The Mystery of Rap1 Suppression of Oncogenic Ras

Ruth Nussinov, Hyunbum Jang, Mingzhen Zhang, Chung Jung Tsai, Anna A. Sablina

Research output: Contribution to journalReview articlepeer-review

Abstract

Decades ago, Rap1, a small GTPase very similar to Ras, was observed to suppress oncogenic Ras phenotype, reverting its transformation. The proposed reason, persisting since, has been competition between Ras and Rap1 for a common target. Yet, none was found. There was also Rap1’s puzzling suppression of Raf-1 versus activation of BRAF. Reemerging interest in Rap1 envisages capturing its Ras suppression action by inhibitors. Here, we review the literature and resolve the enigma. In vivo oncogenic Ras exists in isoform-distinct nanoclusters. The presence of Rap1 within the nanoclusters reduces the number of the clustered oncogenic Ras molecules, thus suppressing Raf-1 activation and mitogen-activated protein kinase (MAPK) signaling. Nanoclustering suggests that Rap1 suppression is Ras isoform dependent. Altogether, a potent Rap1-like inhibitor appears unlikely.

Original languageEnglish
Pages (from-to)369-379
Number of pages11
JournalTrends in Cancer
Volume6
Issue number5
DOIs
StatePublished - May 2020

Keywords

  • BRAF
  • K-RAS
  • K-Ras dimers
  • KRAS
  • KRAS4A
  • KRAS4B
  • NORE1A
  • Raf
  • Raf-1
  • cancer
  • drug discovery
  • inhibitors
  • nanocluster
  • signaling pathways

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