The Mystery of Rap1 Suppression of Oncogenic Ras

Rap1, a small GTPase very similar to Ras, suppresses oncogenic Ras phenotype; albeit not completely. The initial hypothesis was that Ras and Rap1 compete for a common target, but none has been found.One reported function of Rap1 is to modulate the activity of Raf kinases, thus MAPK signaling. Based on published observations, we propose that Rap1 suppresses MAPK signaling via Raf-1 but not via BRAF. We suggest that Rap1 high-affinity binding to Raf-1's cysteine-rich domain (CRD) disfavors Rap1 interaction with Raf-1's Ras-binding domain (RBD). BRAF's CRD has lower affinity to Rap1; its RBD can bind to Rap1.The presence of active Rap1 in oncogenic Ras nanoclusters reduces (dilutes) the number of the oncogenic Ras molecules in the cluster, thus suppressing Ras activation of Raf-1 but not of BRAF.We suggest that Rap1 suppression of Ras is likely to be Ras and Rap1 isoform specific. 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. 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.