Vav1 Is a Component of Transcriptionally Active Complexes

Houlard, Martin; Arudchandran, Ramachandran; Régnier‐Ricard, Fabienne; Germani, Antonia; Gisselbrecht, Sylvie; Blank, Ulrich; Rivera, Juan; Varin‐Blank, Nadine

doi:10.1084/jem.20011701

Cited by 71 publications

(75 citation statements)

References 48 publications

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“…9A). However, the nuclear localization of several GEFs for Rac1 (33)(34)(35) and for other Rho family members (36,37) suggests the interesting possibility that Rac1-GDP converts to Rac1-GTP when the Rac1⅐p120ctn complex arrives at the nuclear pore, where the Rac1⅐p120ctn complex might have access to nuclear GEFs. This possibility is consistent with p120ctn associating with Vav (16), which is a Rac1 GEF that is present in the nucleus (33,34).…”

Section: Discussionmentioning

confidence: 99%

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

Lanning

Ruiz-Velasco

Williams

2003

Journal of Biological Chemistry

131

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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 SmgGDS⅐ Rac1 complexes accumulate in the nucleus because the Rac1 PBR has NLS activity and because Rac1 supplies the appropriate GTP-dependent signal. In contrast, SmgGDS⅐RhoA 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 (ARM) 1 family proteins that contain multiple copies of the ϳ42-amino acid (aa) ARM motif include SmgGDS, p120 catenin (p120ctn), ␤-catenin, plakoglobin, APC, karyopherin ␣ (also known as importin ␣), and several other proteins (reviewed in Refs. 1-3). Nucleocytoplasmic shuttling by many ARM proteins allows them to regulate events in different cellular compartments, including gene transcription and cell adhesion (reviewed in Refs. 2-7). ARM proteins enter the nucleus by different mechanisms (reviewed in Refs. 2-7). Karyopherin ␣ 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. 3). The NLS sequence is believed to anchor within the long surface groove formed by the multiple ARM repeats of karyopherin ␣, promoting the nuclear import of both the NLS-containing protein and karyopherin ␣ (3, 5). APC possesses two NLS sequences and may enter the nucleus by associating with karyopherin ␣ or related proteins (4, 7). 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 (8 -15) or with guanine nucleotide exchange factors (GEFs) for these GTPases (16,17). SmgGDS promotes guanine nucleotide exchange by small GTPases containing a C-terminal polybasic region (PBR), which is a series of adjacent l...

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Section: Discussionmentioning

confidence: 99%

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

Lanning

Ruiz-Velasco

Williams

2003

Journal of Biological Chemistry

131

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“…It has been reported that Vav-induced cell transformation require its GEF function. In addition to their function as regulators of Rho proteins, Vav family proteins regulate gene expression as components of transcription complexes (Doody et al, 2000;Houlard et al, 2002). Role of Vav proteins in lymphocyte function is well characterized in both cellular and animal models.…”

Section: Introductionmentioning

confidence: 99%

VAV2 regulates epidermal growth factor receptor endocytosis and degradation

et al. 2010

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Vav proteins are guanine nucleotide exchange factors for Rho GTPases that regulate cell adhesion, motility, spreading and proliferation in response to growth factor signalling. In this work, we show that Vav2 expression delayed epidermal growth factor receptor (EGFR) internalization and degradation, and enhanced EGFR, ERK and Akt phosphorylations. This effect of Vav2 on EGFR degradation is dependent on its guanine nucleotide exchange function. Knockdown of Vav2 in HeLa cells enhanced EGFR degradation and reduced cell proliferation. epidermal growth factor stimulation led to colocalization of Vav2 with EGFR and Rab5 in endosomes. We further show that the effect of Vav2 on EGFR stability is modulated by its interaction with two endosome-associated proteins and require RhoA function. Thus, in this work, we report for the first time that Vav2 can regulate growth factors receptor signalling by slowing receptor internalization and degradation through its interaction with endosome-associated proteins.

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“…Vav proteins contain various protein-protein interaction domains, including a calponin homology domain, an acidic region, a pleckstrin homology domain, a cysteine-rich domain, and three Src homology domains (40,41). Cybr itself possesses two protein-protein interaction domains, a PDZ domain and a CC domain, and, similar to Tamalin, could be involved in the formation of a large protein complex.…”

Section: Discussionmentioning

confidence: 99%