Review Article | Published:

The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly

Nature Cell Biology volume 4, pages E177E184 (2002) | Download Citation

Subjects

Abstract

The small GTPase Ran is a key regulator of nucleocytoplasmic transport during interphase. The asymmetric distribution of the GTP-bound form of Ran across the nuclear envelope — that is, large quantities in the nucleus compared with small quantities in the cytoplasm — determines the directionality of many nuclear transport processes. Recent findings that Ran also functions in spindle formation and nuclear envelope assembly during mitosis suggest that Ran has a general role in chromatin-centred processes. Ran functions in these events as a signal for chromosome position.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Nucleocytoplasmic transport: the soluble phase. Annu. Rev. Biochem. 67, 265–306 (1998).

  2. 2.

    & Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol. 15, 607–660 (1999).

  3. 3.

    et al. Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation. Genes Dev. 1, 585–593 (1987).

  4. 4.

    , & The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J. Cell Biol. 109, 1389–1397 (1989).

  5. 5.

    & Mitotic regulator protein RCC1 is complexed with a nuclear ras-related polypeptide. Proc. Natl Acad. Sci. USA 88, 10830–10834 (1991).

  6. 6.

    , , & Interaction of the nuclear GTP-binding protein Ran with its regulatory proteins RCC1 and RanGAP1. Biochemistry 34, 639–647 (1995).

  7. 7.

    , , , & RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proc. Natl Acad. Sci. USA 91, 2587–2591 (1994).

  8. 8.

    , , , & Co-activation of RanGTPase and inhibition of GTP dissociation by Ran-GTP binding protein RanBP1. EMBO J. 14, 705–715 (1995).

  9. 9.

    et al. A giant nucleopore protein that binds Ran/TC4. Nature 376, 184–188 (1995).

  10. 10.

    , & A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. J. Cell Biol. 135, 1457–1470. (1996).

  11. 11.

    , , , & A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88, 97–107 (1997).

  12. 12.

    , & Nucleocytoplasmic transport: Ran, beta and beyond. Trends Cell Biol. 11, 497–503 (2001).

  13. 13.

    Dynamics of the endoplasmic reticulum and Golgi apparatus during early sea urchin development. Mol. Biol. Cell 11, 897–914 (2000).

  14. 14.

    , & The spindle: a dynamic assembly of microtubules and motors. Nature Cell Biol. 3, E28–E34 (2001).

  15. 15.

    Ran hits the ground running. Nature Cell Biol. 3, E69–E70 (2001).

  16. 16.

    & Microtubule cytoskeleton: No longer an also Ran. Curr. Biol. 9, R704–R707 (1999).

  17. 17.

    & Beyond nuclear transport. Ran-GTP as a determinant of spindle assembly. J. Cell Biol. 146, 1205–1210 (1999).

  18. 18.

    , & The Ran GTPase regulates mitotic spindle assembly. Curr. Biol. 9, 481–484 (1999).

  19. 19.

    & Stimulation of microtubule aster formation and spindle assembly by the small GTPase Ran. Science 284, 1359–1362 (1999).

  20. 20.

    , , & Self-organization of microtubule asters induced in Xenopus egg extracts by GTP-bound Ran. Science 284, 1356–1358 (1999).

  21. 21.

    et al. Generation of GTP-bound Ran by RCC1 is required for chromatin-induced mitotic spindle formation. Nature 400, 178–181 (1999).

  22. 22.

    , & Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science 295, 2452–2456 (2002).

  23. 23.

    , , , & Ran binds to chromatin by two distinct mechanisms. Curr. Biol. (in the press).

  24. 24.

    et al. Chromosomal association of Ran during meiotic and mitotic divisions. (submitted).

  25. 25.

    et al. Ran induces spindle assembly by reversing the inhibitory effect of Importin α on TPX2 activity. Cell 104, 83–93 (2001).

  26. 26.

    et al. Importin β is a mitotic target of the small GTPase Ran in spindle assembly. Cell 104, 95–106 (2001).

  27. 27.

    et al. Role of Importin-β in coupling Ran to downstream targets in microtubule assembly. Science 291, 653–656 (2001).

  28. 28.

    & Direct binding of NuMA to tubulin is mediated by a novel sequence motif in the tail domain that bundles and stabilizes microtubules. J. Cell Sci. 115, 1815–1824 (2002).

  29. 29.

    , , , & Localization of the kinesin-like protein Xklp2 to spindle poles requires a leucine zipper, a microtubule-associated protein, and dynein. J. Cell Biol. 143, 673–685 (1998).

  30. 30.

    , , & A complex of NuMA and cytoplasmic dynein is essential for mitotic spindle assembly. Cell 87, 447–458 (1996).

  31. 31.

    , , & TPX2, a novel Xenopus MAP involved in spindle pole organization. J. Cell Biol. 149, 1405–1418 (2000).

  32. 32.

    et al. Regulated Ran-binding protein 1 activity is required for organization and function of the mitotic spindle in mammalian cells in vivo. Cell Growth Differ. 11, 455–465 (2000).

  33. 33.

    , & Premature of chromosome condensation in a ts DNA-mutant of BHK cells. Cell 15, 475–483 (1978).

  34. 34.

    & NuMA is required for the proper completion of mitosis. J. Cell Biol. 120, 947–957 (1993).

  35. 35.

    , & Requirement of guanosine triphosphate-bound ran for signal-mediated nuclear protein export. Science 276, 1842–1844 (1997).

  36. 36.

    , , & The fission yeast ran GTPase is required for microtubule integrity. J. Cell Biol. 151, 1101–1111 (2001).

  37. 37.

    , , & The GTPase Ran regulates chromosome positioning and nuclear envelope assembly in vivo. Curr. Biol. 12, 503–507 (2002).

  38. 38.

    , , & Ran-GTP coordinates regulation of microtubule nucleation and dynamics during mitotic-spindle assembly. Nature Cell Biol. 3, 228–234 (2001).

  39. 39.

    et al. Ran stimulates spindle assembly by altering microtubule dynamics and the balance of motor activities. Nature Cell Biol. 3, 221–227 (2001).

  40. 40.

    et al. Kinesin-II is required for axonal transport of choline acetyltransferase in Drosophila. J. Cell Biol. 147, 507–518 (1999).

  41. 41.

    Integration of the centrosome in cell cycle control, stress response and signal transduction pathways. Curr. Opin. Cell Biol. 14, 35–43 (2002).

  42. 42.

    , , , & The NIMA-related kinase X-Nek2B is required for efficient assembly of the zygotic centrosome in Xenopus laevis. J. Cell Sci. 113, 1973–1984 (2000).

  43. 43.

    , , & Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans. J. Cell Biol. 155, 1109–1116 (2001).

  44. 44.

    & Drosophila aurora B kinase is required for histone H3 phosphorylation and condensin recruitment during chromosome condensation and to organize the central spindle during cytokinesis. J. Cell Biol. 152, 669–682 (2001).

  45. 45.

    , & Polo kinase and Asp are needed to promote the mitotic organizing activity of centrosomes. Nature Cell Biol. 3, 421–424 (2001).

  46. 46.

    Dynamics of the endoplasmic reticulum and Golgi apparatus during early sea urchin development. Mol. Biol. Cell 11, 897–914 (2000).

  47. 47.

    & Nuclear envelope assembly after mitosis. Trends Cell Biol. 7, 69–74 (1997).

  48. 48.

    & Nuclear membrane dynamics. Curr. Opin. Cell Biol. 5, 387–394 (1993).

  49. 49.

    , , & The nuclear envelope and the architecture of the nuclear periphery. J. Cell Biol. 91, 39s–50s (1981).

  50. 50.

    & The making and breaking of the endoplasmic reticulum. Traffic 1, 689–694 (2001).

  51. 51.

    & Inner nuclear membrane proteins: functions and targeting. Cell. Mol. Life Sci. 58, 1741–1747 (2001).

  52. 52.

    , & Nuclear lamins: their structure, assembly, and interactions. J. Struct. Biol. 122, 42–66 (1998).

  53. 53.

    , , , & Review: nuclear lamins — structural proteins with fundamental functions. J. Struct. Biol. 129, 313–323 (2001).

  54. 54.

    & Functional organization of the nuclear envelope. Annu. Rev. Cell Biol. 4, 335–374 (1988).

  55. 55.

    , & An integral membrane protein of the pore membrane domain of the nuclear envelope contains a nucleoporin-like region. J. Cell Biol. 122, 513–521 (1993).

  56. 56.

    et al. Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components. J. Cell Biol. 110, 883–894 (1990).

  57. 57.

    The nuclear pore complex. Genome Biol. 2, 47–53 (2001).

  58. 58.

    & From nucleoporins to nuclear pore complexes. Curr. Opin. Cell Biol. 9, 401–411 (1997).

  59. 59.

    & A tense time for the nuclear envelope. Cell 108, 301–304 (2002).

  60. 60.

    , , & The lamin B receptor of the inner nuclear membrane undergoes mitosis-specific phosphorylation and is a substrate for p34cdc2-type protein kinase. J. Biol. Chem. 267, 19035–19038 (1992).

  61. 61.

    & The regulation of mitotic nuclear envelope breakdown: a role for multiple lamin kinases. Prog. Cell Cycle Res. 1, 271–286 (1995).

  62. 62.

    et al. Cytoplasmic dynein as a facilitator of nuclear envelope breakdown. Cell 108, 97–107 (2002).

  63. 63.

    , , , & Nuclear envelope breakdown proceeds by microtubule-induced tearing of the lamina. Cell 108, 83–96 (2002).

  64. 64.

    & Remodeling the walls of the nucleus. Nature Rev. Mol. Cell Biol. (in the press).

  65. 65.

    & Disassembly of the nucleus in mitotic extracts: membrane vesicularization, lamin disassembly, and chromosome condensation are independent processes. Cell 48, 219–230 (1987).

  66. 66.

    & A distinct vesicle population targets membranes and pore complexes to the nuclear envelope in Xenopus eggs. J. Cell Biol. 112, 545–556 (1991).

  67. 67.

    & Distinct egg membrane vesicles differing in binding and fusion properties contribute to sea urchin male pronuclear envelopes formed in vitro. J. Cell Sci. 109, 1275–1283 (1996).

  68. 68.

    et al. Temporal differences in the appearance of NEP-B78 and a LBR-like protein during Xenopus nuclear envelope reassembly reflect the order recruitment of functionally discrete vesicle types. J. Cell Biol. 144, 225–240 (1999).

  69. 69.

    , , , & In vitro nuclear assembly with affinity-purified nuclear precursor vesicle fractions, PV1 and PV2. Eur. J. Cell Biol. 78, 593–600 (1999).

  70. 70.

    & Membrane-associated lamins in Xenopus egg extracts: identification of two vesicle populations. J. Cell Biol. 123, 501–152 (1993).

  71. 71.

    , Domain-specific disassembly and reassembly of nuclear membranes during mitosis. Exp. Cell Res. 230, 133–144 (1997).

  72. 72.

    & Sorting nuclear membrane proteins at mitosis. Trends Cell Biol. 10, 5–8 (2000).

  73. 73.

    et al. Nuclear membrane dynamics and reassembly in living cells: targeting of an inner nuclear membrane protein in interphase and mitosis. J. Cell Biol. 138, 1193–1206 (1997).

  74. 74.

    , & Integral membrane proteins of the nuclear envelope are dispersed throughout the endoplasmic reticulum during mitosis. J. Cell Biol. 137, 1199–1210 (1997).

  75. 75.

    et al. Golgi membranes are absorbed into and reemerge from the ER during mitosis. Cell 99, 589–601 (1999).

  76. 76.

    & Membrane fusion events during nuclear envelope assembly. Subcell. Biochem. 34, 273–302 (2000).

  77. 77.

    & Nuclear assembly. Annu. Rev. Cell Dev. Biol. 13, 669–695 (1997).

  78. 78.

    , , & Nuclear envelope assembly in Xenopus extracts visualized by scanning EM reveals a transport-dependent 'envelope smoothing' event. J. Cell Sci. 110, 1489–1502 (1997).

  79. 79.

    et al. Distinct AAA-ATPase p97 complexes function in discrete steps of nuclear assembly. Nature Cell Biol. 3, 1086–1091 (2001).

  80. 80.

    & Reconstituting the nuclear envelope and endoplasmic reticulum in vivo. Semin. Cell Dev. Biol. 7, 487–496 (1996).

  81. 81.

    & Nuclear envelope dynamics during male pronuclear development. Dev. Growth Differ. 39, 541–550 (1997).

  82. 82.

    , & Sperm decondensation in Xenopus egg cytoplasm is mediated by nucleoplasmin. Cell 65, 569–578 (1991).

  83. 83.

    & Nucleoplasmin remodels sperm chromatin in Xenopus egg extracts. Cell 69, 759–767 (1992).

  84. 84.

    & A trypsin-sensitive receptor on membrane vesicles is required for nuclear envelope formation in vitro. J. Cell Biol. 107, 57–68 (1988).

  85. 85.

    & Characterization of the membrane binding and fusion events during nuclear envelope assembly using purified components. J. Cell Biol. 116, 295–306 (1992).

  86. 86.

    & Nuclear pores and nuclear assembly. Curr. Opin. Cell Biol. 13, 363–375 (2001).

  87. 87.

    & Assembly of the nuclear pore: biochemically distinct steps revealed with NEM, GTPγS, and BAPTA. J. Cell Biol. 132, 5–20 (1996).

  88. 88.

    , & GTP hydrolysis is required for vesicle fusion during nuclear envelope assembly in vitro. J. Cell Biol. 116, 281–294 (1992).

  89. 89.

    & Roles of cytosol and cytoplasmic particles in nuclear envelope assembly and sperm pronuclear formation in cell-free preparations from amphibian eggs. J. Cell Biol. 98, 1222–1230 (1984).

  90. 90.

    , , & Functional role of newly formed pore complexes in postmitotic nuclear reorganization. Chromosoma 98, 233–241 (1989).

  91. 91.

    , & A lamin-independent pathway for nuclear envelope assembly. J. Cell Biol. 111, 2247–2259 (1990).

  92. 92.

    , & Targeting of membranes to sea urchin sperm chromatin is mediated by a lamin B receptor-like integral membrane protein. J. Cell Biol. 135, 1715–1725 (2000).

  93. 93.

    Formation of the sea urchin male pronucleus in cell-free extracts. Mol. Reprod. Dev. 56, 265–270 (2000).

  94. 94.

    , , & Spontaneous assembly of pore complex-containing membranes ('annulate lamellae') in Xenopus egg extract in the absence of chromatin. J. Cell Biol. 112, 1073–1082 (1991).

  95. 95.

    , , , & GTP hydrolysis by Ran is required for nuclear envelope assembly. Mol. Cell 5, 1013–1024 (2000).

  96. 96.

    & Chromatin-independent nuclear envelope assembly induced by Ran GTPase in Xenopus egg extracts. Science 288, 1429–1432 (2000).

  97. 97.

    & Roles of Ran-GTP and Ran-GDP in precursor vesicle recruitment and fusion during nuclear envelope assembly in a human cell-free system. Curr. Biol. 11, 208–212 (2001).

  98. 98.

    , , , & Role of Importin-β in the control of nuclear envelope sssembly by Ran. Curr. Biol. 12, 498–502 (2002).

  99. 99.

    & In vitro formation of the endoplasmic reticulum occurs independently of microtubules by a controlled fusion reaction. J. Cell Biol. 148, 883–898 (2000).

  100. 100.

    et al. Nuclear pore complexes form immobile networks and have a very low turnover in live mammalian cells. J. Cell Biol. 154, 71–84 (2001).

  101. 101.

    The nuclear envelope: filling in gaps. Nature Cell Biol. 3, E273–E274 (2001).

  102. 102.

    , & Roles of LAP2 proteins in nuclear assembly and DNA replication: truncated LAP2β proteins alter lamina assembly, envelope formation, nuclear size, and DNA replication efficiency in Xenopus laevis extracts. J. Cell Biol. 144, 1083–1096 (1999).

  103. 103.

    & Integral membrane proteins of the nuclear envelope interact with lamins and chromosomes, and binding is modulated by mitotic phosphorylation. Cell 73, 1267–1279 (1993).

  104. 104.

    & Rules to remodel by: what drives nuclear envelope disassembly and reassembly during mitosis? Crit. Rev. Eukaryot. Gene Expr. 9, 373–381 (1999).

  105. 105.

    & The AAA team: related ATPases with diverse functions. Trends Cell Biol. 8, 65–71 (1998).

  106. 106.

    et al. p47 is a cofactor for p97-mediated membrane fusion. Nature 388, 75–78 (1997).

  107. 107.

    et al. Role of p97 and syntaxin 5 in the assembly of transitional endoplasmic reticulum. Mol. Biol. Cell 11, 2529–2542 (2000).

  108. 108.

    et al. Syntaxin 5 is a common component of the NSF- and p97-mediated reassembly pathways of Golgi cisternae from mitotic Golgi fragments in vitro. Cell 92, 603–610 (1998).

  109. 109.

    et al. The conserved npl4 protein complex mediates proteasome-dependent membrane-bound transcription factor activation. Mol. Biol. Cell 12, 3226–3241 (2001).

  110. 110.

    et al. Mobilization of processed, membrane-tethered SPT23 transcription factor by CDC48(UFD1/NPL4), a ubiquitin-selective chaperone. Cell 107, 667–677 (2001).

  111. 111.

    , , , & A complex of mammalian Ufd1 and Npl4 links the AAA-ATPase, p97, to ubiquitin and nuclear transport pathways. EMBO J. 19, 2181–2192 (2000).

  112. 112.

    , & Membrane fusion and the cell cycle: Cdc48p participates in the fusion of ER membranes. Cell 82, 885–893 (1995).

  113. 113.

    , & The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652–656 (2001).

  114. 114.

    et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nature Cell Biol. 4, 134–139 (2002).

  115. 115.

    & Nuclear transport defects and nuclear envelope alterations are associated with mutation of the Saccharomyces cerevisiae NPL4 gene. Mol. Biol. Cell 7, 1835–1855 (1996).

  116. 116.

    in Cell Biology Monographs, Continuation of Protoplasmatologia, Vol. 2 (Springer, Wien, New York, 1975).

  117. 117.

    et al. Golgi structure correlates with transitional endoplasmic reticulum organization in Pichia pastoris and Saccharomyces cerevisiae. J. Cell Biol. 145, 68–81 (1999).

  118. 118.

    , , , & Organelle membrane fusion: a novel function for the syntaxin homolog Ufe1p in ER membrane fusion. Cell 92, 611–620 (1998).

  119. 119.

    , , , & Role of the ubiquitin-selective CDC48(UFD1/NPL4) chaperone (segregase) in ERAD of OLE1 and other substrates. EMBO J. 21, 615–619 (2002).

  120. 120.

    , , , & Chromatin docking and exchange activity enhancement of RCC1 by histones H2A and H2B. Science 292, 1540–1543 (2001).

  121. 121.

    & The ran decathlon: multiple roles of Ran. J. Cell Sci. 113, 1111–1118 (2000).

  122. 122.

    The Ran-GTPase and cell-cycle control. BioEssays 23, 77–85 (2001).

Download references

Acknowledgements

We thank W. Antonin, P. Askjaer, R. Carazo-Salas, J. Ellenberg, V. Hachet and T. Walther for critical reading and helpful comments.

Author information

Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany

    • Martin Hetzer
    • , Oliver J. Gruss
    •  & Iain W. Mattaj

Authors

  1. Search for Martin Hetzer in:

  2. Search for Oliver J. Gruss in:

  3. Search for Iain W. Mattaj in:

Corresponding author

Correspondence to Iain W. Mattaj.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/ncb0702-e177

Further reading