Monday, May 5, 2014 - 16:00 to 17:00
Weniger 116
Event Speaker: 
Prof. Xiaolin Nan, OHSU
Local Contact: 

The Ras small GTPases reside on the cell membrane and regulate cell growth, survival, and many other vital processes through the Raf/MAPK and PI3K/Akt pathways. Mutation-activated Ras is a potent oncogenic driver frequently associated human cancer. While it is well established that Ras activity requires binding to the cell membrane and GTP, attempts to inhibit mutant Ras in human cancers based on these mechanisms have proven difficult. Here we show that Ras also needs to form dimers to activate Raf/MAPK and/or PI3K/Akt. Using quantitative photoactivated localization microscopy (PALM), a recent single molecule superresolution imaging technique, we found that formation of Ras-GTP dimers coincides with Raf and/or PI3K activation. Moreover, monomeric Ras is unable to activate these effectors unless artificially dimerized. Furthermore, Ras dimerization and signaling depends on an intact CAAX motif at the C-terminus. Similarly, we demonstrate that Raf also forms dimers under various activating conditions including the presence of mutant Ras. Together, these results suggest that Ras drives cell signaling and oncogenesis through a dimerization-dependent mechanism, and that disruption of Ras dimer formation could be of therapeutic value in mutant Ras-driven tumors.