GAPs Specific for the rap1/Krev-1 Protein

Among the myriad of recently discovered low molecular mass GTP-binding proteins ^{1 , 2} the rap1/Krev-1 protein exhibits the highest degree of identity to p21^ras, particularly in the so-called effector region where the two proteins are virtually identical. ³ While they have apparently different, possibly even opposing activities in vivo, the sequence homology between the ras and rapi proteins suggests they are regulated by similar mechanisms. It is clear from the cellular transforming activities of various p21^ras mutants that the GTP-bound form of the ras protein is required for its activity. ⁴ Likewise, the GTP-bound form of the rapi protein is probably responsible for whatever function it performs in the cell. The activities of these proteins are terminated by hydrolysis of GTP to GDP. In support of this is the finding that an in vitro activity of p21^rap1, the inhibition of rasGAP activity, is GTP-dependent. ^{5 , 6} Moreover, the ability of p21^rap1 to suppress transformation by v-ras also appears to be GTP-dependent. ⁷ However, p21^rap1 possesses only a very weak intrinsic GTPase activity ⁶ and therefore, once activated, would be expected to remain active for a considerable duration. As for p21^ras, though, there exist GTPase-activating proteins (GAPs) that specifically stimulate GTP hydrolysis by p21^rap1. ^{8 , 9} The discovery of GAPs specific for p21^rap1, as well as for other ras-related proteins, uncovers a common theme inherent in the regulation of the ras-related family of GTP-binding proteins. However, on closer examination of rapi-GAP we find that the analogy to the ras system breaks down, revealing an entirely new class of GAP; one that seems related to rasGAP only by virtue of being a GAP.