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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
内容

第2回創薬育薬産学官連携セミナーの開催(大学院講義「薬理・基礎理論」との同時開催)について

 

下記のとおり,第2回創薬育薬産学官連携セミナーを開催します.今回は,低分子量G蛋白質Rasのタンパク質-脂質間相互作用による活性化の時空間制御機構に関する最先端研究ならびにその成果をもとにした創薬への応用展開について御講演していただきます.皆様,奮ってご参加ください.

 

日時:平成24年12月18日(水)午前10時30分~12時00分

場所:薬学部2号館5階第4講堂

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. 

 

【参考文献】

1. Cho KJ et al. Curr Biol, 22, 945-955 (2012). 

2. Walser PJ et al. Cell. 150(4), 752-763 (2012).

3. Kholodenko BN et al. Nat Rev Mol Cell Biol. 11(6), 414-26 (2010). Review.

4. Abankwa D et al. Proc Natl Acad Sci U S A. 107(3),1130-1135 (2010).

5. Tian T et al. Nat Cell Biol. 9(8):905-14 (2007).

 

連絡先:西田基宏(内6557)

創薬育薬産学官連携分野HP: http://soyaku.phar.kyushu-u.ac.jp