Novel Mechanism of the Co-regulation of Nuclear Transport of SmgGDS and Rac1

The armadillo protein SmgGDS promotes guanine nucleotide exchange by small GTPases containing a C-terminal polybasic region (PBR), such as Rac1 and RhoA. Because the PBR resembles a nuclear localization signal (NLS) sequence, we investigated the nuclear transport of SmgGDS with Rac1 or RhoA. We show that the Rac1 PBR has significant NLS activity when it is fused to green fluorescent protein (GFP) or in the context of full-length Rac1. In contrast, the RhoA PBR has very poor NLS activity when it is fused to GFP or in the context of full-length RhoA. The nuclear accumulation of both Rac1 and SmgGDS is enhanced by Rac1 activation and diminished by mutation of the Rac1 PBR. Conversely, SmgGDS nuclear accumulation is diminished by interactions with RhoA. An SmgGDS nuclear export signal sequence that we identified promotes SmgGDS nuclear export. These results suggest that SmgGDS· Rac1 complexes accumulate in the nucleus because the Rac1 PBR has NLS activity and because Rac1 supplies the appropriate GTP-dependent signal. In contrast, SmgGDS·RhoA complexes accumulate in the cytoplasm because the RhoA PBR does not have NLS activity. This model may be applicable to other armadillo proteins in addition to SmgGDS, because we demonstrate that activated Rac1 and RhoA also provide stimulatory and inhibitory signals, respectively, for the nuclear accumulation of p120 catenin. These results indicate that small GTPases with a PBR can regulate the nuclear transport of armadillo proteins. The armadillo protein SmgGDS promotes guanine nucleotide exchange by small GTPases containing a C-terminal polybasic region (PBR), such as Rac1 and RhoA. Because the PBR resembles a nuclear localization signal (NLS) sequence, we investigated the nuclear transport of SmgGDS with Rac1 or RhoA. We show that the Rac1 PBR has significant NLS activity when it is fused to green fluorescent protein (GFP) or in the context of full-length Rac1. In contrast, the RhoA PBR has very poor NLS activity when it is fused to GFP or in the context of full-length RhoA. The nuclear accumulation of both Rac1 and SmgGDS is enhanced by Rac1 activation and diminished by mutation of the Rac1 PBR. Conversely, SmgGDS nuclear accumulation is diminished by interactions with RhoA. An SmgGDS nuclear export signal sequence that we identified promotes SmgGDS nuclear export. These results suggest that SmgGDS· Rac1 complexes accumulate in the nucleus because the Rac1 PBR has NLS activity and because Rac1 supplies the appropriate GTP-dependent signal. In contrast, SmgGDS·RhoA complexes accumulate in the cytoplasm because the RhoA PBR does not have NLS activity. This model may be applicable to other armadillo proteins in addition to SmgGDS, because we demonstrate that activated Rac1 and RhoA also provide stimulatory and inhibitory signals, respectively, for the nuclear accumulation of p120 catenin. These results indicate that small GTPases with a PBR can regulate the nuclear transport of armadillo proteins. armadillo amino acid(s) Chinese hamster ovary guanine nucleotide exchange factor green fluorescent protein enhanced green fluorescent protein guanosine 5′-3-O-(thio)triphosphate hemagglutinin nuclear export signal nuclear localization signal p120 catenin polybasic region Triton X-100 aliphatic amino acid dominant negative phosphate-buffered saline tetramethylrhodamine isothiocyanate Armadillo (ARM)1 family proteins that contain multiple copies of the ∼42-amino acid (aa) ARM motif include SmgGDS, p120 catenin (p120ctn), ॆ-catenin, plakoglobin, APC, karyopherin α (also known as importin α), and several other proteins (reviewed in Refs. 1Peifer M. Berg S. Reynolds A.B. Cell. 1994; 76: 789-791Google Scholar, 2Hatzfeld M. Int. Rev. Cytol. 1999; 186: 179-224Google Scholar, 3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar). Nucleocytoplasmic shuttling by many ARM proteins allows them to regulate events in different cellular compartments, including gene transcription and cell adhesion (reviewed in Refs. 2Hatzfeld M. Int. Rev. Cytol. 1999; 186: 179-224Google Scholar, 3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar, 4Henderson B.R. Fagotto F. EMBO Rep. 2002; 3: 834-839Google Scholar, 5Goodwin D.J. Whitehouse A. J. Biol. Chem. 2001; 276: 19905-19912Google Scholar, 6van Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google Scholar, 7Zhang F. White R.L. Neufeld K.L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 12577-12582Google Scholar). ARM proteins enter the nucleus by different mechanisms (reviewed in Refs. 2Hatzfeld M. Int. Rev. Cytol. 1999; 186: 179-224Google Scholar, 3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar, 4Henderson B.R. Fagotto F. EMBO Rep. 2002; 3: 834-839Google Scholar, 5Goodwin D.J. Whitehouse A. J. Biol. Chem. 2001; 276: 19905-19912Google Scholar, 6van Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google Scholar, 7Zhang F. White R.L. Neufeld K.L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 12577-12582Google Scholar). Karyopherin α enters the nucleus when it associates with proteins containing a nuclear localization signal (NLS) sequence consisting of a series of adjacent lysines or arginines (reviewed in Ref. 3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar). The NLS sequence is believed to anchor within the long surface groove formed by the multiple ARM repeats of karyopherin α, promoting the nuclear import of both the NLS-containing protein and karyopherin α (3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar, 5Goodwin D.J. Whitehouse A. J. Biol. Chem. 2001; 276: 19905-19912Google Scholar). APC possesses two NLS sequences and may enter the nucleus by associating with karyopherin α or related proteins (4Henderson B.R. Fagotto F. EMBO Rep. 2002; 3: 834-839Google Scholar, 7Zhang F. White R.L. Neufeld K.L. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 12577-12582Google Scholar). The mechanisms by which other ARM proteins enter the nucleus are less clear, because some of these proteins neither possess classic NLS sequences, nor have they been reported to associate with NLS-containing proteins. Several ARM proteins interact with the Rho family of small GTPases (8Vithalani K. Parent C. Thorn E. Penn M. Larochelle D. Devreotes P. De Lozanne A. Mol. Biol. Cell. 1998; 9: 3095-3106Google Scholar, 9Anastasiadis P.Z. Moon S.Y. Thoreson M.A. Mariner D.J. Crawford H.C. Zheng Y. Reynolds A.B. Nat. Cell Biol. 2000; 2: 637-644Google Scholar, 10Anastasiadis P.Z. Reynolds A.B. Curr. Opin. Cell Biol. 2001; 13: 604-610Google Scholar, 11Mizuno T. Kaibuchi K. Yamamoto T. Kawamura M. Sakoda T. Fujioka H. Matsuura Y. Takai Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6442-6446Google Scholar, 12Orita S. Kaibuchi K. Kuroda S. Shimizu K. Nakanishi H. Takai Y. J. Biol. Chem. 1993; 268: 25542-25546Google Scholar, 13Chuang T.H. Xu X. Quilliam L.A. Bokoch G.M. Biochem. J. 1994; 303: 761-767Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; Scholar, D. J. Biol. Chem. 2000; or with guanine nucleotide exchange for these GTPases K. J. Cell Biol. 2000; Scholar, Y. T. T. T. Y. T. 2000; Scholar). SmgGDS promotes guanine nucleotide exchange by small GTPases containing a C-terminal polybasic region (PBR), which is a series of adjacent lysines or arginines T. Kaibuchi K. Yamamoto T. Kawamura M. Sakoda T. Fujioka H. Matsuura Y. Takai Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6442-6446Google Scholar, 12Orita S. Kaibuchi K. Kuroda S. Shimizu K. Nakanishi H. Takai Y. J. Biol. Chem. 1993; 268: 25542-25546Google Scholar, 13Chuang T.H. Xu X. Quilliam L.A. Bokoch G.M. Biochem. J. 1994; 303: 761-767Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; Scholar, D. J. Biol. Chem. 2000; Scholar, Quilliam L.A. J. Biol. Chem. 2000; Scholar). We a sequence the PBR of small GTPases that interact with SmgGDS and the NLS sequence of proteins that associate with the ARM protein karyopherin is that the ARM repeats of SmgGDS a surface groove that the PBR of small as the ARM repeats of karyopherin α a groove that the NLS sequences of different proteins (3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar). we that the PBR of small GTPases as promoting the of these GTPases with SmgGDS and the nuclear accumulation of the We by the nuclear accumulation of SmgGDS in with or Rac1 or RhoA. We show that the nuclear accumulation of SmgGDS is enhanced by interactions with Rac1 diminished by interactions with RhoA. The PBR of not to have NLS activity. These a model in which the of the Rac1 PBR to as NLS promotes the nuclear accumulation of Conversely, the of the RhoA PBR to as NLS promotes the accumulation of SmgGDS·RhoA This model may be applicable to other ARM proteins in addition to SmgGDS, because we demonstrate that the nuclear accumulation of is enhanced by Rac1 not by RhoA. These a of Rac1 and RhoA and a for the nuclear accumulation of SmgGDS and other ARM proteins. The of the for hemagglutinin or proteins that for have been in the which these and other to the as a to for or SmgGDS, or RhoA in The by for two copies of the which is by the the The which for copies of the that is by a of the The The and for the and of Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google by van Roy of and The H. Kaibuchi K. K. Yamamoto T. Kawamura M. Sakoda T. T. Takai Y. J. Biol. Chem. which by as the of the full-length SmgGDS sequence of the the in we for SmgGDS or SmgGDS containing in the sequence or the C-terminal sequence or or in both the and C-terminal sequences These the to for proteins with the the to for proteins with in the to for green fluorescent protein (GFP) fused to the of the to the to the to the and to the a for the of the GFP sequence in the the We the the containing for Rac1 Rac1 containing a or dominant negative Rac1 containing We the the Rac1 PBR in these with to the and as in We also the containing for RhoA RhoA containing a and dominant negative RhoA containing the The the RhoA PBR in these with to the and as in The the to for proteins with GFP the in the to for proteins with The cell which for of the in is a Chinese hamster ovary cell with the This cell D. J. Biol. Chem. 2000; Scholar, H. Cell Res. 1999; Scholar, D. K. H. S. J. J. Biol. Chem. 1999; Scholar, J. Biol. Chem. 2002; because we are the of activation the and which be the of a In the of for the which is the in the not H. Cell Res. 1999; Scholar, D. K. H. S. J. J. Biol. Chem. 1999; Scholar). The by in of containing of the and by a a The to and for in consisting of and The in the or in and for for the localization of the proteins. proteins by the proteins with proteins or with the with in phosphate-buffered saline and with in to The with or with Triton X-100 in as D. J. Biol. Chem. 2000; Scholar, J. Biol. Chem. 2002; Scholar). with containing the with to or to by with The in containing and and a as J. Biol. Chem. 2002; Scholar). of the a and In the nuclear localization of proteins in different with the the of which to the The of a protein that in the nucleus of cell the or very nuclear and nuclear and nuclear and nuclear and nuclear and or very We that some the of nuclear protein to protein in to be the of these in and This of when the of GFP and proteins in are with in and This also when the of and in and are with in because it to be in the of the or Rac1 and RhoA nuclear accumulation of SmgGDS is diminished by RhoA. with for or and the or RhoA proteins. with the and The proteins and proteins by the of and respectively, in the and In two of the of show the of the proteins and the proteins are of The and the nuclear localization of or in that the proteins by not the of the or proteins by the are the in the indicate a the two within a indicate a the and the of with GFP not the in consisting of and and The for in the or of and in containing D. J. Biol. Chem. 2000; Scholar). The in the for with of the cell by proteins are by as by to nuclear proteins such as in of the not The the the the or the as D. J. Biol. Chem. 2000; Scholar). The to by as D. J. Biol. Chem. 2000; Scholar). These as by D. J. Biol. Chem. 2000; Scholar). the by a for with containing with and The with and the of to the Rac1 proteins by The of the of by to be different in the In in the Because SmgGDS with nuclear proteins K. H. S. T. K. H. Takai Y. J. Biol. Chem. Scholar, K. H. T. S. Takai Y. J. Biol. Chem. 1998; and proteins T. Kaibuchi K. Yamamoto T. Kawamura M. Sakoda T. Fujioka H. Matsuura Y. Takai Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6442-6446Google Scholar, 12Orita S. Kaibuchi K. Kuroda S. Shimizu K. Nakanishi H. Takai Y. J. Biol. Chem. 1993; 268: 25542-25546Google Scholar, 13Chuang T.H. Xu X. Quilliam L.A. Bokoch G.M. Biochem. J. 1994; 303: 761-767Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; Scholar, D. J. Biol. Chem. 2000; Scholar, Quilliam L.A. J. Biol. Chem. 2000; we for sequences in SmgGDS that classic NLS sequences are not in SmgGDS, sequences, consisting of in which the are by (reviewed in Ref. 6van Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google are the and the as by the We for SmgGDS or SmgGDS proteins containing in the or C-terminal sequences of these in that the nuclear accumulation of SmgGDS is by the sequence not by the C-terminal sequence and of the nuclear export protein by H. D. M. S. Proc. Natl. Acad. Sci. U. S. A. 96: the nuclear accumulation of both SmgGDS and SmgGDS the C-terminal sequence the nuclear accumulation of SmgGDS the sequence and These results indicate that SmgGDS the nucleus and The nuclear export of SmgGDS is the sequence and We that SmgGDS enters the nucleus when it associates with small GTPases containing a PBR that as The PBR is in the amino the region in Rac1 and RhoA as by the for these fused to GFP and in GFP in both the nucleus and cytoplasm of the the of GFP nuclear The nuclear localization of the GFP protein is by the PBR of Rac1 by the PBR of RhoA for GFP fused to the amino of also to GFP containing the PBR the sequence of of these in that the PBR of not as a NLS in the of the sequence the PBR as NLS in the context of full-length Rac1 or we for or dominant negative Rac1 or RhoA proteins containing a or PBR a and of these in that Rac1 nuclear accumulation is enhanced by activation of as by the enhanced nuclear accumulation of and and diminished by of the as by the nuclear accumulation of the proteins and Rac1 nuclear accumulation is both by to the and by with the PBR as The of the and Rac1 proteins are not by the GFP with a not This that the PBR Rac1 nuclear accumulation when Rac1 is small to nuclear the RhoA proteins less nuclear accumulation the Rac1 proteins with the of the RhoA PBR to as of the RhoA PBR does not can the nuclear accumulation of RhoA proteins that the RhoA PBR does not as is that proteins not accumulate in the nucleus because they are in the cytoplasm to interactions with proteins. and Rac1 proteins and for proteins with complexes with and with J. Biol. Chem. 2002; Scholar). These proteins not with or that of the PBR the of Rac1 with proteins. The of proteins with proteins may for that mutation of the PBR the of to and a localization The of proteins with proteins also the that proteins in the cytoplasm because they are by proteins. these are with the model that proteins in the cytoplasm because the NLS has been by the PBR. The of the proteins by in small GTPases small GTPases in T. Kaibuchi K. Yamamoto T. Kawamura M. Sakoda T. Fujioka H. Matsuura Y. Takai Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6442-6446Google Scholar, Scholar). We that Rac1 and proteins of Rac1 and proteins with the J. Mol. Cell. Biol. proteins These results indicate that the proteins are the of the proteins are not to in of these proteins. the of the Rac1 we the of the Rac1 and proteins to less does with a of which in a of J. Biol. Chem. 2002; Scholar). negative also less does with the mutation of in the of to J. Biol. Chem. 2002; Scholar). does and that of the PBR does not can with that SmgGDS promotes guanine nucleotide exchange by Rac1 S. Kaibuchi K. Kuroda S. Shimizu K. Nakanishi H. Takai Y. J. Biol. Chem. 1993; 268: 25542-25546Google Scholar, 13Chuang T.H. Xu X. Quilliam L.A. Bokoch G.M. Biochem. J. 1994; 303: 761-767Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; we that of or by and in The results of the indicate that Rac1 and proteins are to interact with SmgGDS or SmgGDS containing a the of these protein we the Rac1 proteins with or in We that and and These results with the model that GTPases complexes with SmgGDS, because the GTPases associate with SmgGDS guanine nucleotide exchange D. J. Biol. Chem. 2000; Scholar, J. Biol. Chem. 2002; Scholar). Conversely, dominant negative GTPases complexes with SmgGDS, because dominant negative GTPases not and not SmgGDS guanine nucleotide exchange D. J. Biol. Chem. 2000; J. Biol. Chem. 2002; Scholar). The proteins not with and that mutation of the Rac1 PBR the of the of the is with enhanced of guanine nucleotide exchange by with as by the and complexes are less complexes may in a of by proteins by Rac1 proteins. does not of the Rac1 or proteins that mutation of the SmgGDS the of the This of complexes may to the enhanced of guanine nucleotide exchange by in the of with indicate that SmgGDS with RhoA with Rac1 S. Kaibuchi K. Kuroda S. Shimizu K. Nakanishi H. Takai Y. J. Biol. Chem. 1993; 268: 25542-25546Google Scholar, 13Chuang T.H. Xu X. Quilliam L.A. Bokoch G.M. Biochem. J. 1994; 303: 761-767Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; Scholar, D. J. Biol. Chem. 2000; Scholar, J. Biol. Chem. 2002; Scholar). with these we that both and RhoA proteins they Rac1 proteins that SmgGDS associates with RhoA with Rac1. These are with that SmgGDS with with in D. J. Biol. Chem. 2000; Scholar, J. Biol. Chem. 2002; Scholar). of the RhoA PBR or the SmgGDS the of complexes to the of these complexes that SmgGDS accumulate in the nucleus when it with not with because the PBR of not has NLS activity. we the nuclear localization of and in Rac1 or RhoA proteins with a or PBR The nuclear accumulation of is enhanced by and that supplies a signal that promotes SmgGDS nuclear of the PBR the of to SmgGDS nuclear accumulation a with the Rac1 PBR as NLS for of dominant negative which supplies neither a GTP-dependent signal nor a nuclear accumulation a The inhibitory of and SmgGDS nuclear accumulation are in the of diminished SmgGDS nuclear as by a and and the nuclear accumulation of is in with in with This may because of Rac1 to the which promotes the nuclear accumulation of Rac1 is by by the and proteins not the nuclear localization of and it in some the inhibitory of the RhoA proteins and nuclear accumulation are when the RhoA PBR is This may because mutation of the PBR the of RhoA to interact with SmgGDS The of Rac1 and RhoA to regulate the nuclear localization of other ARM proteins by the of in with the or GTPases The nuclear accumulation of is by a and by a and This that both GTP-dependent and Rac1 the nuclear accumulation of In contrast, the nuclear accumulation of is diminished by and This inhibitory of nuclear accumulation is when the are with and which reported to nuclear export Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google Scholar). the of with we the or of Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google with or in we the and the and of the the we not of the or proteins with the proteins not we the or proteins the we not of or the or of with the proteins not a model in which SmgGDS nuclear accumulation is by and to the of SmgGDS with it to which a GTP-dependent signal that promotes the nuclear accumulation of the This GTP-dependent signal may the activation of Rac1 model the nucleus with SmgGDS This of the nucleus is with the enhanced nuclear accumulation of in and and the nuclear accumulation of Rac1 in other cell K. Kuroda S. M. T. T. Matsuura Y. A. Kaibuchi K. J. Biol. Chem. 1998; Scholar, C. Bokoch G.M. M.A. S. 2000; Scholar, J. Biol. Chem. 2001; 276: Scholar). model that complexes in the nucleus This is with to of the Rac1 or proteins with which is in the nucleus to the of in the nucleus to with Rac1 and proteins. We that is less Rac1 in promoting SmgGDS nuclear accumulation because has a with SmgGDS and because does not provide NLS for SmgGDS These of may also to the diminished nuclear accumulation of with Rac1 and to associates with SmgGDS to the in the of with SmgGDS This is with to complexes of The of with SmgGDS may the nuclear accumulation of SmgGDS because provide a GTP-dependent signal and because the of Rac1 with SmgGDS The of with SmgGDS in the cytoplasm may also to the nuclear accumulation of and model also for the inhibitory of RhoA SmgGDS nuclear accumulation results indicate that SmgGDS associates with RhoA with Rac1 We that RhoA the nuclear accumulation of SmgGDS because the PBR of RhoA does not provide NLS and because RhoA the of Rac1 with SmgGDS The of to may SmgGDS, SmgGDS to interact with Rac1 that SmgGDS associates with RhoA with may for in some the nuclear accumulation of SmgGDS is by RhoA proteins by proteins indicate that Rac1 supplies both and a GTP-dependent signal to the nuclear accumulation of The of these in to other has not been is nuclear accumulation of SmgGDS in the of in the of or This that the enhanced GTP-dependent signal can the nuclear accumulation of SmgGDS when for is that that with complexes of SmgGDS with Rac1. to Rac1 supplies the NLS for the Rac1 to the nuclear accumulation of the Rac1 In may the nuclear accumulation of Rac1 NLS and may not these complexes the An of model is that the Rac1 PBR as NLS for complexes of promoting the nuclear of This of SmgGDS nuclear is very to the enhanced nuclear of karyopherin α when it associates with NLS-containing proteins such as The ARM repeats of SmgGDS may a that has and to the by the ARM repeats of karyopherin Karyopherin α is believed to two NLS-containing proteins NLS by the sequence (reviewed in Ref. 3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar). Karyopherin α has sequences the NLS and two sequences the NLS (reviewed in Ref. 3Chook Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar). We that SmgGDS has sequence which is in SmgGDS and in SmgGDS The of the sequence in SmgGDS is with the Rac1 PBR as NLS that promotes the and nuclear accumulation of The that SmgGDS has less sequences karyopherin α is with SmgGDS with a of NLS-containing proteins small GTPases with with karyopherin α, which with a of NLS-containing proteins. are the nuclear of SmgGDS with Rac1 and the nuclear of karyopherin α with NLS-containing are also some Karyopherin α interact with importin the nuclear to enter the This the importin of karyopherin α (reviewed in Y.M. Blobel G. Curr. Opin. Struct. Biol. 2001; 11: 703-715Google Scholar). We have not in SmgGDS, that SmgGDS does not interact with importin when the that the of importin with the small a model for the of SmgGDS with small GTPases L.A. Res. Mol. Biol. 2002; Scholar). This which is the of to the ARM repeats of importin (reviewed in Ref. L.A. Res. Mol. Biol. 2002; has to the of a PBR in the the and the interactions may provide the of small GTPases and SmgGDS, which these proteins to The Rac1 PBR and with a classic NLS the Rac1 PBR also has other including the of Rac1 to associate with complexes and the Rac1 Y. D. J. Biol. Chem. 1998; Scholar). is that the diminished interactions of with these proteins to the diminished of to accumulate in the and the diminished of to the nuclear accumulation of the of the Rac1 PBR to as NLS for SmgGDS and the of the RhoA PBR to as NLS provide a for indicate SmgGDS, the nuclear accumulation of is enhanced by GTP-dependent and by Rac1 not by RhoA. model of the and of SmgGDS nuclear accumulation to the and of nuclear Rac1 nuclear localization in the that it SmgGDS nuclear Rac1 interact with we have been to complexes of Rac1 with or with the or of of may in the they may be to by of may be as as complexes of which are also to SmgGDS and complexes are to both Rac1 and interact with SmgGDS in the as by the enhanced of by Rac1 and in the of SmgGDS it reported that with RhoA in P.Z. Moon S.Y. Thoreson M.A. Mariner D.J. Crawford H.C. Zheng Y. Reynolds A.B. Nat. Cell Biol. 2000; 2: 637-644Google with model that with as as with we these interactions the of with RhoA and Rac1 or the of proteins. We that the nuclear accumulation of SmgGDS does not the nuclear accumulation of This may because of the different of SmgGDS and to as a for Rac1. to the of complexes guanine nucleotide exchange by the of SmgGDS to interact with Rac1 and enter the nucleus In contrast, may not a with because does not as a for Rac1 P.Z. Moon S.Y. Thoreson M.A. Mariner D.J. Crawford H.C. Zheng Y. Reynolds A.B. Nat. Cell Biol. 2000; 2: 637-644Google Scholar). The of to a less of nuclear with the of to SmgGDS nuclear model the of to in the complexes of or the nuclear the nuclear localization of several for Rac1 J. Biol. Chem. Scholar, M. F. A. S. U. J. J. 2002; Scholar, P. J. Biol. Chem. 2001; 276: and for other Rho family Curr. Biol. 1999; 9: Scholar, A. A. J. Biol. Chem. 2002; the that to when the the nuclear the have to nuclear This is with associating with K. J. Cell Biol. 2000; which is a Rac1 that is in the nucleus J. Biol. Chem. M. F. A. S. U. J. J. 2002; Scholar). Nucleocytoplasmic shuttling allows ARM proteins to in many cellular including the of small gene cell and (reviewed in Refs. 2Hatzfeld M. Int. Rev. Cytol. 1999; 186: 179-224Google Scholar, 4Henderson B.R. Fagotto F. EMBO Rep. 2002; 3: 834-839Google Scholar, 6van Hengel J. Vanhoenacker P. Staes K. van Roy F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7980-7985Google Scholar, and 10Anastasiadis P.Z. Reynolds A.B. Curr. Opin. Cell Biol. 2001; 13: 604-610Google Scholar). that Rac1 and RhoA regulate the shuttling of SmgGDS and the that these GTPases the nuclear localization of other ARM proteins. small GTPases with a which have been reported to interact with SmgGDS, include T.H. Xu X. Quilliam L.A. Bokoch G.M. Biochem. J. 1994; 303: 761-767Google H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; T. Kaibuchi K. Yamamoto T. Kawamura M. Sakoda T. Fujioka H. Matsuura Y. Takai Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6442-6446Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; Quilliam L.A. J. Biol. Chem. 2000; T. Kaibuchi K. Yamamoto T. Kawamura M. Sakoda T. Fujioka H. Matsuura Y. Takai Y. Proc. Natl. Acad. Sci. U. S. A. 1991; 88: 6442-6446Google Scholar, 14Yaku H. Sasaki T. Takai Y. Biochem. Biophys. Res. 1994; and Quilliam L.A. J. Biol. Chem. 2000; Scholar). The of these GTPases may have to of Rac1 and RhoA. This is by a that the of to interact with SmgGDS a C-terminal region containing the PBR K. A. K. S. Sakoda T. K. Takai Y. Scholar). The of these small GTPases in the nuclear accumulation of SmgGDS and other armadillo proteins to be We Y. Takai for the of the and F. van Roy for the of the and