• セミナー
40 ExCELLSセミナー


第40回 ExCELLSセミナーを開催いたします。
本セミナーは、共同利用・共同研究システム形成事業 「学際領域展開ハブ形成プログラム」

 ※本セミナーは日本語で実施されます。Seminar Language: Japanese


2024年3月4日(月) 16:00〜17:00


  【会場】山手3号館2F西 大会議室   
  【配信】Zoom ※所内メールでURLをお知らせします 


Prof. Mitsuhiko Ikura
Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto


Targeting the untargetable: RAS in cancer


RAS proteins are frequently mutated in cancer (~30% of all human tumours). Despite enormous efforts in RAS research over three decades, RAS has been considered as “untargetable” until very recently, mainly because there is no obvious pocket in known structures. Furthermore, our understanding on how RAS proteins function at the plasma membrane surface and how it interacts with effector and regulatory proteins has been incomplete, since most previous biochemical and biophysical studies were carried out using truncated RAS proteins in membrane-free states. Human isoform KRAS4B associates with the plasma membrane through a farnesylated C-terminus and an adjacent polybasic region, which influences its orientation on the membrane surface. KRAS is also regulated by various post-translational modifications as well as interactions with other cellular factors, making our research task even more challenging. The lecture will discuss our NMR approaches to investigate KRAS at the membrane surface using the ‘nanodisc’ membrane platform, as well as our recent structural and biochemical studies of two regulatory pathways which directly act on KRAS: Src phosphorylation of KRAS (Gebregiworgis/Kano et al., Nat. Commun. 2019 & 2021) and Ca2+-calmodulin (CaM)-dependent translocation of KRAS (Grant et al., Sic. Signal. 2020). Several oncogenic mutants of KRAS were studied in conjunction with these and other regulatory pathways as well as their effects on the GTPase cycle and RAS function. Our studies provide more comprehensive insights into the intracellular signaling circuits in controlling RAS function and provide valuable clues for inhibitor development. Supported by CCS, CIHR, NSERC, CFI & PMCF.



加藤 晃一(生体分子動秩序創発研究グループ)