Nucleocytoplasmic protein transport and recycling of Ran

The active transport of proteins into and out of the nucleus is mediated by specific signals, the nuclear localization signal (NLS) and nuclear export signal (NES), respectively. The best characterized NLS is that of the SV40 large T antigen, which contains a cluster of basic amino acids. The NESs w ere first identified in the protein kinase inhibitor (PKI) and HIV Rev prot ein, which are rich in leucine residues. The SV40 T-NLS containing transpor t substrates are carried into the nucleus by an importin alpha/beta heterod imer. Importin a recognizes the NLS and acts as an adapter between the NLS and importin beta, whereas importin beta interacts with importin alpha boun d to the NLS, and acts as a carrier of the NLS/importin alpha/beta trimer. It is generally thought that importin alpha and beta are part of a large pr otein family. The leucine rich NES-containing proteins are exported from th e nucleus by one of the importin beta family molecules, CRM1/exportin 1. A Ras-Like small GTPase Ran plays a crucial role in both import/export pathwa ys and determines the directionality of nuclear transport. It has recently been demonstrated in living cells that Ran actually shuttles between the nu cleus and the cytoplasm and that the recycling of Ran is essential for the nuclear transport. Furthermore, it has been shown that nuclear transport fa ctor 2 (NTF2) mediates the nuclear import of RanGDP. This review largely fo cuses on the issue concerning the functional divergence of importin alpha f amily molecules and the role of Ran in nucleocytoplasmic protein transport.