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

Elife. 2015 Aug 14:4:e08905. doi: 10.7554/eLife.08905.


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.

Keywords: Ras; biophysics; cancer; cell biology; human; membrane; nanoclustering; signalling; structural biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Membrane / metabolism
  • Cell Proliferation
  • Cell Transformation, Neoplastic*
  • Humans
  • Mutation*
  • Neoplasms / pathology*
  • Protein Multimerization
  • Signal Transduction
  • ras Proteins / genetics*
  • ras Proteins / metabolism*


  • ras Proteins