The small GTPase Ran: interpreting the signs

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Abstract

The small GTPase Ran has roles in nuclear transport, mitotic spindle assembly and nuclear envelope assembly. During the past three years, it has become clear that many of these processes rely on conserved molecular mechanisms involving Ran–GTP-binding proteins of the importin-β superfamily. Moreover, recent experimental evidence has documented the distribution of Ran-GTP within cells and supported the notion that Ran plays a central role in the spatial and temporal organization of the eukaryotic cell.

Introduction

To direct spatially regulated processes, the sites of Ran–GTP generation and utilization must be carefully localized. Like other Ras-family members, Ran has slow intrinsic rates of GTP hydrolysis and nucleotide exchange, and these reactions are enzymatically catalyzed in vivo. The Ran GTPase-activating protein (RanGAP) is localized in the interphase cytoplasm 1., 2., 3. and the Ran nucleotide exchange factor RCC1 is bound to chromatin 4., 5.. Therefore, Ran is GDP-bound in the cytoplasm during interphase and GTP-bound in the nucleus. During mitosis, Ran–GTP is generated on chromosomes, establishing a field of Ran–GTP around mitotic chromosomes. Although several lines of evidence support a model wherein gradients of Ran–GTP are interpreted to spatially organize cells, recent studies also suggest that the role of Ran in cellular function is more complex in both its design and regulation.

Here, we discuss the mechanisms through which the distribution of Ran–GTP controls nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope assembly.

Section snippets

Ran–GTP distribution

Ran nucleotide exchange occurs in association with chromatin. RCC1 binds to chromatin through histones H2A and H2B, causing a modest twofold stimulation of the exchange activity of RCC1 [6••]. Ran also binds to chromatin [7], both through RCC1 and through RCC1-independent interactions with histones H3 and H4 [8••]. Both Ran–GTP and Ran–GDP appear to bind in this fashion. Although the functional consequences of Ran–histone interactions are not fully apparent, it is clear that these interactions

Nuclear transport

The role of Ran in nuclear trafficking has been studied extensively and a well-established scheme developed [9]. Ran–GTP binds to importin-β-family transport receptors and regulates their association with cargo (Figure 2). The polarized nuclear–cytoplasmic distribution of Ran–GTP during interphase leads to vectorial transport across the nuclear pore complex (NPC). Import receptors bind their cargo in the cytosol. After entering the nucleus, import cargo is released through receptor binding to

Conclusions

Current models suggest that high levels of Ran–GTP generated by its chromatin-bound exchange factor serve to organize numerous processes with respect to the location of chromosomes. However, we are only beginning to understand how generation and utilization of Ran–GTP are spatially directed. Intriguing interspecies differences could further point the way toward understanding the evolution of this pathway to conform to the cellular dynamics and environmental requirements for different organisms.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

We would like to thank Jomon Joseph and Alexei Arnaoutov for critical reading of the manuscript.

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