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.

几十年前，人们观察到 Rap1（一种与 Ras 非常相似的小型 GTP 酶）可以抑制致癌 Ras 表型，从而恢复其转化。所提出的理由一直存在，一直是 Ras 和 Rap1 之间为了共同目标而竞争。然而，什么也没有找到。还有令人费解的是 Rap1 对 Raf-1 的抑制与对 BRAF 的激活。人们对 Rap1 重新产生兴趣，设想通过抑制剂捕获其 Ras 抑制作用。在这里，我们回顾文献并解开谜团。体内致癌 Ras 存在于不同亚型的纳米簇中。纳米簇内 Rap1 的存在减少了成簇致癌 Ras 分子的数量，从而抑制 Raf-1 激活和丝裂原激活蛋白激酶 (MAPK) 信号传导。纳米聚类表明 Rap1 抑制依赖于 Ras 同工型。总而言之，似乎不太可能出现有效的 Rap1 样抑制剂。