal adhesions. Therefore, we want to dissect the molecular mechanisms by which diverse RNA binding proteins influence focal adhesions. With these studies we will fundamentally expand the existing knowledge of the cell biology of focal adhesions and contribute to a better understanding of the diverse mechanisms coming together to shape focal adhesion dynamics and cell migration in health and disease.

• DFG Programme: Research Grants