Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation

eLife

Kari Kopra¹  Harri Härmä¹  Hong Liang²  Yong Zhou²  John F Hancock²  Tero Aittokallio³  Alok Jaiswal³  Camilo Guzmán⁴  Benoit Lectez⁴  Alessio Ligabue⁴  Daniel Abankwa⁴  Maja Šolman⁴  Olga Blaževitš⁴ 

[1] Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku, Turku, Finland;Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, United States;Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;Turku Centre for Biotechnology, Åbo Akademi University, Turku, Finland;

关键词: Ras;    cancer;    membrane;    nanoclustering;    signalling;   

DOI  :  10.7554/eLife.08905

来源: DOAJ

【 摘 要 】

Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.

【 授权许可】

Unknown