[Are rap genes anti-oncogenes?]

The products of the ras-related rap genes (rap1 and rap2) are small G-proteins that share a high degree of structural (around 50% of identical amino acids) and functional homology with the products of ras oncogenes. In particular, the sequence of the effector domain of ras and rap proteins is identical, which has prompted speculations that they might compete for interaction with a common effector. In effect, by attempting to identify genes whose expression would be capable of reverting the phenotype of ras-transformed cells, the laboratory of Makoto Noda isolated the Krev-1 gene that was found to encode the same protein as the rap1A gene. Biochemical studies have since shown that the rap1 protein effectively competes with ras proteins for their interaction with the p120-GAP protein, a potential effector of the biological activity of ras proteins that strongly stimulates their GTPase activity; however, p120-GAP does not stimulate the GTPase activity of the rap1 protein. In contrast, the rap2 protein has no effect on the interaction between ras proteins and p120-GAP. Similarly, whereas overexpression of the rap1 protein is able to antagonize the transforming potential of oncogenic ras proteins, a considerable overexpression of normal or mutated rap2 proteins has no effect on cellular proliferation or transformation induced by ras oncogenes. It is therefore concluded that rap genes cannot be considered as anti-oncogenes; whether the physiological function of the rap1 protein is to modulate the activity of ras proteins, or its antagonistic effect is merely attributable to its experimental overexpression remains to be established.