Signal transduction of the actin-binding protein cortactin in bacterial pathogenesis

• Applicant: Dr. Nicole Tegtmeyer
• Subject Area: Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 289286761

Many microbial pathogens manipulate signal transduction processes of their eukaryotic hosts for their own benefit and disease development. The cytoskeleton assembly plays a fundamental role in many vital cellular processes, such as membrane dynamics, migration, adhesion and transport. Thus, by targeting the cytoskeleton and various kinases, pathogens can radically and rapidly reprogram their host target cell and can trigger disease-associated processes (Müller*, Tegtmeyer* et al. 2012). Among the proteins involved in the host cytoskeletal network, cortactin appears as one of the favourite targets of microbial effectors. Initial studies on pathogenic Escherichia coli, Neisseria, Listeria, Shigella, Campylobacter, Helicobacter and Staphylococcus, have shown that cortactin may play a role in invasion, actin-based motility, pedestal formation and cell scattering. We have recently shown that this frequently coincides with a change in the localization and/or phosphorylation of cortactin (Tegtmeyer et al. 2011). Thus, cortactin is emerging as important cellular target of microbes, suggesting that it can be regarded as an Achilles heel of the actin cytoskeleton. However, the molecular mechanisms involved in this scenario are widely unknown. In particular, cortactin is a target of various kinases, but it remained unclear which candidate tyrosines (Y-421, Y-470, Y-486) and/or serines (S-113, S-405, S-418) are phosphorylated during infection and which downstream signalling pathways are regulated by individual phospho-sites in cortactin. In particular, we would like to investigate the role of bacterial factors in the modulation of cortactin with emphasis on how they manipulate cortactin phosphorylation to hijack specific cellular signalling pathways. This approach will allow us to reconstruct the sequence of events occurring at the pathogen-host cell interface, and to identify novel key pathogenicity determinants, which are important for the future development of new antimicrobial treatment regimes. * (equal contribution, shared first authorship)

• DFG Programme: Research Grants