nuclear export signals

Summary

Summary: Specific amino acid sequences present in the primary amino acid sequence of proteins which mediate their export from the CELL NUCLEUS. They are rich in hydrophobic residues, such as LEUCINE and ISOLEUCINE.

Top Publications

  1. Itoh K, Brott B, Bae G, Ratcliffe M, Sokol S. Nuclear localization is required for Dishevelled function in Wnt/beta-catenin signaling. J Biol. 2005;4:3 pubmed
    ..We discuss the relevance of these findings to existing models of Wnt signal transduction to the nucleus. ..
  2. Jeyasekharan A, Liu Y, Hattori H, Pisupati V, Jonsdottir A, Rajendra E, et al. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 2013;20:1191-8 pubmed publisher
    ..Our findings suggest a mechanism for the regulation of the nucleocytoplasmic distribution of BRCA2 and RAD51 and its impairment by a heterozygous disease-associated mutation. ..
  3. Chen L, Liu D, Songyang Z. Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol. 2007;27:5898-909 pubmed
  4. Zheng C, Lin F, Wang S, Xing J. A novel virus-encoded nucleocytoplasmic shuttling protein: the UL3 protein of herpes simplex virus type 1. J Virol Methods. 2011;177:206-10 pubmed publisher
    ..Heterokaryon assays confirmed that UL3 was capable of shuttling between the nucleus and the cytoplasm. These results demonstrate that the UL3 protein is a novel HSV-1 encoded nucleocytoplasmic shuttling protein...
  5. Jin Q, Yan T, Ge X, Sun C, Shi X, Zhai Q. Cytoplasm-localized SIRT1 enhances apoptosis. J Cell Physiol. 2007;213:88-97 pubmed
    ..In summary, we found SIRT1 is able to localize in cytoplasm, and cytoplasm-localized SIRT1 enhances apoptosis. ..
  6. Xu D, Farmer A, Collett G, Grishin N, Chook Y. Sequence and structural analyses of nuclear export signals in the NESdb database. Mol Biol Cell. 2012;23:3677-93 pubmed publisher
    ..Finally, we also tested CRM1-binding of 40 NESs that were found in the 56 structures. We found that 16 of the NES peptides did not bind CRM1, hence illustrating how NESs are easily misidentified...
  7. Lischka P, Rauh C, Mueller R, Stamminger T. Human cytomegalovirus UL84 protein contains two nuclear export signals and shuttles between the nucleus and the cytoplasm. J Virol. 2006;80:10274-80 pubmed
    ..Sequence inspection of this domain revealed the presence of motifs with homology to leucine-rich nuclear export signals. Here, we report the identification of two functional, autonomous nuclear export signals and show that ..
  8. Verhagen J, Donnelly M, Elliott G. Characterization of a novel transferable CRM-1-independent nuclear export signal in a herpesvirus tegument protein that shuttles between the nucleus and cytoplasm. J Virol. 2006;80:10021-35 pubmed publisher
    ..As this new sequence bears little similarity to other export signals so far defined, we suggest it may be involved in bUL47 export from the nucleus via a novel cellular receptor...
  9. Lee B, Cansizoglu A, Süel K, Louis T, Zhang Z, Chook Y. Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell. 2006;126:543-58 pubmed
    ..These studies define and validate a new NLS that could not be predicted by primary sequence analysis alone. ..

More Information

Publications62

  1. Xu D, Farmer A, Chook Y. Recognition of nuclear targeting signals by Karyopherin-? proteins. Curr Opin Struct Biol. 2010;20:782-90 pubmed publisher
    ..We review recent findings relating to how these three classes of nuclear targeting signals are recognized by their Karyopherin-? nuclear transport factors. ..
  2. North B, Verdin E. Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis. PLoS ONE. 2007;2:e784 pubmed
    ..The findings suggest a novel mechanism of regulating SIRT2 function by nucleo-cytoplasmic shuttling, as well as a role for SIRT2 in the nucleus during interphase and throughout mitosis. ..
  3. Wilson J, Le V, Zimmerman C, Marmorstein R, Pillus L. Nuclear export modulates the cytoplasmic Sir2 homologue Hst2. EMBO Rep. 2006;7:1247-51 pubmed
    ..Our identification of putative nuclear export sequences in numerous vertebrate SIRT2 proteins shows that active nuclear export can be a conserved mechanism for regulating Sir2 homologues. ..
  4. Stauber R, Rabenhorst U, Rekik A, Engels K, Bier C, Knauer S. Nucleocytoplasmic shuttling and the biological activity of mouse survivin are regulated by an active nuclear export signal. Traffic. 2006;7:1461-72 pubmed
    ..The survivin-Crm1 axis is essential for the biological activities of murine survivin, and mouse models will allow investigating its functional implications during development and tumorigenesis. ..
  5. Cai M, Wang S, Xing J, Zheng C. Characterization of the nuclear import and export signals, and subcellular transport mechanism of varicella-zoster virus ORF9. J Gen Virol. 2011;92:621-6 pubmed publisher
  6. Chevalier S, Meertens L, Calattini S, Gessain A, Kiemer L, Mahieux R. Presence of a functional but dispensable nuclear export signal in the HTLV-2 Tax protein. Retrovirology. 2005;2:70 pubmed
    ..Finally, we also show that Tax1 NES function is dependent upon the positioning of the nuclear export signal "vis-à-vis" GFP. HTLV-2 Tax NES is functional but dispensable for the protein localization in vitro. ..
  7. Han X, Saito H, Miki Y, Nakanishi A. A CRM1-mediated nuclear export signal governs cytoplasmic localization of BRCA2 and is essential for centrosomal localization of BRCA2. Oncogene. 2008;27:2969-77 pubmed
    ..Our results suggest that disruption of the NES function by genetic changes results in deregulation of BRCA2 export, which ultimately leads to centrosome disorder. ..
  8. Nishino T, Miyazaki M, Hoshino H, Miwa Y, Horinouchi S, Yoshida M. 14-3-3 regulates the nuclear import of class IIa histone deacetylases. Biochem Biophys Res Commun. 2008;377:852-6 pubmed publisher
    ..Phosphorylation-induced 14-3-3 binding biases the balance of nucleo-cytoplasmic shuttling toward the cytoplasm by inhibiting nuclear import. ..
  9. Ellyard J, Benk A, Taylor B, Rada C, Neuberger M. The dependence of Ig class-switching on the nuclear export sequence of AID likely reflects interaction with factors additional to Crm1 exportin. Eur J Immunol. 2011;41:485-90 pubmed publisher
    ..The results suggest that CSR, as well as the stabilisation of AID, depend on an interaction between the AID C-terminal decapeptide and factor(s) additional to Crm1. ..
  10. Dong X, Biswas A, Süel K, Jackson L, Martinez R, Gu H, et al. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature. 2009;458:1136-41 pubmed publisher
    ..Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport. ..
  11. Nakagawa M, Hosokawa Y, Yonezumi M, Izumiyama K, Suzuki R, Tsuzuki S, et al. MALT1 contains nuclear export signals and regulates cytoplasmic localization of BCL10. Blood. 2005;106:4210-6 pubmed
    ..The nucleocytoplasmic shuttling of MALT1 and BCL10 complex may indicate that these molecules are involved not only in the nuclear factor kappaB (NF-kappaB) pathway but also in other biologic functions in lymphocytes. ..
  12. Engelsma D, Rodriguez J, Fish A, Giaccone G, Fornerod M. Homodimerization antagonizes nuclear export of survivin. Traffic. 2007;8:1495-502 pubmed
    ..Survivin shuttles between nucleus and cytoplasm under the influence of one or more nuclear export signals (NESs)...
  13. Kosugi S, Hasebe M, Tomita M, Yanagawa H. Nuclear export signal consensus sequences defined using a localization-based yeast selection system. Traffic. 2008;9:2053-62 pubmed publisher
    Proteins bearing nuclear export signals (NESs) are translocated to the cytoplasm from the nucleus mainly through the CRM1-dependent pathway...
  14. Van Neck T, Pannecouque C, Vanstreels E, Stevens M, Dehaen W, Daelemans D. Inhibition of the CRM1-mediated nucleocytoplasmic transport by N-azolylacrylates: structure-activity relationship and mechanism of action. Bioorg Med Chem. 2008;16:9487-97 pubmed publisher
    ..These specific CRM1 inhibitors are of interest as tool for analyzing the mechanisms of post-transcriptional control of gene expression and provide insight in the design of new agents. ..
  15. Williams P, Verhagen J, Elliott G. Characterization of a CRM1-dependent nuclear export signal in the C terminus of herpes simplex virus type 1 tegument protein UL47. J Virol. 2008;82:10946-52 pubmed publisher
    ..Finally, we show that the hUL47 NES is sensitive to the inhibitor of CRM1-mediated nuclear export leptomycin B. Hence, hUL47 joins a growing list of virus-encoded RNA-binding proteins that use CRM1 to exit the nucleus...
  16. Brodie K, Henderson B. Characterization of BRCA1 protein targeting, dynamics, and function at the centrosome: a role for the nuclear export signal, CRM1, and Aurora A kinase. J Biol Chem. 2012;287:7701-16 pubmed publisher
    ..Moreover, Aurora A binding and phosphorylation of BRCA1 enhanced its centrosomal retention and regulation of centrosome amplification. Thus, CRM1, BARD1 and Aurora A promote the targeting and function of BRCA1 at centrosomes...
  17. Geisberger R, Rada C, Neuberger M. The stability of AID and its function in class-switching are critically sensitive to the identity of its nuclear-export sequence. Proc Natl Acad Sci U S A. 2009;106:6736-41 pubmed publisher
  18. Fu S, Huang H, Horton P, Juan H. ValidNESs: a database of validated leucine-rich nuclear export signals. Nucleic Acids Res. 2013;41:D338-43 pubmed publisher
    ..We present ValidNESs, an integrated, up-to-date database holding 221 NES-containing proteins, combined with a web interface to prediction by NESsential. ..
  19. Itahana Y, Yeh E, Zhang Y. Nucleocytoplasmic shuttling modulates activity and ubiquitination-dependent turnover of SUMO-specific protease 2. Mol Cell Biol. 2006;26:4675-89 pubmed
    ..Thus, the function of SENP2 is regulated by both nucleocytoplasmic shuttling and polyubiquitin-mediated degradation. ..
  20. Knapp A, McManus P, Bockstall K, Moroianu J. Identification of the nuclear localization and export signals of high risk HPV16 E7 oncoprotein. Virology. 2009;383:60-8 pubmed publisher
    ..The presence of both NLSs and an NES suggests that HPV16 E7 shuttles between the cytoplasm and nucleus which is consistent with E7 having functions in both of these cell compartments. ..
  21. Ernoult Lange M, Wilczynska A, Harper M, Aigueperse C, Dautry F, Kress M, et al. Nucleocytoplasmic traffic of CPEB1 and accumulation in Crm1 nucleolar bodies. Mol Biol Cell. 2009;20:176-87 pubmed publisher
    ..They could rather constitute a platform providing factors for ribosome assembly or export. The behavior of CPEB1 in CNoBs raises the possibility that it is involved in ribosome biogenesis. ..
  22. David Watine B. Silencing nuclear pore protein Tpr elicits a senescent-like phenotype in cancer cells. PLoS ONE. 2011;6:e22423 pubmed publisher
    ..Our findings also point to new roles for Tpr in the regulation of SUMO-1 conjugation at the nuclear pore and directly confirm Tpr involvement in the nuclear export of NES-proteins. ..
  23. Muscolini M, Montagni E, Palermo V, Di Agostino S, Gu W, Abdelmoula Souissi S, et al. The cancer-associated K351N mutation affects the ubiquitination and the translocation to mitochondria of p53 protein. J Biol Chem. 2011;286:39693-702 pubmed publisher
    ..These data identify K351N as a critical mutation of p53 that contributes to the development and maintenance of resistance to cisplatin. ..
  24. Neyton S, Lespinasse F, Lahaye F, Staccini P, Paquis Flucklinger V, Santucci Darmanin S. CRM1-dependent nuclear export and dimerization with hMSH5 contribute to the regulation of hMSH4 subcellular localization. Exp Cell Res. 2007;313:3680-93 pubmed
    ..Our findings suggest that nucleocytoplasmic traffic may constitute a regulatory mechanism for MSH4 and MSH5 functions. ..
  25. Gotoh I, Uekita T, Seiki M. Regulated nucleo-cytoplasmic shuttling of human aci-reductone dioxygenase (hADI1) and its potential role in mRNA processing. Genes Cells. 2007;12:105-17 pubmed
    ..Thus, hADI1 may have acquired a novel role in nuclear mRNA processing possibly by modulating U1-70K-related functions, an activity negatively regulated by a non-classical NES sequence. ..
  26. Prieto G, Fullaondo A, Rodriguez J. Prediction of nuclear export signals using weighted regular expressions (Wregex). Bioinformatics. 2014;30:1220-7 pubmed publisher
    Leucine-rich nuclear export signals (NESs) are short amino acid motifs that mediate binding of cargo proteins to the nuclear export receptor CRM1, and thus contribute to regulate the localization and function of many cellular proteins...
  27. Falini B, Bolli N, Shan J, Martelli M, Liso A, Pucciarini A, et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc+ AML. Blood. 2006;107:4514-23 pubmed
    ..These findings indicate that potential therapeutic strategies aimed to retarget NPM to its physiological sites will have to overcome 2 obstacles, the new NES motif and the mutated tryptophan(s) at the NPM mutant C-terminus. ..
  28. Neuber A, Franke J, Wittstruck A, Schlenstedt G, Sommer T, Stade K. Nuclear export receptor Xpo1/Crm1 is physically and functionally linked to the spindle pole body in budding yeast. Mol Cell Biol. 2008;28:5348-58 pubmed publisher
    ..In addition, we find a subpopulation of Xpo1 localized at the SPB. Based on these data, we propose a functional link between Xpo1 and the SPB and discuss a role for this exportin in spindle biogenesis in budding yeast. ..
  29. Nilsen T, Rosendal K, Sørensen V, Wesche J, Olsnes S, Wiedłocha A. A nuclear export sequence located on a beta-strand in fibroblast growth factor-1. J Biol Chem. 2007;282:26245-56 pubmed
    ..The FGF-1 NES was found to be situated along a beta-strand, which has not been reported before, since NESs usually are alpha-helical. ..
  30. Falini B, Albiero E, Bolli N, De Marco M, Madeo D, Martelli M, et al. Aberrant cytoplasmic expression of C-terminal-truncated NPM leukaemic mutant is dictated by tryptophans loss and a new NES motif. Leukemia. 2007;21:2052-4; author reply 2054; discussion 2055-6 pubmed
  31. Vissinga C, Yeo T, Warren S, Brawley J, Phillips J, Cerosaletti K, et al. Nuclear export of NBN is required for normal cellular responses to radiation. Mol Cell Biol. 2009;29:1000-6 pubmed publisher
  32. Yu M, Liu X, Cao S, Zhao Z, Zhang K, Xie Q, et al. Identification and characterization of three novel nuclear export signals in the influenza A virus nucleoprotein. J Virol. 2012;86:4970-80 pubmed publisher
    ..In the present study, three novel nuclear export signals (NESs) of the NP--NES1, NES2, and NES3--were identified as being responsible for mediating its nuclear ..
  33. Scheifele L, Kenney S, Cairns T, Craven R, Parent L. Overlapping roles of the Rous sarcoma virus Gag p10 domain in nuclear export and virion core morphology. J Virol. 2007;81:10718-28 pubmed publisher
    ..Together, these results indicate that the p10 NES domain of Gag is critical for virus replication and that it plays overlapping roles required for the nuclear shuttling of Gag and for the maintenance of proper virion core morphology...
  34. Gonzalez Mariscal L, Ponce A, Alarcón L, Jaramillo B. The tight junction protein ZO-2 has several functional nuclear export signals. Exp Cell Res. 2006;312:3323-35 pubmed
    ..The canine sequence of ZO-2 displays four putative nuclear export signals (NES), two at the second PDZ domain (NES-0 and NES-1) and the rest at the GK region (NES-2 and NES-3)...
  35. Guttler T, Madl T, Neumann P, Deichsel D, Corsini L, Monecke T, et al. NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1. Nat Struct Mol Biol. 2010;17:1367-76 pubmed publisher
    Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs...
  36. Niu Y, Roy F, Saltel F, Andrieu Soler C, Dong W, Chantegrel A, et al. A nuclear export signal and phosphorylation regulate Dok1 subcellular localization and functions. Mol Cell Biol. 2006;26:4288-301 pubmed
    ..Nuclear export modulated by external stimuli and phosphorylation may be a mechanism by which Dok1 is maintained in the cytoplasm and membrane, thus regulating its signaling functions. ..
  37. Yan Y, Peng D, Tian J, Chi J, Tan J, Yin X, et al. Essential sequence of the N-terminal cytoplasmic localization-related domain of huntingtin and its effect on huntingtin aggregates. Sci China Life Sci. 2011;54:342-50 pubmed publisher
    ..These studies provide new insight into the molecular mechanism of htt aggregation in HD. ..
  38. Fu S, Imai K, Horton P. Prediction of leucine-rich nuclear export signal containing proteins with NESsential. Nucleic Acids Res. 2011;39:e111 pubmed publisher
    ..Finally, we list 70 recently discovered NES-containing proteins, doubling the number available to the community. ..
  39. Liso A, Bogliolo A, Freschi V, Martelli M, Pileri S, Santodirocco M, et al. In human genome, generation of a nuclear export signal through duplication appears unique to nucleophosmin (NPM1) mutations and is restricted to AML. Leukemia. 2008;22:1285-9 pubmed
  40. Migdall Wilson J, Bates C, Schlegel J, BRANDAO L, Linger R, DeRyckere D, et al. Prolonged exposure to a Mer ligand in leukemia: Gas6 favors expression of a partial Mer glycoform and reveals a novel role for Mer in the nucleus. PLoS ONE. 2012;7:e31635 pubmed publisher
    ..Our results identify several novel features of Mer that expand the breadth of its functions and impact the development of therapeutic modalities designed to target Mer. ..
  41. Simon Areces J, Acaz Fonseca E, Ruiz Palmero I, Garcia Segura L, Arevalo M. A CRM1-mediated nuclear export signal is essential for cytoplasmic localization of neurogenin 3 in neurons. PLoS ONE. 2013;8:e55237 pubmed publisher
    ..Pharmacological perturbation of the cytoskeleton revealed that cytoplasmic Ngn3 is associated with microtubules. ..
  42. Khacho M, Mekhail K, Pilon Larose K, Pause A, Cote J, Lee S. eEF1A is a novel component of the mammalian nuclear protein export machinery. Mol Biol Cell. 2008;19:5296-308 pubmed publisher
    ..These results also provide a link between the translational apparatus and subcellular trafficking machinery demonstrating that these two central pathways in basic metabolism can act cooperatively. ..
  43. Pesch M, Schultheiß I, Digiuni S, Uhrig J, Hulskamp M. Mutual control of intracellular localisation of the patterning proteins AtMYC1, GL1 and TRY/CPC in Arabidopsis. Development. 2013;140:3456-67 pubmed publisher
    ..Genetic analysis of mutants and overexpression lines supports the hypothesis that AtMYC1 represses the activity of TRY and CPC. ..
  44. Deng M, Li F, Ballif B, Li S, Chen X, Guo L, et al. Identification and functional analysis of a novel cyclin e/cdk2 substrate ankrd17. J Biol Chem. 2009;284:7875-88 pubmed publisher
    ..Taken together, these data indicate that Ankrd17 is an important downstream effector of cyclin E/Cdk2 and positively regulates G(1)/S transition. ..
  45. Thaa B, Herrmann A, Veit M. The polybasic region is not essential for membrane binding of the matrix protein M1 of influenza virus. Virology. 2009;383:150-5 pubmed publisher
    ..We have equipped M1 with nuclear export signals and showed that the constructs are bound to cellular membranes...
  46. Acconcia F, Barnes C, Singh R, Talukder A, Kumar R. Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase. Proc Natl Acad Sci U S A. 2007;104:6782-7 pubmed
    ..Together, these results suggest that ILK is a PAK1 substrate, undergoes phosphorylation-dependent shuttling between the cell nucleus and cytoplasm, and interacts with gene-regulatory chromatin. ..
  47. Mariano A, Colombo E, Luzi L, Martinelli P, Volorio S, Bernard L, et al. Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal. Oncogene. 2006;25:4376-80 pubmed
  48. Shapiro M, Chen Y, Shapiro V. The carboxyl-terminal segment of the adaptor protein ALX directs its nuclear export during T cell activation. J Biol Chem. 2005;280:38242-6 pubmed
  49. Fryrear K, Durkin S, Gupta S, Tiedebohl J, Semmes O. Dimerization and a novel Tax speckled structure localization signal are required for Tax nuclear localization. J Virol. 2009;83:5339-52 pubmed publisher
    ..Tax has defined nuclear localization (NLS) and nuclear export signals that enable shuttling between the two compartments...
  50. Xu D, Grishin N, Chook Y. NESdb: a database of NES-containing CRM1 cargoes. Mol Biol Cell. 2012;23:3673-6 pubmed publisher
    ..NESdb will be updated regularly and will serve as an important resource for nuclear export signals. NESdb is freely available to nonprofit organizations at http://prodata.swmed.edu/LRNes.
  51. Papp L, Lu J, Striebel F, Kennedy D, Holmgren A, Khanna K. The redox state of SECIS binding protein 2 controls its localization and selenocysteine incorporation function. Mol Cell Biol. 2006;26:4895-910 pubmed
  52. Gladfelter A, Hungerbuehler A, Philippsen P. Asynchronous nuclear division cycles in multinucleated cells. J Cell Biol. 2006;172:347-62 pubmed
    ..We hypothesize that the continuous cytoplasm in these cells promoted the evolution of a nuclear division cycle in which CDK inhibitors primarily control CDK activity rather than oscillating mitotic cyclin proteins. ..
  53. Bembenek J, Kang J, Kurischko C, Li B, Raab J, Belanger K, et al. Crm1-mediated nuclear export of Cdc14 is required for the completion of cytokinesis in budding yeast. Cell Cycle. 2005;4:961-71 pubmed
    ..Our results suggest a requirement for Crm1p-dependent nuclear export of Cdc14p in coordinating mitotic exit and cytokinesis in budding yeast. ..