Trends in Cell Biology
OpinionRan GTPase: a master regulator of nuclear structure and function during the eukaryotic cell division cycle?
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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2015, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The Ras subfamily of small GTPase controls cell growth [1], whereas the Rho subfamily regulates cell morphology and migration [2]. The Rab subfamily modulates dynamic inner membrane transport [3], and the Ran subfamily regulates nuclear transport [4]. In the Rab subfamily, Rab5 was first identified as a factor that regulates early endocytic pathways [5] and vacuolar function [6].