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Gene Review

Ran  -  RAN, member RAS oncogene family

Rattus norvegicus

Synonyms: GTP-binding nuclear protein Ran, GTPase Ran, Ras-like protein TC4, Ras-related nuclear protein
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Disease relevance of Ran

  • Akt activation is followed by signaling through the mTOR kinase and upregulation of Ran in primary type II pneumocytes, a cell type implicated in the development of lung adenocarcinoma [1].

High impact information on Ran

  • These data demonstrate that H(2)O(2) inhibits nuclear protein import and that this effect is mediated by mitogen-activated protein (MAP) kinase activation, possibly by altering Ran/TC4 function [2].
  • Immunocytochemistry revealed that H(2)O(2) treatment of whole cells increased cytosolic Ran/TC4 levels, an effect reversible by catalase or PD98059 [2].
  • Unexpectedly, exogenously added, fluorescently labeled Ran, although it accessed the nuclear interior, was found to dock at the nuclear rim in a punctate pattern, suggesting the existence of Ran-binding sites at the nuclear pore complex [3].
  • These data indicate that export of proteins from the nucleus requires Ran and GTP hydrolysis but not ATP hydrolysis [3].
  • We have used a range of complementary biochemical and biophysical methods to investigate the interactions between nuclear transport factor 2 (NTF2), the Ras family GTPase Ran, and XFXFG nucleoporin repeats that are crucial for nuclear trafficking [4].

Biological context of Ran

  • Ran binding domains promote the interaction of Ran with p97/beta-karyopherin, linking the docking and translocation steps of nuclear import [5].
  • These data suggest a physical link between docking and translocation mediated by a Ran GTPase-Ran binding protein complex [5].
  • RanBP2, a protein containing FG repeat motifs and four binding sites for the guanosine triphosphatase Ran, is localized at the cytoplasmic periphery of the nuclear pore complex (NPC) and is believed to play a critical role in nuclear protein import [6].
  • Overexpression of myr-Akt or Ran-wt in type II pneumocytes increased Akt ser-473 phosphorylation and mitosis in a catalase-dependent manner, indicating that H2O2 is essential for Akt and Ran signaling [1].
  • TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis [1].

Anatomical context of Ran

  • Our results are consistent with models for nuclear protein import in which Ran nucleotide exchange modulates the binding of the importin-substrate complexes during translocation through nuclear pore complexes [7].
  • Confocal microscopy demonstrates that Ran-GTPase localizes in the nucleus of round spermatids and along the microtubules of the manchette in elongating spermatids [8].
  • When the manchette disassembles, Ran-GTPase immunoreactivity is visualized in the centrosome region of maturing spermatids [8].
  • In contrast, the fluorescently labeled, 890-nucleotide-long viral RNA segment does not dock to the nuclear envelope or enter the nucleus either in the presence of exogenous cytosol or of karyopherin heterodimer, Ran, and p10 [9].

Associations of Ran with chemical compounds

  • T42A-Ran binds guanine nucleotides as well as wild-type Ran and responds as well as wild-type Ran to GTP or GDP exchange stimulated by the Ran-specific guanine nucleotide exchange factor, RCC1 [10].

Other interactions of Ran

  • Nuclear/nucleolar import conferred by the NTS of angiogenin is reduced by cytosolic factors as well as ATP and is independent of importins and Ran [11].

Analytical, diagnostic and therapeutic context of Ran

  • We have used X-ray crystallography to determine the structure of the macromolecular complex formed between GDP-Ran and nuclear transport factor 2 (NTF2) at 2.5 A resolution [12].


  1. TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis. Radisavljevic, Z.M., González-Flecha, B. J. Cell. Biochem. (2004) [Pubmed]
  2. Hydrogen peroxide inhibition of nuclear protein import is mediated by the mitogen-activated protein kinase, ERK2. Czubryt, M.P., Austria, J.A., Pierce, G.N. J. Cell Biol. (2000) [Pubmed]
  3. Protein export from the nucleus requires the GTPase Ran and GTP hydrolysis. Moroianu, J., Blobel, G. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  4. Dissecting the interactions between NTF2, RanGDP, and the nucleoporin XFXFG repeats. Chaillan-Huntington, C., Braslavsky, C.V., Kuhlmann, J., Stewart, M. J. Biol. Chem. (2000) [Pubmed]
  5. Ran binding domains promote the interaction of Ran with p97/beta-karyopherin, linking the docking and translocation steps of nuclear import. Lounsbury, K.M., Richards, S.A., Perlungher, R.R., Macara, I.G. J. Biol. Chem. (1996) [Pubmed]
  6. RanGTP targets p97 to RanBP2, a filamentous protein localized at the cytoplasmic periphery of the nuclear pore complex. Delphin, C., Guan, T., Melchior, F., Gerace, L. Mol. Biol. Cell (1997) [Pubmed]
  7. Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import. Percipalle, P., Clarkson, W.D., Kent, H.M., Rhodes, D., Stewart, M. J. Mol. Biol. (1997) [Pubmed]
  8. Ran, a GTP-binding protein involved in nucleocytoplasmic transport and microtubule nucleation, relocates from the manchette to the centrosome region during rat spermiogenesis. Kierszenbaum, A.L., Gil, M., Rivkin, E., Tres, L.L. Mol. Reprod. Dev. (2002) [Pubmed]
  9. Nuclear import of influenza virus RNA can be mediated by viral nucleoprotein and transport factors required for protein import. O'Neill, R.E., Jaskunas, R., Blobel, G., Palese, P., Moroianu, J. J. Biol. Chem. (1995) [Pubmed]
  10. A T42A Ran mutation: differential interactions with effectors and regulators, and defect in nuclear protein import. Murphy, G.A., Moore, M.S., Drivas, G., Pérez de la Ossa, P., Villamarin, A., D'Eustachio, P., Rush, M.G. Mol. Biol. Cell (1997) [Pubmed]
  11. Novel properties of the nucleolar targeting signal of human angiogenin. Lixin, R., Efthymiadis, A., Henderson, B., Jans, D.A. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  12. Structural basis for molecular recognition between nuclear transport factor 2 (NTF2) and the GDP-bound form of the Ras-family GTPase Ran. Stewart, M., Kent, H.M., McCoy, A.J. J. Mol. Biol. (1998) [Pubmed]
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