scholarly journals Rac1 Signaling Modulates BCL-6-Mediated Repression of Gene Transcription

2009 ◽  
Vol 29 (15) ◽  
pp. 4156-4166 ◽  
Author(s):  
Patrícia Barros ◽  
Peter Jordan ◽  
Paulo Matos
Keyword(s):  
Cell Adhesion ◽  
Gene Transcription ◽  
Transcriptional Repressor ◽  
Small Gtpases ◽  
Luciferase Reporter ◽  
Luciferase Reporter Construct ◽  
Kinase Activation ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Species Production

ABSTRACT Rac1 is a member of the Rho family of small GTPases that not only regulates signaling pathways involved in cell adhesion and migration but also regulates gene transcription. Here we show that the transcriptional repressor BCL-6 is regulated by Rac1 signaling. Transfection of active Rac1 mutants into colorectal DLD-1 cells led to increased expression of a BCL-6-controlled luciferase reporter construct. Conversely, inhibition of endogenous Rac1 activation by the Rac1 inhibitor NSC23766 decreased reporter activity. Moreover, BCL-6 lost its typical localization to nuclear dots upon activation of Rac1 and became predominantly soluble in a non-chromatin-bound cell fraction. Rac1 signaling also regulated the expression of endogenous BCL-6-regulated genes, including the p50 precursor NF-κB1/p105 and the cell adhesion molecule CD44. Interestingly, these effects were not stimulated by the alternative splice variant Rac1b. The mechanism of BCL-6 inhibition does not involve formation of a stable Rac1/BCL-6 complex and is independent of Rac-induced reactive oxygen species production or Jun NH2-terminal kinase activation. We show that PAK1 mediates inhibition downstream of Rac and can directly phosphorylate BCL-6. Together, these data provide substantial evidence that Rac1 signaling inhibits the transcriptional repressor BCL-6 in colorectal cells and reveal a novel pathway that links Rac1 signaling to the regulation of gene transcription.

scholarly journals FRL, a Novel Formin-Related Protein, Binds to Rac and Regulates Cell Motility and Survival of Macrophages

2000 ◽  
Vol 20 (18) ◽  
pp. 6872-6881 ◽  
Author(s):  
Shinri Yayoshi-Yamamoto ◽  
Ichiro Taniuchi ◽  
Takeshi Watanabe
Keyword(s):  
Cell Death ◽  
Cell Adhesion ◽  
Bone Marrow Cells ◽  
Apoptotic Cell ◽  
Small Gtpases ◽  
Apoptotic Cell Death ◽  
Cell Adhesion And Migration ◽  
Rho Family ◽  
And Migration ◽  
Related Proteins

ABSTRACT We have isolated a cDNA, frl(formin-related gene in leukocytes), a novel mammalian member of the formin gene family. The frlcDNA encodes a 160-kDa protein, FRL, that possesses FH1, FH2, and FH3 domains that are well conserved among other Formin-related proteins. An FRL protein is mainly localized in the cytosol and is highly expressed in spleen, lymph node, and bone marrow cells. Formin-related genes and proteins have been reported to play crucial roles in morphogenesis, cell polarity, and cytokinesis through interaction with Rho family small GTPases. FRL binds to Rac at its N-terminal region including the FH3 domain and associates with profilin at the FH1 domain. In a macrophage cell line, P388D1, overexpression of a truncated form of FRL containing only the FH3 domain (FH3-FRL) strongly inhibited cell adhesion to fibronectin and migration upon stimulation with a chemokine. Moreover, expression of the truncated FH3-FRL protein resulted in apoptotic cell death of P388D1 cells, suggesting that the truncated FH3-FRL protein may interfere with signals of FRL. Overexpression in the P388D1 cells of full-length FRL or of the truncated protein containing the FH3 and FH1 domains, with simultaneous expression of the truncated FH3-FRL protein, blocked apoptotic cell death and inhibition of cell adhesion and migration. These results suggest that FRL may play a role in the control of reorganization of the actin cytoskeleton in association with Rac and also in the regulation of the signal for cell survival.

scholarly journals CXCL12 Modulates Prostate Cancer Cell Adhesion by Altering the Levels or Activities ofβ1-Containing Integrins

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Mehdi Dehghani ◽  
Sedigheh Kianpour ◽  
Ana Zangeneh ◽  
Zohreh Mostafavi-Pour
Keyword(s):  
Prostate Cancer ◽  
Cell Adhesion ◽  
Collagen I ◽  
Integrin Receptors ◽  
High Concentration ◽  
Kinase Activation ◽  
Potential Biomarker ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Recombinant Fragments

The mechanisms by which prostate cancer (PCa) cell adhesion and migration are controlled during metastasis are not well understood. Here, we studied the effect of CXCL12 in PCa cell adhesion and spreading in DU145 and PC3 cell lines using as substrates collagen I, fibronectin (FN), and their recombinant fragments. CXCL12 treatment increasedβ1 integrin-dependent PC3 cell adhesion on FN which correlated with increased focal adhesion kinase activation. However neitherα5β1 norα4β1 subunits were involved in this adhesion. By contrast, CXCL12 decreased DU145 adhesion and spreading on FN by downregulatingα5 andβ1 integrin expression. To demonstrate the clinical relevance of CXCL12 in PCa, we measured CXCL12 levels in plasma by using ELISA and found that the chemokine is elevated in PCa patients when compared to controls. The high concentration of CXCL12 in patients suffering from PCa in comparison to those with benign disease or healthy individuals implicates CXCL12 as a potential biomarker for PCa. In addition these data show that CXCL12 may be crucial in controlling PCa cell adhesion on fibronectin and collagen I, possibly via crosstalk with integrin receptors and/or altering the expression levels of integrin subunits.

Role of the docking protein Gab2 in β1-integrin signaling pathway-mediated hematopoietic cell adhesion and migration

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2351-2359 ◽  
Author(s):  
Wen-Mei Yu ◽  
Teresa S. Hawley ◽  
Robert G. Hawley ◽  
Cheng-Kui Qu
Keyword(s):  
Cell Adhesion ◽  
Signaling Pathway ◽  
Hematopoietic Cell ◽  
Integrin Signaling ◽  
Pleckstrin Homology Domain ◽  
Β1 Integrin ◽  
Kinase Activation ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
Docking Protein

Gab2, a newly identified pleckstrin homology domain-containing docking protein, is a major binding protein of SHP-2 tyrosine phosphatase in interleukin (IL)-3–stimulated hematopoietic cells. Its signaling mechanism remains largely unknown. We report here an important regulatory role for Gab2 in β1 integrin signaling pathway that mediates hematopoietic cell adhesion and migration. Cross-linking of the β1 integrin on Ba/F3 cells induced rapid tyrosine phosphorylation of Gab2 and its association with Syk kinase, SHP-2 phosphatase, and the p85 subunit of phosphatidylinositol (PI)-3 kinase. In addition, Gab2 was also constitutively associated with SHP-1 phosphatase via its C-terminal Src homology 2 domain. Overexpression of the pleckstrin homology domain or a mutant Gab2 molecule lacking SHP-2 binding sites resulted in significant reductions in Ba/F3 cell adhesion and migration. Biochemical analyses revealed that enforced expression of Gab2 mutant molecules dramatically reduced β1-integrin ligation-triggered PI3 kinase activation, whereas Erk kinase activation remained unaltered. Furthermore, transduction of primary hematopoietic progenitor cells from viable motheaten mice with these mutant Gab2 molecules also significantly ameliorated their enhanced migration capacity associated with theSHP1 gene mutation. Taken together, these results suggest an important signaling role for Gab2 in regulating hematopoietic cell adhesion and migration.

scholarly journals Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases

Oncogene ◽  
2020 ◽  
Vol 39 (18) ◽  
pp. 3666-3679 ◽  
Author(s):  
Mario De Piano ◽  
Valeria Manuelli ◽  
Giorgia Zadra ◽  
Jonathan Otte ◽  
Per-Henrik D. Edqvist ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Adhesion ◽  
Cancer Cell ◽  
Rho Gtpases ◽  
Prostate Cancer Cell ◽  
Cancer Cell Adhesion ◽  
Cell Adhesion And Migration ◽  
And Migration

Differences in phosphatase modulation of α4 β1 and α5 β1 integrin-mediated adhesion and migration of B16F1 cells

1999 ◽  
Vol 77 (5) ◽  
pp. 409-420 ◽  
Author(s):  
Dolores Hangan-Steinman ◽  
Wai-chi Ho ◽  
Priti Shenoy ◽  
Bosco MC Chan ◽  
Vincent L Morris
Keyword(s):  
Cell Adhesion ◽  
Adhesive Strength ◽  
Cell Movement ◽  
Protein Tyrosine Phosphatases ◽  
Β1 Integrin ◽  
Phosphatase Inhibitors ◽  
Β1 Integrins ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
B16f1 Cell

It is well established that a biphasic relationship exists between the adhesive strength of β1 integrins and their ability to mediate cell movement. Thus, cell movement increases progressively with adhesive strength, but beyond a certain point of optimal interaction, cell movement is reduced with further increases in adhesive function. The interplay between the various kinase and phosphatase activities provides the balance in β1 integrin-mediated cell adhesion and migration. In the present study, the significance of protein tyrosine phosphatases (PTP) and ser/thr protein phosphatases (PP) in α4β1 and α5β1 integrin-mediated mouse melanoma B16F1 cell anchorage and migration on fibronectin was characterized using phosphatase inhibitors. At low fibronectin concentration, α5β1 functioned as the predominant receptor for cell movement; a role for α4β1 in B16F1 cell migration increased progressively with fibronectin concentration. Treatment of B16F1 cells with PTP inhibitors, sodium orthovanadate (Na3VO4) and phenylarsine oxide (PAO), or PP-1/2A inhibitor, okadaic acid (OA), abolished cell movement. Inhibition of cell movement by PAO and OA was associated by a reduction in the adhesive strength of α4β1 and α5β1. In contrast, treatment of B16F1 cells with Na3VO4 resulted in selective stimulation of the adhesive function of α5β1, but not α4β1. Therefore, our results demonstrate that (i) both PTP and PP-1/2A have roles in cell movement, (ii) modulation of cell movement by PTP and PP-1/2A may involve either a stimulation or reduction of β1 integrin adhesive strength, and (iii) distinct phosphatase-mediated signaling pathways for differential regulation of the various β1 integrins exist. Key words: phosphatases, integrins, cell movement, cell adhesion.

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