The Cdc42/Rac Nucleotide Exchange Factor Protein β1Pix (Pak-interacting Exchange Factor) Modulates β-Catenin Transcriptional Activity in Colon Cancer Cells

Chahdi, Ahmed; Raufman, Jean‐Pierre

doi:10.1074/jbc.m113.480103

Cited by 15 publications

(18 citation statements)

References 53 publications

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“…Interactions between active Rac1 and β-catenin have been previously reported in the nuclei of cells ( Esufali et al, 2007 ; Buongiorno et al, 2008 ); however, this is the first detection of an interaction between inactive Rac1 (T17N) and β-catenin and evidence that the distribution is regulated. Upon addition of Wnt we observed both an increase in active Rac1–β-catenin complex number and a specific increase in the nucleus, but it is unclear whether this was due to Wnt activation of Rac1 as previously suggested ( Habas et al, 2003 ; Malliri et al, 2006 ; Bikkavilli et al, 2008 ; Wu et al, 2008 ; Valls et al, 2012 ; Chahdi and Raufman, 2013 ) or via the stabilization and increased expression of β-catenin. These data highlight the possibility that Wnt not only stabilizes β-catenin but may also activate Rac1 itself or Rac1-GEFs to ensure nuclear persistence of active Rac1–β-catenin complexes.…”

Section: Discussionsupporting

confidence: 49%

Rac1 augments Wnt signaling by stimulating β-catenin–lymphoid enhancer factor-1 complex assembly independent of β-catenin nuclear import

Jamieson

Lui

Brocardo

et al. 2015

Journal of Cell Science

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ABSTRACTβ-Catenin transduces the Wnt signaling pathway and its nuclear accumulation leads to gene transactivation and cancer. Rac1 GTPase is known to stimulate β-catenin-dependent transcription of Wnt target genes and we confirmed this activity. Here we tested the recent hypothesis that Rac1 augments Wnt signaling by enhancing β-catenin nuclear import; however, we found that silencing/inhibition or up-regulation of Rac1 had no influence on nuclear accumulation of β-catenin. To better define the role of Rac1, we employed proximity ligation assays (PLA) and discovered that a significant pool of Rac1–β-catenin protein complexes redistribute from the plasma membrane to the nucleus upon Wnt or Rac1 activation. More importantly, active Rac1 was shown to stimulate the formation of nuclear β-catenin–lymphoid enhancer factor 1 (LEF-1) complexes. This regulation required Rac1-dependent phosphorylation of β-catenin at specific serines, which when mutated (S191A and S605A) reduced β-catenin binding to LEF-1 by up to 50%, as revealed by PLA and immunoprecipitation experiments. We propose that Rac1-mediated phosphorylation of β-catenin stimulates Wnt-dependent gene transactivation by enhancing β-catenin–LEF-1 complex assembly, providing new insight into the mechanism of cross-talk between Rac1 and canonical Wnt/β-catenin signaling.

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Section: Discussionsupporting

confidence: 49%

Rac1 augments Wnt signaling by stimulating β-catenin–lymphoid enhancer factor-1 complex assembly independent of β-catenin nuclear import

Jamieson

Lui

Brocardo

et al. 2015

Journal of Cell Science

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“…WNT10B Activates RAC1 and Inhibits RHOA in Human CECs-RhoGTPases have been reported previously to regulate cell proliferation through modulation of ␤-catenin signaling (40,41,50,51). GTP-bound CDC42 was detected in positive control (WNT5A)-treated cells but not in negative control-(WNT3A) or vehicle control-treated human CECs (Fig.…”

Section: Il-1␤ Stimulation Leads To Cell Proliferation and Wnt10bmentioning

confidence: 96%

WNT10B Enhances Proliferation through β-Catenin and RAC1 GTPase in Human Corneal Endothelial Cells

Lee

Heur

2015

Journal of Biological Chemistry

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Background: Adult human corneal endothelial cells are G 1 -arrested, often necessitating transplantation in patients with endothelial dysfunction. Results: WNT10B enhances proliferation in human corneal endothelial cells. Conclusion: Modulation of the WNT10B pathway could be used to treat vision loss because of corneal endothelial dysfunction. Significance: Modulation of the WNT10B pathway may provide a means of addressing the impending increase in donor cornea demand.

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“…Among these genes, several factors, including Cofilin, Lef‐1, Tcf and WNT,, have been reported as critical for neuron development and growth. In addition, certain GEFs—β1Pix (Pak‐interacting exchange factor) and VaV1—have been identified as nuclear proteins that regulate the transcriptional activity of genes independently of their GEF activity. It is possible that nuclear localized TIAM2S protein exerts its function also in a GEF‐independent manner but the molecular details remain an open question that will be further investigated.…”

Section: Discussionmentioning

confidence: 99%

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

et al. 2020

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Abbreviations: CA3, cornu ammonis 3; Cdc42, cell division control protein 42 homolog; DG, dentate gyrus; GEF, guanine nucleotide exchange factor; GFAP, glial fibrillary acidic protein; HTR1B, 5-hydroxytryptamine receptor 1B; MAP-2, microtubule-associated protein 2; PARP, poly (ADP-ribose) polymerase; PDGF, platelet-derived growth factor; Rac1, Ras-related C3 botulinum toxin substrate 1; RhoA, Ras homolog gene family member A; STEF, SIF and Tiam1-like exchange factor; TIAM1/2, T cell lymphoma invasion and metastasis1/2. ABSTRACTTIAM2S, the short form of human T-cell lymphoma invasion and metastasis 2, can have oncogenic effects when aberrantly expressed in the liver or lungs. However, it is also abundant in healthy, non-neoplastic brain tissue, in which its primary function is still unknown. Here, we examined the neurobiological and behavioral significance of human TIAM2S using the human brain protein panels, a human NT2/D1-derived neuronal cell line model (NT2/N), and transgenic mice that overexpress human TIAM2S (TIAM2S-TG). Our data reveal that TIAM2S exists primarily in neurons of the restricted brain areas around the limbic system and in well-differentiated NT2/N cells. Functional studies revealed that TIAM2S has no guanine nucleotide exchange factor (GEF) activity and is mainly located in the nucleus. Furthermore, whole-transcriptome and enrichment analysis with total RNA sequencing revealed that TIAM2S-knockdown (TIAM2S-KD) was strongly associated with the cellular processes of the brain structural development and differentiation, serotonin-related signaling, and the diseases markers representing neurobehavioral developmental disorders. Moreover, TIAM2S-KD cells display decreased neurite outgrowth and reduced serotonin levels. Moreover, TIAM2S overexpressing TG mice show increased number and length of serotonergic fibers at early postnatal stage, results in higher serotonin levels at both the serum and brain regions, and higher neuroplasticity and hyperlocomotion in latter adulthood. Taken together, our results illustrate the nononcogenic functions of human TIAM2S and demonstrate that TIAM2S is a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior. K E Y W O R D Sguanine nucleotide exchange factor (GEF), hyperlocomotion, neuroplasticity, serotonergic fiber, serotonin (5-HT), TIAM2 3268 | CHU et al. | 3269CHU et al.

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The Cdc42/Rac Nucleotide Exchange Factor Protein β1Pix (Pak-interacting Exchange Factor) Modulates β-Catenin Transcriptional Activity in Colon Cancer Cells

Cited by 15 publications

References 53 publications

Rac1 augments Wnt signaling by stimulating β-catenin–lymphoid enhancer factor-1 complex assembly independent of β-catenin nuclear import

Rac1 augments Wnt signaling by stimulating β-catenin–lymphoid enhancer factor-1 complex assembly independent of β-catenin nuclear import

WNT10B Enhances Proliferation through β-Catenin and RAC1 GTPase in Human Corneal Endothelial Cells

TIAM2S as a novel regulator for serotonin level enhances brain plasticity and locomotion behavior

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