A new mechanism of Ras activation in cancer and how to drug target it
KTH Applied Physics seminars
Tuesday 13 October 2015
to 17:00 at
Daniel Abankwa (PhD, Turku Centre for Biotechnology, Åbo Akademi University)
The small GTPase Ras is highly mutated in human cancers and thus a major driver of cell transformation and tumorigenesis. In the plasma membrane approximately 40% of Ras proteins are organized into nanoscopic signaling platforms, called nanocluster. Ras nanocluster are dynamic proteo-lipid complexes that contain 6-8 Ras proteins and they are essential for Ras signaling. Lateral segregation of Ras isoforms to distinct nanocluster furthermore contributes to their specific activity. However, little is known about the composition, functioning and physiological relevance of Ras nanocluster.
Using biochemical, molecular cell biological, fluorescence superresolution microscopic and computational methods, we investigate how isoform-specific Ras nanoclusters are regulated. In addition, we exploit chemical screening to generate new tools to study Ras nanocluster and explore the potential to generate new lead compounds against Ras in cancer.
Our latest results revealed an unprecedented mechanism of Ras over-activation in cancer. Certain tumor-associated mutations increase Ras activity by uniquely augmenting its nanoclustering, as not other biochemical activities are significantly affected. These findings validate Ras nanocluster as drug-targets. We therefore use customized nanoclustering-FRET biosensors to identify compounds that specifically affect the membrane organization of Ras and thus its signaling. This recently lead us to the discovery of cancer stem cell active drugs, which specifically affect K-ras signaling.
Our work aims at the complete description of the Ras signalling architecture on the membrane. We expect that improved understanding of Ras nanoclustering has special potential to yield innovative cancer-drug targets, biomarkers and -drugs. Based on our evidence for nanoclustering of other classes of membrane anchored signalling proteins, we propose a broad implication of this mechanism in biology.