Journal
TRENDS IN CANCER
Volume 6, Issue 5, Pages 369-379Publisher
CELL PRESS
DOI: 10.1016/j.trecan.2020.02.002
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Funding
- National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]
- H2020 European Research Council (ub-RASDisease)
- Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research
- NATIONAL CANCER INSTITUTE [ZIABC010440, ZIABC010441, ZIABC010442] Funding Source: NIH RePORTER
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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.
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