Understanding control of protein concentration and cell fate in the absence of extracellular stimulation (360G-Wellcome-109156_Z_15_A)

Intricate cellular signaling pathways are essential for maintaining cellular homeostasis and enabling the cell to respond appropriately to extracellular stimuli. Aberrant cell signaling has been implicated in many diseases in particular cancer. The non-stimulated state is particularly important for cancer research as it mimics the early stages of tumourgenesis, when cells at the centre of a growing tumour are unable to receive any stimulus due to surrounding cells. In the absence of extracellular stimulation aberrant signaling can be caused by fluctuations in protein concentrations. Grb2 is a ubiquitously expressed adaptor protein, essential to many signaling pathways. Preliminary data suggests that Grb3-3 a naturally occurring isoform of Grb2 exerts dominant negative control over Grb2. Therefore the balance between the intrinsic levels of these two proteins will influence key signaling pathways. Grb3-3 expression was observed in non-cancerous breast cells but was reduced in breast cancer cells suggesting a potential role of Grb3-3 in rescuing deregulated Grb2 mediated signaling. The aims of this project are to determine structurally and mechanistically how Grb3-3 binds and inhibits Grb2, to investigate their expression in normal and cancer cells and to understand what controls the levels of these two proteins in the cell.