The Full Wiki

RanGTP: Wikis


Note: Many of our articles have direct quotes from sources you can cite, within the Wikipedia article! This article doesn't yet, but we're working on it! See more info or our list of citable articles.


(Redirected to Ran (biology) article)

From Wikipedia, the free encyclopedia

RAN, member RAS oncogene family

PDB rendering based on 1a2k.
Available structures
1a2k, 1byu, 1i2m, 1ibr, 1k5d, 1k5g, 1qbk, 1qg2, 1qg4, 1rrp, 1wa5, 2bku, 3ran
Symbols RAN; ARA24; Gsp1; TC4
External IDs OMIM601179 MGI1333112 HomoloGene68143 GeneCards: RAN Gene
EC number
RNA expression pattern
PBB GE RAN 200750 s at tn.png
PBB GE RAN 200749 at tn.png
More reference expression data
Species Human Mouse
Entrez 5901 19384
Ensembl ENSG00000132341 n/a
UniProt P62826 n/a
RefSeq (mRNA) NM_006325 NM_009391
RefSeq (protein) NP_006316 NP_033417
Location (UCSC) Chr 12:
129.92 - 129.93 Mb
PubMed search [1] [2]

Ran (RAs-related Nuclear protein) is a small 25Kda protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.[1][2][3]

Ran is a GTP binding protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. The Ran protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of Ran requires the presence of regulator of chromosome condensation 1 (RCC1). Mutations in Ran disrupt DNA synthesis. Because of its many functions, it is likely that Ran interacts with several other proteins.[4]


Ran cycle

Schematic representation of the Ran cycle

Ran exists in the cell in two nucleotide-bound forms: GDP-bound and GTP-bound. RanGDP is converted into RanGTP through the action of RCC1, the nucleotide exchange factor for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic GTPase-activity is activated through interaction with Ran GTPase activating protein (RanGAP), facilitated by complex formation with Ran-binding protein (RanBP). GTPase-activation leads to the conversion of RanGTP to RanGDP, thus closing the Ran cycle.

Ran can diffuse freely within the cell, but because RCC1 and RanGAP are located in different places in the cell, the concentration of RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes. RCC1 is bound to chromatin and therefore located inside the nucleus. RanGAP is cytoplasmic in yeast and bound to the nuclear envelope in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the nuclear pore complex via interaction with the nucleoporin RanBP2 (Nup358). This difference in location of the accessory proteins in the Ran cycle leads to a high RanGTP to RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus. In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein itself, with a higher concentration of Ran in the nucleus than in the cytoplasm. Cytoplasmic RanGDP is imported into the nucleus by the small protein NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GTP for GDP on Ran.

Role in nuclear transport during interphase

Ran cycle involvement in nucleocytoplasmic transport at the nuclear pore

Ran is involved in the transport of proteins across the nuclear envelope by interacting with karyopherins and changing their ability to bind or release cargo molecules. Cargo proteins containing a nuclear localization signal (NLS) are bound by importins and transported into the nucleus. Inside the nucleus, RanGTP binds to importin and releases the import cargo. Cargo that needs to get out of the nucleus into the cytoplasm binds to exportin in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.

Role in mitosis

During mitosis, the Ran cycle is involved in mitotic spindle assembly and nuclear envelope reassembly after the chromosomes have been separated.[5][6] During prophase, the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles. RanGTP concentration stays high around the chromosomes as RCC1, a nucleotide exchange factor, stays attached to chromatin. RanBP2 (Nup358) and RanGAP move to the kinetochores where they facilitate the attachment of spindle fibers to chromosomes. Moreover, RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as NuMA and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle . In telophase, RanGTP hydrolysis and nucleotide exchange are required for vesicle fusion at the reforming nuclear envelopes of the daughter nuclei.

Ran and the androgen receptor

RAN is an androgen receptor (AR) coactivator (ARA24) that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of Kennedy's disease.[7][8]


Ran (biology) has been shown to interact with XPO5,[9] RANGAP1,[10][11][12] XPO1,[13][14][15] KPNB1,[16][17][15] Transportin 1,[18][19] NUTF2,[20][21] RCC1,[22][23][24][25] RANBP1,[25][22][15] TNPO2[19] and NEK9.[26]

See also


  1. ^ Moore MS, Blobel G (May 1994). "A G protein involved in nucleocytoplasmic transport: the role of Ran". Trends Biochem. Sci. 19 (5): 211–6. doi:10.1016/0968-0004(94)90024-8. PMID 7519373.  
  2. ^ Avis JM, Clarke PR (October 1996). "Ran, a GTPase involved in nuclear processes: its regulators and effectors". J. Cell. Sci. 109 ( Pt 10): 2423–7. PMID 8923203.  
  3. ^ Dasso M, Pu RT (August 1998). "Nuclear transport: run by Ran?". Am. J. Hum. Genet. 63 (2): 311–6. doi:10.1086/301990. PMID 9683621.  
  4. ^ Sazer S, Dasso M (April 2000). "The ran decathlon: multiple roles of Ran". J. Cell. Sci. 113 ( Pt 7): 1111–8. PMID 10704362.  
  5. ^ Gruss OJ, Vernos I (September 2004). "The mechanism of spindle assembly: functions of Ran and its target TPX2". J. Cell Biol. 166 (7): 949–55. doi:10.1083/jcb.200312112. PMID 15452138.  
  6. ^ Ciciarello M, Mangiacasale R, Lavia P (August 2007). "Spatial control of mitosis by the GTPase Ran". Cell. Mol. Life Sci. 64 (15): 1891–914. doi:10.1007/s00018-007-6568-2. PMID 17483873.  
  7. ^ Hsiao PW, Lin DL, Nakao R, Chang C (July 1999). "The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator". J. Biol. Chem. 274 (29): 20229–34. doi:10.1074/jbc.274.29.20229. PMID 10400640.  
  8. ^ Sampson ER, Yeh SY, Chang HC, Tsai MY, Wang X, Ting HJ, Chang C (2001). "Identification and characterization of androgen receptor associated coregulators in prostate cancer cells". J. Biol. Regul. Homeost. Agents 15 (2): 123–9. PMID 11501969.  
  9. ^ Brownawell, Amy M; Macara Ian G (Jan. 2002). "Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins". J. Cell Biol. (United States) 156 (1): 53–64. doi:10.1083/jcb.200110082. ISSN 0021-9525. PMID 11777942.  
  10. ^ Hillig, R C; Renault L, Vetter I R, Drell T, Wittinghofer A, Becker J (Jun. 1999). "The crystal structure of rna1p: a new fold for a GTPase-activating protein". Mol. Cell (UNITED STATES) 3 (6): 781–91. ISSN 1097-2765. PMID 10394366.  
  11. ^ Becker, J; Melchior F, Gerke V, Bischoff F R, Ponstingl H, Wittinghofer A (May. 1995). "RNA1 encodes a GTPase-activating protein specific for Gsp1p, the Ran/TC4 homologue of Saccharomyces cerevisiae". J. Biol. Chem. (UNITED STATES) 270 (20): 11860–5. ISSN 0021-9258. PMID 7744835.  
  12. ^ Bischoff, F R; Klebe C, Kretschmer J, Wittinghofer A, Ponstingl H (Mar. 1994). "RanGAP1 induces GTPase activity of nuclear Ras-related Ran". Proc. Natl. Acad. Sci. U.S.A. (UNITED STATES) 91 (7): 2587–91. ISSN 0027-8424. PMID 8146159.  
  13. ^ Tickenbrock, Lara; Cramer Janina, Vetter Ingrid R, Muller Oliver (Aug. 2002). "The coiled coil region (amino acids 129-250) of the tumor suppressor protein adenomatous polyposis coli (APC). Its structure and its interaction with chromosome maintenance region 1 (Crm-1)". J. Biol. Chem. (United States) 277 (35): 32332–8. doi:10.1074/jbc.M203990200. ISSN 0021-9258. PMID 12070164.  
  14. ^ Fornerod, M; Ohno M, Yoshida M, Mattaj I W (Sep. 1997). "CRM1 is an export receptor for leucine-rich nuclear export signals". Cell (UNITED STATES) 90 (6): 1051–60. ISSN 0092-8674. PMID 9323123.  
  15. ^ a b c Plafker, K; Macara I G (May. 2000). "Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1". Mol. Cell. Biol. (UNITED STATES) 20 (10): 3510–21. ISSN 0270-7306. PMID 10779340.  
  16. ^ Kutay, U; Izaurralde E, Bischoff F R, Mattaj I W, Görlich D (Mar. 1997). "Dominant-negative mutants of importin-beta block multiple pathways of import and export through the nuclear pore complex". EMBO J. (ENGLAND) 16 (6): 1153–63. doi:10.1093/emboj/16.6.1153. ISSN 0261-4189. PMID 9135132.  
  17. ^ Percipalle, P; Clarkson W D, Kent H M, Rhodes D, Stewart M (Mar. 1997). "Molecular interactions between the importin alpha/beta heterodimer and proteins involved in vertebrate nuclear protein import". J. Mol. Biol. (ENGLAND) 266 (4): 722–32. doi:10.1006/jmbi.1996.0801. ISSN 0022-2836. PMID 9102465.  
  18. ^ Chook, Y M; Blobel G (May. 1999). "Structure of the nuclear transport complex karyopherin-beta2-Ran x GppNHp". Nature (ENGLAND) 399 (6733): 230–7. doi:10.1038/20375. ISSN 0028-0836. PMID 10353239.  
  19. ^ a b Shamsher, Monee K; Ploski Jonathan, Radu Aurelian (Oct. 2002). "Karyopherin beta 2B participates in mRNA export from the nucleus". Proc. Natl. Acad. Sci. U.S.A. (United States) 99 (22): 14195–9. doi:10.1073/pnas.212518199. ISSN 0027-8424. PMID 12384575.  
  20. ^ Cushman, Ian; Bowman Brian R, Sowa Mathew E, Lichtarge Olivier, Quiocho Florante A, Moore Mary Shannon (Nov. 2004). "Computational and biochemical identification of a nuclear pore complex binding site on the nuclear transport carrier NTF2". J. Mol. Biol. (England) 344 (2): 303–10. doi:10.1016/j.jmb.2004.09.043. ISSN 0022-2836. PMID 15522285.  
  21. ^ Stewart, M; Kent H M, McCoy A J (Apr. 1998). "Structural basis for molecular recognition between nuclear transport factor 2 (NTF2) and the GDP-bound form of the Ras-family GTPase Ran". J. Mol. Biol. (ENGLAND) 277 (3): 635–46. doi:10.1006/jmbi.1997.1602. ISSN 0022-2836. PMID 9533885.  
  22. ^ a b Steggerda, S M; Paschal B M (Jul. 2000). "The mammalian Mog1 protein is a guanine nucleotide release factor for Ran". J. Biol. Chem. (UNITED STATES) 275 (30): 23175–80. doi:10.1074/jbc.C000252200. ISSN 0021-9258. PMID 10811801.  
  23. ^ Renault, L; Kuhlmann J, Henkel A, Wittinghofer A (Apr. 2001). "Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1)". Cell (United States) 105 (2): 245–55. ISSN 0092-8674. PMID 11336674.  
  24. ^ Azuma, Y; Renault L, García-Ranea J A, Valencia A, Nishimoto T, Wittinghofer A (Jun. 1999). "Model of the ran-RCC1 interaction using biochemical and docking experiments". J. Mol. Biol. (ENGLAND) 289 (4): 1119–30. doi:10.1006/jmbi.1999.2820. ISSN 0022-2836. PMID 10369786.  
  25. ^ a b Ren, M; Villamarin A, Shih A, Coutavas E, Moore M S, LoCurcio M, Clarke V, Oppenheim J D, D'Eustachio P, Rush M G (Apr. 1995). "Separate domains of the Ran GTPase interact with different factors to regulate nuclear protein import and RNA processing". Mol. Cell. Biol. (UNITED STATES) 15 (4): 2117–24. ISSN 0270-7306. PMID 7891706.  
  26. ^ Roig, Joan; Mikhailov Alexei, Belham Christopher, Avruch Joseph (Jul. 2002). "Nercc1, a mammalian NIMA-family kinase, binds the Ran GTPase and regulates mitotic progression". Genes Dev. (United States) 16 (13): 1640–58. doi:10.1101/gad.972202. ISSN 0890-9369. PMID 12101123.  

External links



Got something to say? Make a comment.
Your name
Your email address