Retrograde trafficking to the trans-Golgi network and its effect on β1 integrin function

• Applicant: Dr. Ralph Thomas Böttcher
• Subject Area: Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 456848726

Essentially all morphogenetic events of multicellular organisms during tissue homeostasis, wound healing and tumorigenesis, require dynamic cell-cell and cell-matrix adhesion mediated by transmembrane receptors of the integrin family. Hence, integrins fulfil key functions in cell adhesion and migration crucial for development, physiology and pathology. Integrins are continuously endocytozed and trafficked through the endosomal system to regulate their protein stability, distribution on the cell surface and the signalling crosstalk with growth factor receptors. While Rab4- and Rab11-dependent recycling routes of integrins have been studied, little is known about the retrograde trafficking of integrins via the trans-golgi network, how retrograde integrin trafficking is regulated, and how it contributes to integrin function. Our previous studies show the importance of cytosolic integrin interactors for integrin trafficking. Further preliminary experiments identified a golgin-associated protein complex involved in vesicle tethering as α5β1 integrin interactor and revealed theimportance of this interaction for the retrograde transport of α5β1 integrin. It is therefore the aim of this proposal to characterize the molecular mechanism underlying retrograde integrin trafficking and to study its role for integrin-mediated processes such as cell adhesion and migration using a combination of proteomic, biochemical and cellbiological approaches. For this, we established mass spectrometry methods to analyze the interaction of α5β1 integrin with the golgin-associated protein complex and to identify novel interactors involved in retrograde trafficking of α5β1 integrins. The successful completion of these aims will contribute to a better understanding of vesicle tethering at golgi membranes and will shed light on the role of retrograde transport for integrin-mediated processes. The long-term goal of this study is to gain insights on how intracellular transport of integrins through the endosomal system affects their function to regulate cell-adhesion and –migration. These findings will contributeto our understanding of diseases such as metastasis, migration of immune cells and help to develop novel therapeutic approaches.

• DFG Programme: Research Grants