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Spatial and temporal coordination of mitosis by Ran GTPase

Nature Reviews Molecular Cell Biology volume 9, pages 464–477 (2008)Cite this article

Key Points

  • Ran, a small Ras-related GTPase, controls the directionality of transport of macromolecules across the nuclear envelope through the nuclear pore complex.

  • RanGTP is generated in the nucleus by a Ran-specific guanine nucleotide-exchange factor, RCC1, whereas GTP hydrolysis by Ran requires its interaction with the GTPase-activating protein RanGAP and Ran-binding proteins. The compartmentalization of these regulators of the GTP–GDP cycle of Ran, together with the active import of Ran into the nucleus, ensures a high concentration of RanGTP in the nucleus.

  • RanGTP functions by binding karyopherins, proteins of the importin and exportin family of transport factors, causing them to either bind (exportins) or release (importins) their transport cargoes.

  • Ran also has important roles during mitosis, when the boundary between the nucleoplasm and the cytoplasm breaks down in animal cells. Production of RanGTP by RCC1 on chromatin during mitosis is proposed to generate a gradient of RanGTP away from chromosomes that provides a spatial signal for the proper assembly of the spindle.

  • Ran directs mitotic spindle assembly by promoting the release of spindle assembly factors from inhibited complexes with importins. RanGTP might also cause the assembly of multimeric protein complexes at specific sites such as kinetochores and centrosomes.

  • Ran, acting through importins, has an important role in the reassembly of the nuclear envelope at the end of mitosis and in the formation of nuclear pore complexes.

  • The Ran system provides examples of the spatial regulation of subcellular organization through diffusible signalling gradients and the control of the assembly multimeric protein complexes on specific structures.

Abstract

The small nuclear GTPase Ran controls the directionality of macromolecular transport between the nucleus and the cytoplasm. Ran also has important roles during mitosis, when the nucleus is dramatically reorganized to allow chromosome segregation. Ran directs the assembly of the mitotic spindle, nuclear-envelope dynamics and the timing of cell-cycle transitions. The mechanisms that underlie these functions provide insights into the spatial and temporal coordination of the changes that occur in intracellular organization during the cell-division cycle.

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Figure 1: Ran directs nucleocytoplasmic transport.
Figure 2: Disruption of the GTP–GDP cycle of Ran causes aberrant mitotic spindle assembly.
Figure 3: Generation of a gradient of RanGTP complexed to importin-β from mitotic chromosomes.
Figure 4: Release of spindle assembly factors from inhibitory complexes by RanGTP during mitotic spindle assembly.
Figure 5: Regulation of multiprotein complexes by RanGTP during mitotic spindle assembly.
Figure 6: A simple model for the role of Ran in nuclear-envelope assembly.
Figure 7: Regulation of RanGTP generation during prometaphase and metaphase by phosphorylation.

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Acknowledgements

We acknowledge the many contributions towards the understanding of the Ran system that we have not been able to discuss here owing to space constraints. We thank H. Sanderson and F. Hood for comments on the manuscript. P.R.C. wishes to acknowledge the pioneering work of T. Nishimoto, A. Wittinghofer, C. Klebe, H. Ponstingl and F. R. Bischoff, who first interested him in Ran. Work in our laboratories is supported by the Biotechnology and Biological Sciences Research Council (P.R.C.), and the National Natural Science Foundation of China, the State Key Basic Research and Development Plan, and Scientific Research Foundation for Returned Overseas Chinese Scholars (C.Z.). P.R.C is a Royal Society-Wolfson Research Award holder and C.Z. is a Changjiang Professorship holder.

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Authors and Affiliations

  1. Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland, UK

    Paul R. Clarke

  2. The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education; and The National Key Laboratory of Bio-membrane and Membrane Biotechnology, College of Life Sciences, Peking University,

    Chuanmao Zhang

  3. and The National Key Laboratory of Bio-membrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China

    Chuanmao Zhang

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Glossary

Mitotic spindle

The bipolar structure assembled from microtubules that is focused at the poles by a microtubule-organizing centre, usually a centrosome in animal cells, on which duplicated chromosomes are aligned in the middle in metaphase and then separated, with one copy going towards each pole during anaphase.

Kinetochore

A large multiprotein complex that assembles onto the centromere of the chromosome and links the chromosome to the microtubules of the mitotic spindle.

Guanine nucleotide-exchange factor

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

GTPase-activating protein

(GAP).A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs can negatively regulate GTPases by converting them from active (GTP bound) to inactive (GDP bound).

Nucleoporin

A protein subunit of the nuclear pore complex. Many nucleoporins have hydrophobic regions containing Phe-Gly (FG) repeats.

Exportin

A transport factor, such as CRM1, that is involved in the export of complexes from the nucleus to the cytoplasm.

Nuclear export signal

A short sequence motif on a protein that acts as a binding site for an exportin and thereby targets the protein to the cytoplasm. An example is the Leu-rich sequence that binds CRM1.

Nuclear localization signal

A short sequence motif on a protein that acts as a binding site for an importin and thereby targets the protein to the nucleus. An example is a Lys-rich sequence that binds importin-α.

Karyopherin

A protein that acts as a receptor for nuclear localization or nuclear export sequences. Common karyopherins that are involved in protein transport are the members of the importin-β superfamily.

HEAT repeat

A sequence of ∼40 amino-acid residues found in diverse proteins and characterized by conserved hydrophobic amino acids that are folded into a bent helix and a straight helix.

Centriole

A small organelle consisting of two short, barrel-like arrays of microtubules that organize the centrosome and contributes to cytokinesis and cell-cycle progression.

FRET reporter

(Fluorescence resonance energy transfer reporter). A fusion protein that contains two fluorescent groups, between which fluorescence energy transfer can occur in order to omit light at a different wavelength. A reporter protein can either lose a FRET signal, as the two fluorescent groups are moved away from each other, or gain a FRET signal, when they are brought together. These signal changes can be caused by a conformational change following target-protein binding.

E3 ubiquitin ligase

The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

E3 SUMO ligase

The final enzyme in a series that transfers the small ubiquitin-related polypeptide SUMO to a substrate protein.

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Clarke, P., Zhang, C. Spatial and temporal coordination of mitosis by Ran GTPase. Nat Rev Mol Cell Biol 9, 464–477 (2008). https://doi.org/10.1038/nrm2410

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