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タイトル Ras plasma membrane interactions: identifying new drug targets
講演者 John F. Hancock教授
所属 University of Texas Medical School at Houston
開催日 2012-12-18 10:30
終了日 2012-12-18 12:00







講演者:John F. Hancock教授(テキサス大学医学部ヒューストン校)

タイトル:Ras plasma membrane interactions: identifying new drug targets

要旨:Ras proteins regulate signaling pathways important for cell growth, differentiation and survival. Oncogenic mutant Ras proteins are commonly expressed in human tumors, with mutations of the K-Ras isoform being most prevalent. To be active, Ras proteins must undergo posttranslational processing and associate with the plasma membrane. The plasma membrane is a complex, dynamic structure with heterogeneity on many length and time scales that in turn imposes a non-random distribution on both integral and peripheral lipid anchored proteins. We have studied plasma membrane lateral heterogeneity in the context of Ras and shown that the three ubiquitously expressed Ras isoforms H-, K-Ras, N-Ras operate in spatially discrete, transient, dynamic nanoclusters on the plasma membrane. H-, K- and N-Ras all undergo GTP-regulated segregation between different types of nanodomain. Our results show that approximately 30–40% of Ras proteins assemble into clusters of 6–8 proteins on the plasma membrane. These protein-lipid assemblies have a radius of ~9nm and lifetime of 0.1-0.5s. Importantly, Ras.GTP nanoclusters are the exclusive sites of effector recruitment and activation on the plasma membrane such that Ras signal transmission fails if nanoclustering is abrogated. We are now interested in determining the structural, biophysical and molecular basis for Ras nanoclustering, as well as deciphering the poorly characterized trafficking pathway used by K-Ras to access the plasma membrane from the ER.  I will discuss our recent work in these areas and show that Ras nanoclustering on the plasma membrane, and K-Ras trafficking both represent tractable drug targets in the quest for novel anti-Ras therapeutics. 



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