The cell polarity regulator, Scribble, is an evolutionarily conserved suppressor of neoplastic tumour growth that is frequently dysregulated in human cancers and developmental birth defects. Scribble is a multi-domain protein that has an extensive interaction network and acts as a hub for cellular signalling, coordinating a wide variety of processes ranging from wound healing and immune response to learning and memory. Consequently, Scribble’s membrane-bound localisation is essential to its function, where aberrant localisation is implicated in the progression of aggressive epithelial cancers that correlate with poor survival and lethal neural tube defects in human patients. Despite increasing knowledge on Scribble, the exact mechanism by which its mislocalisation contributes to disease remains unclear.
I hypothesise that Scribble operates as a spatial organiser of signalling that drives dysregulation of cellular processes when mislocalised, leading to loss of cell polarity and tissue disorganisation. Using the in-cell proximity-labelling technique, known as APEX2, combined with proteomic analysis of Scribble’s interacting domains, I have begun to map the surrounding protein network of Scribble when localised normally at the plasma membrane compared to when mislocalised to the cytoplasm. Using the above proteomics approaches together with complementary cellular structure function studies of patient-derived Scribble alleles, we will obtain a deep integrative understanding of how mislocalisation of Scribble alters cellular dynamics in human cancers and developmental defect.