Ran GTPase: a master regulator of nuclear structure and function during the eukaryotic cell division cycle?

doi:10.1016/S0962-8924(01)02071-2

Trends in Cell Biology

Volume 11, Issue 9, 1 September 2001, Pages 366-371

https://doi.org/10.1016/S0962-8924(01)02071-2 Get rights and content

Abstract

Ran is an abundant GTPase that is highly conserved in eukaryotic cells and has been implicated in many aspects of nuclear structure and function, especially determining the directionality of nucleocytoplasmic transport during interphase. However, cell-free systems have recently shown that Ran plays distinct roles in mitotic spindle assembly and nuclear envelope (NE) formation in vitro. During spindle assembly, Ran controls the formation of complexes with importins, the same effectors that control nucleocytoplasmic transport. Here, we review these advances and discuss a general model for Ran in the coordination of nuclear processes throughout the cell division cycle via common biochemical mechanisms.

Section snippets

Molecular marker of the nucleus?

Like other GTPases, Ran exists in GTP- and GDP-bound conformations that interact differently with effectors. Conversion between these forms and the assembly or disassembly of effector complexes requires the interaction of regulator proteins. The intrinsic GTPase activity of Ran is very low, but it is greatly stimulated by a GTPase-activating protein (RanGAP1) located in the cytoplasm. By contrast, RCC1, a guanine nucleotide exchange factor that generates Ran–GTP, is bound to chromatin and

Ran directs nucleocytoplasmic transport…

A gradient in Ran–GTP concentrations across the NE has been proposed to be crucial for the directionality of transport of many macromolecules through the nuclear pores 7, 8, 9 (Fig. 1). In nucleocytoplasmic transport, Ran functions by controlling the assembly and disassembly of complexes formed between transported cargoes and a family of Ran-binding proteins that act as receptors for targeting sequences on the cargo ⁶. In the nucleus, association of Ran–GTP with receptors that are required for

…mitotic spindle assembly…

Ran or its interacting proteins have been implicated in aspects of cell cycle progression for many years, but it was difficult to distinguish direct effects from secondary effects that undoubtedly occur when nucleocytoplasmic transport is disrupted. In 1999, the breakthrough demonstration of a role in mitosis came from a number of groups using Xenopus egg extracts as a model cell-free system that is amenable to biochemical dissection 12, 13, 14, 15, 16. Kalab et al.¹³ provided the first

…and NE assembly!

At the end of mitosis, the mitotic spindle is disassembled and microtubules return to interphase dynamics. The NE is re-assembled around chromatin, nuclear pore complexes are reformed, nucleocytoplasmic transport is restarted and the distinct environment of the nucleus is re-established. Interphase Xenopus egg extracts provide a model system for studying the assembly of the nucleus from sperm chromatin. First, the chromatin undergoes decondensation, a process that involves the exchange of basic

Does Ran coordinate the cell division cycle?

Does Ran play a merely passive role during the reorganization of nuclear morphology and function during the cell division cycle, or does it control the timing or otherwise coordinate these events? Ran seems to act through common biochemical mechanisms, so how are its effects directed towards specific substrates during interphase and mitosis? And how does it switch from organizing the spindle during mitosis to inducing NE assembly after mitosis? One possibility is that Ran–GTP is relatively

Are Ran's functions common to all eukaryotic cells?

Are the roles of Ran identified in Xenopus egg extracts, namely nucleocytoplasmic transport, mitotic spindle assembly and NE assembly, also valid in vivo and are they conserved among all eukaryotes? There is good evidence that disruption of the Ran system perturbs nucleocytoplasmic transport in intact cells ⁶, but its roles in mitosis are less well characterized. Ran itself is a highly conserved protein and is present in all eukaryotic cells that have been examined, including the primitive

Conclusions

It is now apparent that nucleocytoplasmic transport is only one of Ran's functions and that it plays a wider role in coordinating nuclear functions throughout the cell cycle. In nucleocytoplasmic transport and mitotic spindle assembly, Ran acts through common effectors to direct distinct processes. The challenge now is to determine how the system is regulated during the cell division cycle. Because the processes in which Ran is involved, particularly correct segregation of the genome on the

Acknowledgements

We thank our colleagues W. Moore, J. Hutchins and F. Nicolás for helpful discussion. Work in our laboratory is supported by the Biotechnology and Biological Sciences Research Council, the Medical Research Council and The Cancer Research Campaign.

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Citation Excerpt :
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Trends in Cell Biology

OpinionRan GTPase: a master regulator of nuclear structure and function during the eukaryotic cell division cycle?

Abstract

Section snippets

Molecular marker of the nucleus?

Ran directs nucleocytoplasmic transport…

…mitotic spindle assembly…

…and NE assembly!

Does Ran coordinate the cell division cycle?

Are Ran's functions common to all eukaryotic cells?

Conclusions

Acknowledgements

Cell

Trends Cell Biol.

Cell

Mol. Cell

FEBS Lett.

Curr. Biol.

Cell

Cell

Curr. Biol.

Curr. Opin. Cell Biol.

J. Mol. Biol.

J. Biol. Chem.

Chromatin-independent nuclear envelope assembly induced by Ran GTPase in Xenopus egg extracts

Science

Transport between the cell nucleus and the cytoplasm

Annu. Rev. Cell Dev. Biol.

The GTP-binding protein Ran/TC4 is required for protein import into the nucleus

Nature

The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus

EMBO J.

The direction of transport through the nuclear pore can be inverted

Proc. Natl. Acad. Sci. U. S. A.

Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors and nucleoporins

Cell

Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic spindle formation

Nature

Self-organization of microtubule asters induced in Xenopus egg extracts by GTP-bound Ran

Science

Opinion
Ran GTPase: a master regulator of nuclear structure and function during the eukaryotic cell division cycle?