Profiling n3-PUFA modulation on Ras nanocluster organisation and function (360G-Wellcome-109309_Z_15_A)

Ras proteins are molecular switches that regulate signalling pathways involved in cell proliferation and survival. These form transient nanoclusters on the plasma membrane, whereby Ras effectors are recruited. The spatiotemporal organisation of lipids within the Ras nanoclusters determine Ras function in signal transduction. Incorporation of dietary fats such as omega 3 polyunsaturated fatty acids (n3-PUFA) into the membrane phospholipid bilayer alters their biophysical properties. In addition, n3-PUFA has been associated with cancer prevention and attenuation of Ras signalling. We propose that n3-PUFA modulation of Ras nanoclustering is responsible for the attenuated signalling response. Different Ras isoforms occupy distinct nanoclusters. In addition, both isoform and oncogenic mutation-specific Ras signalling differ. It is unclear whether the role of n3-PUFA is highly context specific or if they are pan-Ras modulators. Therefore, to test our hypothesis and determine the specificity of n3-PUFA effects, we will profile the proteome microenvironment of different Ras isoforms and mutation variants treated +/- n3-PUFA. In parallel, studies measuring the nanoclustering responses of the same Ras variants to n3-PUFA will also be performed. These results will be correlated with studies profiling the signalling network response. Together, these studies will define the extent to which n3-PUFA modulates oncogenic Ras signalling.