Differential Expression and Sequence-specific Interaction of Karyopherin α with Nuclear Localization Sequences
1997; Elsevier BV; Volume: 272; Issue: 7 Linguagem: Inglês
10.1074/jbc.272.7.4310
ISSN1083-351X
AutoresSteven G. Nadler, Douglas Tritschler, Omar K. Haffar, James Blake, A. Gregory Bruce, Jeffrey S. Cleaveland,
Tópico(s)Neurogenetic and Muscular Disorders Research
ResumoThe process of nuclear protein transport requires the interaction of several different proteins, either directly or indirectly with nuclear localization or targeting sequences (NLS). Recently, a number of karyopherins α, or NLS-binding proteins, have been identified. We have found that the karyopherins hSRP1 and hSRP1α are differentially expressed in various leukocyte cell lines and could be induced in normal human peripheral blood lymphocytes. We show that the two karyopherins bind with varied specificities in a sequence specific manner to different NLSs and that the sequence specificity is modulated by other cytosolic proteins. There was a correlation between binding of karyopherins α to different NLSs and their ability to be imported into the nucleus. Taken together, these data provide evidence for multiple levels of control of the nuclear import process. The process of nuclear protein transport requires the interaction of several different proteins, either directly or indirectly with nuclear localization or targeting sequences (NLS). Recently, a number of karyopherins α, or NLS-binding proteins, have been identified. We have found that the karyopherins hSRP1 and hSRP1α are differentially expressed in various leukocyte cell lines and could be induced in normal human peripheral blood lymphocytes. We show that the two karyopherins bind with varied specificities in a sequence specific manner to different NLSs and that the sequence specificity is modulated by other cytosolic proteins. There was a correlation between binding of karyopherins α to different NLSs and their ability to be imported into the nucleus. Taken together, these data provide evidence for multiple levels of control of the nuclear import process. INTRODUCTIONActive nuclear transport of proteins with molecular weights greater than 40-60 kDa requires at least four different proteins, which act in a sequential manner with karyophilic proteins containing nuclear localization targeting sequences (NLS) 1The abbreviations used are:NLSnuclear localization sequenceK1hSRP1K2hSRP1αBSAbovine serum albuminFITCfluorescein isothiocyanateECLelectrochemiluminescentPBSphosphate-buffered salineGSTglutathione S-transferasePAGEpolyacrylamide gel electrophoresis. (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar, 2Hurt E.C. Cell. 1996; 84: 509-515Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 3Csermely P. Schnaider T. Szanto I. Biochim. Biophys. ACTA. 1995; 1241: 425-452Crossref PubMed Scopus (57) Google Scholar, 4Simos G. Hurt E.C. FEBS Lett. 1995; 369: 107-112Crossref PubMed Scopus (37) Google Scholar). There appear to be several discrete steps in the import process which involves: 1) binding of the NLS-binding protein, karyopherin α, to an NLS; 2) interaction of this complex with karyopherin β; 3) targeting to nuclear pore proteins; and 4) the ATP/GTP-dependent translocation through the nuclear pore mediated by ran (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar, 5Gorlich D. Vogel F. Mills A.D. Hartmann E. Laskey R.A. Nature. 1995; 377: 246-248Crossref PubMed Scopus (408) Google Scholar, 6Moroianu J. Hijikata M. Blobel G. Radu A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6532-6536Crossref PubMed Scopus (249) Google Scholar).Recently, the proteins involved in NLS binding and transport have been identified. Those proteins that interact directly with the NLS have been termed karyopherins α (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar, 8O'Neill R.E. Palese P. Virology. 1995; 206: 116-125Crossref PubMed Scopus (133) Google Scholar, 9Cortes P. Zheng-Sheng Y. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7633-7637Crossref PubMed Scopus (168) Google Scholar, 10Cuomo C.A. Kirch S.A. Gyuris J. Brent R. Oettinger M.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6156-6160Crossref PubMed Scopus (163) Google Scholar, 11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar). The Xenopus protein importin 60 was the first karyopherin α to be cloned, sequenced, and shown to be involved in nuclear protein import (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar). Subsequently, a number of other karyopherins α have been identified, which suggests that there is a family of these NLS-binding proteins. The two major groups of karyopherins α include 1) the yeast protein SRP1 (12Yano R. Oakes M. Yamagishi M. Dodd J.A. Nomura M. Mol. Cell. Biol. 1992; 12: 5640-5641Crossref PubMed Scopus (156) Google Scholar) and the human proteins hSRP1 and NPI-1 (8O'Neill R.E. Palese P. Virology. 1995; 206: 116-125Crossref PubMed Scopus (133) Google Scholar, 9Cortes P. Zheng-Sheng Y. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7633-7637Crossref PubMed Scopus (168) Google Scholar), and 2) importin 60 (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar) and the human proteins hSRP1α (11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar) and Rch1 (10Cuomo C.A. Kirch S.A. Gyuris J. Brent R. Oettinger M.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6156-6160Crossref PubMed Scopus (163) Google Scholar). In this report we have termed hSRP1 and hSRP1α, K1 and K2, respectively. Each of these karyopherins α are capable of binding to NLSs and facilitating nuclear import. Recently it was shown that there was tissue-specific expression of the mouse K1 (mSRP1) and K2 (mPendulin). The levels of K1 RNA appear higher in the brain and cerebellum, whereas K2 RNA was found mostly in the thymus and spleen (13Prieve M.G. Guttridge K.L. Munguia J.E. Waterman M.L. J. Biol. Chem. 1996; 271: 7654-7658Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar).Similar to karyopherin α, there are several homologs of karyopherin β, (also called importin 90 or p97) (11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar, 14Gorlich D. Kostka S. Kraft R. Dingwall L. Laskey R.A. Hartmann E. Prehn S. Curr. Biol. 1995; 5: 383-392Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). The function of karyopherin β appears to be the targeting of the karyophile-karyopherin α complex to the nuclear pore (11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar, 16Radu A. Blobel G. Moore M.S. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1769-1773Crossref PubMed Scopus (383) Google Scholar). The interaction of karyopherin β with karyopherin α has been shown to enhance the latter protein's affinity for the NLS containing protein (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar). Although the protein factors described above are sufficient to support nuclear protein transport, there are accessory factors which are also important for regulating nuclear transport. These factors include p10 (17Moore M.S. Blobel G. Nature. 1993; 365: 661-663Crossref PubMed Scopus (638) Google Scholar, 18Saitoh H. Dasso M. J. Biol. Chem. 1995; 270: 10658-10663Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 19Yokoyama N. Hayashi N. Seki T. Pante N. Ohba T. Nishii K. Kuma K. Hayashida T. Miyata T. Aebi U. Fukui M. Nishimoto T. Nature. 1995; 376: 184-188Crossref PubMed Scopus (411) Google Scholar, 20Corbett A.H. Koepp D.M. Schlenstedt G. Lee M.S. Hopper A.K. Silver P.A. J. Cell. Biol. 1995; 130: 1017-1026Crossref PubMed Scopus (152) Google Scholar), Rna1p (20Corbett A.H. Koepp D.M. Schlenstedt G. Lee M.S. Hopper A.K. Silver P.A. J. Cell. Biol. 1995; 130: 1017-1026Crossref PubMed Scopus (152) Google Scholar), and the heat shock protein Hsc73 (21Shi Y. Thomas J.O. Mol. Cell. Biol. 1992; 12: 2186-2192Crossref PubMed Scopus (300) Google Scholar).Perhaps most important for nuclear protein transport is the targeting sequence or NLS. Although there is a consensus for other organellar targeting sequences, there is little amino acid sequence homology among the large number of NLSs that have been identified (22Boulikas T. Crit. Rev. Eukaryotic Gene Expr. 1993; 3: 193-227PubMed Google Scholar). The most conserved feature of either the “simple” (5-7 amino acid sequences) or “bipartite” (two sets of positively charged amino acids separated by 10-11 amino acids) is the presence of two basic amino acids which constitutes the core of the NLS. Two mechanisms for regulating the activity of the NLS include protein phosphorylation and masking of the NLS to prevent its recognition by karyopherin α (23Vandromme M. Gauthier-Rouviere C. Lamb N. Fernandez A. Trends Bicohem. Sci. 1996; 21: 59-64Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 24Jans D.A. Biochem. J. 1995; 311: 705-716Crossref PubMed Scopus (179) Google Scholar).In this report we show that there are multiple levels of control of nuclear import. These control points include the sequence specific binding of karyopherins α to various NLSs and modulation of this interaction by other cytoplasmic proteins. In addition, the differential and inducible expression of karyopherins α may play a role in regulating nuclear protein transport.DISCUSSIONMany of the recent studies on nuclear protein transport have focused on the mechanics of the import process in nonhematopoietic cells such as HeLa and Xenopus oocytes, as well as in reconstituted in vitro systems (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar, 4Simos G. Hurt E.C. FEBS Lett. 1995; 369: 107-112Crossref PubMed Scopus (37) Google Scholar). In contrast to these studies, we have focused on the transport machinery in lymphocytes and leukocyte cell lines. In the studies presented here, we have analyzed the expression and interactions of human karyopherins α with different NLSs.Lymphocyte activation induces the expression of a wide variety of genes, which are dependent upon the translocation of specific transcription factors to the nucleus (26Bauerle P.A. Henkel T. Annu. Rev. Immunol. 1994; 12: 141-179Crossref PubMed Scopus (4580) Google Scholar, 27Whiteside S.T. Goodburn S. J. Cell Sci. 1993; 104: 949-955Crossref PubMed Google Scholar). A key protein in this translocation process is karyopherin α, the NLS-binding protein (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar). We found that, in general, the less differentiated cells (THP-1, 70Z/3, HSB-2) have lower levels of karyopherin α and tend to express only one predominant form (Fig. 1). In contrast, the more mature Raji and Jurkat cell lines express much higher levels of both K1 and K2. Differences were also seen in the cytoplasmic:nuclear ratios of the karyopherins. The differences in both overall expression and intracellular distribution of karyopherins may reflect the transcriptional activity of the particular cell line and the requirement for transport of particular proteins into the nucleus. Unexpectedly, the levels of both K1 and K2 were very low in resting human peripheral blood lymphocytes in comparison to the cell lines. This suggested that other karyopherins α may be expressed in these cells, or that the levels are low due to the “resting” state of the cells which require a low level of transcription. We found that commonly used stimuli of peripheral blood lymphocytes were able to induce the expression of K1 and K2. Although it has been shown that cell activation leads to increased numbers of nuclear pores to facilitate protein nuclear transport (28Bonifaci N. Sitia R. Rubartelli A. AIDS. 1995; 9: 995-1000Crossref PubMed Scopus (47) Google Scholar), the increased expression of the proteins involved in the transport process may be an additional mechanism for enhancing nuclear transport rates.Another potential mechanism for regulation of nuclear transport could be at the level of the NLS itself. Previous studies have shown that different NLSs have varying abilities to target proteins to the nucleus (29Feldherr C.M. Akin D. Exp. Cell Res. 1993; 205: 179-186Crossref PubMed Scopus (94) Google Scholar, 30Lanford R.E. Feldherr C.M. White R.G. Dunham R.G. Kanda P. Exp. Cell Res. 1990; 186: 32-38Crossref PubMed Scopus (27) Google Scholar). In order to determine whether NLSs vary in their ability to interact with the NLS-binding proteins K1 and K2, we precipitated intracellular proteins using NLS affinity resins and found that there were differences in the ability of K1 and K2 to interact with NLSs (Fig. 2). These results were confirmed using a solution binding assay. These data suggest that the different classes of karyopherins have both different and overlapping specificities for the various NLSs.The specificity for the NLSs was also dependent upon the cell type. For example there was no binding of K1 to the Myc and ICP8 NLS in the Jurkat cell, whereas there was binding to these NLSs in the Raji cell extract. These data suggest that other cytosolic proteins may influence the way in which K1 or K2 interact with NLSs. To address this possibility we analyzed the ability of a K2 fusion protein to interact with NLSs in the presence or absence of other cytosolic proteins. As seen in Fig. 3, the binding specificity of K2 for the NLS is clearly altered in the presence of other cytosolic proteins. This modulation of binding could be explained by a number of possibilities. One possibility is that karyopherin β, which has previously been shown to increase the affinity of karyopherin α for NLSs, may also alter its binding specificity. The heat shock protein Hsc73, which has been shown to play a role in nuclear transport (21Shi Y. Thomas J.O. Mol. Cell. Biol. 1992; 12: 2186-2192Crossref PubMed Scopus (300) Google Scholar), may modulate NLS:karyopherin α interactions. In fact, Hsc73 does bind to NLSs and appears to modulate the association and dissociation reaction of karyopherins. 2S. G. Nadler and J. S. Cleaveland, manuscript in preparation. A third possibility is that endogenous NLS-containing proteins can compete for binding of karyopherins α to the NLS affinity resins. These possibilities are now being explored.Finally, we analyzed the ability of different NLS substrates to be targeted to the nucleus. The ability of NLS-BSA conjugates to be imported into the nucleus appeared to be determined by the strength of the interaction between the NLS and karyopherin α. Although the Jurkat, HSB-2, and 70Z/3 cells expressed different levels and ratios of the two karyopherins α, there were only subtle differences in the ability of extracts from these cells to facilitate nuclear import. This would suggest that there may be other karyopherins expressed that are not detected by our antibodies or that other cytoplasmic proteins can modulate the ability of the existing karyopherins to import proteins to the nucleus. It appears that the ability of proteins to be imported into the nucleus is predominantly determined by the interaction of the NLS with karyopherins and to a limited extent by the differential expression of the karyopherins.The process of nuclear protein import plays a key role in gene regulation based on its ability to modulate transcription factor nuclear localization. The results described above suggest that there are multiple levels of control of nuclear import in lymphocytes and leukocyte cell lines. Studies are in progress to determine whether the activation and induction of karyopherins in resting, G0, peripheral blood lymphocytes has an impact on nuclear transport. Taken together, our data suggest their are complex mechanisms for the regulation of nuclear import in different leukocyte cell lines that are mainly governed by the NLS and its sequence specific interaction with karyopherin α. INTRODUCTIONActive nuclear transport of proteins with molecular weights greater than 40-60 kDa requires at least four different proteins, which act in a sequential manner with karyophilic proteins containing nuclear localization targeting sequences (NLS) 1The abbreviations used are:NLSnuclear localization sequenceK1hSRP1K2hSRP1αBSAbovine serum albuminFITCfluorescein isothiocyanateECLelectrochemiluminescentPBSphosphate-buffered salineGSTglutathione S-transferasePAGEpolyacrylamide gel electrophoresis. (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar, 2Hurt E.C. Cell. 1996; 84: 509-515Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 3Csermely P. Schnaider T. Szanto I. Biochim. Biophys. ACTA. 1995; 1241: 425-452Crossref PubMed Scopus (57) Google Scholar, 4Simos G. Hurt E.C. FEBS Lett. 1995; 369: 107-112Crossref PubMed Scopus (37) Google Scholar). There appear to be several discrete steps in the import process which involves: 1) binding of the NLS-binding protein, karyopherin α, to an NLS; 2) interaction of this complex with karyopherin β; 3) targeting to nuclear pore proteins; and 4) the ATP/GTP-dependent translocation through the nuclear pore mediated by ran (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar, 5Gorlich D. Vogel F. Mills A.D. Hartmann E. Laskey R.A. Nature. 1995; 377: 246-248Crossref PubMed Scopus (408) Google Scholar, 6Moroianu J. Hijikata M. Blobel G. Radu A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6532-6536Crossref PubMed Scopus (249) Google Scholar).Recently, the proteins involved in NLS binding and transport have been identified. Those proteins that interact directly with the NLS have been termed karyopherins α (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar, 8O'Neill R.E. Palese P. Virology. 1995; 206: 116-125Crossref PubMed Scopus (133) Google Scholar, 9Cortes P. Zheng-Sheng Y. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7633-7637Crossref PubMed Scopus (168) Google Scholar, 10Cuomo C.A. Kirch S.A. Gyuris J. Brent R. Oettinger M.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6156-6160Crossref PubMed Scopus (163) Google Scholar, 11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar). The Xenopus protein importin 60 was the first karyopherin α to be cloned, sequenced, and shown to be involved in nuclear protein import (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar). Subsequently, a number of other karyopherins α have been identified, which suggests that there is a family of these NLS-binding proteins. The two major groups of karyopherins α include 1) the yeast protein SRP1 (12Yano R. Oakes M. Yamagishi M. Dodd J.A. Nomura M. Mol. Cell. Biol. 1992; 12: 5640-5641Crossref PubMed Scopus (156) Google Scholar) and the human proteins hSRP1 and NPI-1 (8O'Neill R.E. Palese P. Virology. 1995; 206: 116-125Crossref PubMed Scopus (133) Google Scholar, 9Cortes P. Zheng-Sheng Y. Baltimore D. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 7633-7637Crossref PubMed Scopus (168) Google Scholar), and 2) importin 60 (7Gorlich D. Prehn S. Laskey R.A. Hartmann E. Cell. 1994; 79: 767-778Abstract Full Text PDF PubMed Scopus (599) Google Scholar) and the human proteins hSRP1α (11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar) and Rch1 (10Cuomo C.A. Kirch S.A. Gyuris J. Brent R. Oettinger M.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 6156-6160Crossref PubMed Scopus (163) Google Scholar). In this report we have termed hSRP1 and hSRP1α, K1 and K2, respectively. Each of these karyopherins α are capable of binding to NLSs and facilitating nuclear import. Recently it was shown that there was tissue-specific expression of the mouse K1 (mSRP1) and K2 (mPendulin). The levels of K1 RNA appear higher in the brain and cerebellum, whereas K2 RNA was found mostly in the thymus and spleen (13Prieve M.G. Guttridge K.L. Munguia J.E. Waterman M.L. J. Biol. Chem. 1996; 271: 7654-7658Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar).Similar to karyopherin α, there are several homologs of karyopherin β, (also called importin 90 or p97) (11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar, 14Gorlich D. Kostka S. Kraft R. Dingwall L. Laskey R.A. Hartmann E. Prehn S. Curr. Biol. 1995; 5: 383-392Abstract Full Text Full Text PDF PubMed Scopus (413) Google Scholar). The function of karyopherin β appears to be the targeting of the karyophile-karyopherin α complex to the nuclear pore (11Weis K. Mattaj I.W. Lamond A.I. Science. 1995; 268: 1049-1054Crossref PubMed Scopus (306) Google Scholar, 16Radu A. Blobel G. Moore M.S. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1769-1773Crossref PubMed Scopus (383) Google Scholar). The interaction of karyopherin β with karyopherin α has been shown to enhance the latter protein's affinity for the NLS containing protein (1Rexach M. Blobel G. Cell. 1995; 83: 683-692Abstract Full Text PDF PubMed Scopus (662) Google Scholar). Although the protein factors described above are sufficient to support nuclear protein transport, there are accessory factors which are also important for regulating nuclear transport. These factors include p10 (17Moore M.S. Blobel G. Nature. 1993; 365: 661-663Crossref PubMed Scopus (638) Google Scholar, 18Saitoh H. Dasso M. J. Biol. Chem. 1995; 270: 10658-10663Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 19Yokoyama N. Hayashi N. Seki T. Pante N. Ohba T. Nishii K. Kuma K. Hayashida T. Miyata T. Aebi U. Fukui M. Nishimoto T. Nature. 1995; 376: 184-188Crossref PubMed Scopus (411) Google Scholar, 20Corbett A.H. Koepp D.M. Schlenstedt G. Lee M.S. Hopper A.K. Silver P.A. J. Cell. Biol. 1995; 130: 1017-1026Crossref PubMed Scopus (152) Google Scholar), Rna1p (20Corbett A.H. Koepp D.M. Schlenstedt G. Lee M.S. Hopper A.K. Silver P.A. J. Cell. Biol. 1995; 130: 1017-1026Crossref PubMed Scopus (152) Google Scholar), and the heat shock protein Hsc73 (21Shi Y. Thomas J.O. Mol. Cell. Biol. 1992; 12: 2186-2192Crossref PubMed Scopus (300) Google Scholar).Perhaps most important for nuclear protein transport is the targeting sequence or NLS. Although there is a consensus for other organellar targeting sequences, there is little amino acid sequence homology among the large number of NLSs that have been identified (22Boulikas T. Crit. Rev. Eukaryotic Gene Expr. 1993; 3: 193-227PubMed Google Scholar). The most conserved feature of either the “simple” (5-7 amino acid sequences) or “bipartite” (two sets of positively charged amino acids separated by 10-11 amino acids) is the presence of two basic amino acids which constitutes the core of the NLS. Two mechanisms for regulating the activity of the NLS include protein phosphorylation and masking of the NLS to prevent its recognition by karyopherin α (23Vandromme M. Gauthier-Rouviere C. Lamb N. Fernandez A. Trends Bicohem. Sci. 1996; 21: 59-64Abstract Full Text PDF PubMed Scopus (158) Google Scholar, 24Jans D.A. Biochem. J. 1995; 311: 705-716Crossref PubMed Scopus (179) Google Scholar).In this report we show that there are multiple levels of control of nuclear import. These control points include the sequence specific binding of karyopherins α to various NLSs and modulation of this interaction by other cytoplasmic proteins. In addition, the differential and inducible expression of karyopherins α may play a role in regulating nuclear protein transport.
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