Global and local cellular signaling
Quantitative Phosphoproteomics, System Biology. Epithelial Cells, Signaling Networks, Trafficking, Receptor Tyrosine Kinases (RTKs), Receptor Recycling, Fibroblast Growth Factor Receptor (FGFR) family, APEX, local phosphoproteomics
Receptor Tyrosine Kinases (RTKs) elicit signaling cascades from different sub-cellular compartments, such as plasma membrane, intracellular vesicles, organelles, and nucleus (Sigismund et al., 2021). However, a global analysis of changes in signaling networks and long-term cellular responses upon RTK activation from one or more cellular compartment is still missing. Here, we will use sub-cellular fractionation techniques, proximity-labeling assays, quantitative proteomics, bioinformatics, and functional assays (i.e. high-content microscopy) to uncover which signaling pathways are activated depending on receptor sub-cellular localization.
We will focus on FGFR2b, an epithelial cells-specific member of the FGFR family activated by its ligands FGF3, FGF7, and FGF10 (Francavilla et al., 2013; Ornitz and Itoh, 2021; Ferguson et al., 2021) and on EGFR activated by EGF and TGFalpha (Francavilla et al., 2016; Smith, Ferguson et al., 2021). This project will help our understanding of the spatio-temporal regulation of signaling networks and will identify signaling molecules that could be targeted to re-direct long-term cellular responses.
Recent data shows that FGFR signalling from the recycling endosomes, here defined local or proximal signalling, activates the autophagy kinase ULK1 and regulates autophagy and cell survival (Watson, Ferguson et al., Nat Comm, 2022).