scholarly journals Modulation of Wnt signaling by the nuclear localization of cellular FLIP-L

2009 ◽  
Vol 123 (1) ◽  
pp. 23-28 ◽  
Author(s):  
R. Katayama ◽  
T. Ishioka ◽  
S. Takada ◽  
R. Takada ◽  
N. Fujita ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Nuclear Localization ◽  
Cellular Flip

scholarly journals Cellular FLIP Inhibits β-Catenin Ubiquitylation and Enhances Wnt Signaling

2004 ◽  
Vol 24 (19) ◽  
pp. 8418-8427 ◽  
Author(s):  
Mikihiko Naito ◽  
Ryohei Katayama ◽  
Toshiyasu Ishioka ◽  
Akiko Suga ◽  
Kohei Takubo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Responses ◽  
Wnt Signaling ◽  
Axis Formation ◽  
Caspase Activity ◽  
Additional Mechanism ◽  
Long Form ◽  
Fas Signaling ◽  
Canonical Wnt ◽  
Cellular Flip

ABSTRACT Cellular FLIP (cFLIP) is a close homologue of caspase 8 without caspase activity that inhibits Fas signaling. The cFLIP protein is often expressed in human tumors and is believed to suppress antitumor immune responses involving the Fas system. Here, we report that a long form of cFLIP (cFLIP-L) inhibits β-catenin ubiquitylation and increases endogenous cytosolic β-catenin, which results in translocation of β-catenin into nuclei and induction of β-catenin-dependent gene expression in cFLIP-L-expressing cells. When cells stably expressing cFLIP-L were stimulated with Wnt3a, enhanced Wnt signaling was observed compared with the control cells. Conversely, depletion of endogenous cFLIP results in reduced Wnt signaling. Furthermore, cFLIP-L increases secondary-body axis formation when coinjected with suboptimal doses of β-catenin into early Xenopus embryos. Down-regulation of FADD by RNA-mediated interference abolishes the β-catenin-dependent gene expression induced by cFLIP-L. These results indicate that cFLIP-L, in cooperation with FADD, enhances canonical Wnt signaling by inhibiting proteasomal degradation of β-catenin, thus suggesting an additional mechanism involved with tumorgenesis, in addition to inhibiting Fas signaling.

scholarly journals IQGAP1 Functions as a Modulator of Dishevelled Nuclear Localization in Wnt Signaling

PLoS ONE ◽  
2013 ◽  
Vol 8 (4) ◽  
pp. e60865 ◽  
Author(s):  
Toshiyasu Goto ◽  
Atsushi Sato ◽  
Masahiro Shimizu ◽  
Shungo Adachi ◽  
Kiyotoshi Satoh ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Nuclear Localization

Distinct Regulation of β- and γ-Catenin throughout Hematopoietic Development Contrasts with Their Cooperative Roles In Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1573-1573
Author(s):  
Rhys Gareth Morgan ◽  
Lorna Pearn ◽  
Kate Liddiard ◽  
Robert Hills ◽  
Alan Burnett ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Nuclear Localization ◽  
Myeloid Leukemia ◽  
Nuclear Translocation ◽  
Differentiated Cells ◽  
Cd34 Cells ◽  
Normal Human ◽  
Acute Myeloid

Abstract Abstract 1573 Wnt proteins are important developmental regulators and are known to play a role in maintenance of hematopoietic stem cells (HSC). Wnt signaling has also been identified as one of the most frequently dysregulated processes associated with acute myeloid leukemia (AML), though the significance of this observation is as yet poorly understood. Here we investigate the role of two Wnt signaling proteins; β-catenin and γ-catenin and their respective roles in both normal human hematopoiesis and in AML. These proteins have dual and overlapping roles as transcriptional activators of Wnt target genes in the nucleus, and as structural components of the cytoskeleton. To determine the potential scope of influence of these proteins, we first examined their expression levels and subcellular location throughout normal human hematopoiesis using multi-parameter flow cytometric analysis and confocal microscopy. As expected β-catenin was strongly expressed in human cord blood derived HSC (212 MFI ±124, n=6) and at lower levels in differentiated subsets; surprisingly however β-catenin expression was maintained in granulocytic (1182 MFI±568) and monocytic cells (284 MFI±107). Nuclear localization was independent of cytoplasmic expression level, being strongly nuclear-localized in early progenitors and predominantly cytoplasmic in differentiated cells (58%±5 nuclear-localized in CD34+ cells vs 27%±1 in granulocytes, P=0.008). The expression pattern of γ-catenin was similar to β-catenin but showed a reciprocal pattern of subcellular localization, with levels of nuclear γ-catenin strongest in differentiated cells (10%±2 in CD34+ cells vs 44%±3 in monocytes P=0.0005). These data imply complementary roles for β and γ-catenin in normal hematopoiesis and show that nuclear localization of these proteins is regulated independently and irrespective of their expression level. In AML patients, β-catenin dysregulation has been previously reported; however, we also observed frequent overexpression of γ-catenin (over 5 fold in 25% of patients). This overexpression was associated with lower remission rates (OR 1.23 per log increase, P=0.03, CI 1.02–1.49) arising from resistant disease (OR 1.57 per log increase, P=0.003, CI 1.16–2.14) in a cohort of 243 AML patients adjusted for baseline diagnostic variables. In contrast to normal hematopoiesis, we found that nuclear localization of γ-catenin correlated with nuclear localization of β-catenin in AML (R=0.5, n=59) suggesting that the capacity to independently regulate the nuclear entry/retention of these catenins is disrupted in AML. To investigate this, we examined the effect of ectopic overexpression of γ-catenin in normal cord blood derived CD34+ cells and AML cell lines. Three-fold overexpression of γ-catenin failed to induce nuclear translocation of γ- or β-catenin in normal progenitors, which exhibited no major developmental defects. In contrast, in 3 of 4 AML cell lines, overexpression of γ-catenin strongly promoted its nuclear localization (9-16 fold) and was associated with a block in agonist-induced differentiation - a phenotype previously associated with β-catenin. In accord with this, we found that as in primary AML, nuclear translocation of γ-catenin in AML cell lines was associated with translocation of β-catenin (2-22 fold). In conclusion, we propose that in normal hematopoiesis, nuclear translocation of β- and γ-catenin is tightly and independently regulated for each catenin. In contrast, most AML cells lack this regulation resulting in correlated nuclear levels of β- and γ-catenin. In addition, we found while overexpression of γ-catenin has little consequence for normal cells; in malignant cells γ-catenin facilitates nuclear translocation of β-catenin. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Rac1 Activation Controls Nuclear Localization of β-catenin during Canonical Wnt Signaling

Cell ◽  
2008 ◽  
Vol 133 (2) ◽  
pp. 340-353 ◽  
Author(s):  
Ximei Wu ◽  
Xiaolin Tu ◽  
Kyu Sang Joeng ◽  
Matthew J. Hilton ◽  
David A. Williams ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Nuclear Localization ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

CDCP1 enhances Wnt signaling in colorectal cancer promoting nuclear localization of β-catenin and E-cadherin

Oncogene ◽  
2019 ◽  
Vol 39 (1) ◽  
pp. 219-233 ◽  
Author(s):  
Yaowu He ◽  
Claire M. Davies ◽  
Brittney S. Harrington ◽  
Linh Hellmers ◽  
Yonghua Sheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Wnt Signaling ◽  
Nuclear Localization ◽  
E Cadherin

scholarly journals Membrane-tethered Drosophila Armadillo cannot transduce Wingless signal on its own

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1327-1335 ◽  
Author(s):  
R.T. Cox ◽  
L.M. Pai ◽  
J.R. Miller ◽  
S. Orsulic ◽  
J. Stein ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Nuclear Localization ◽  
Nuclear Export ◽  
Current Model ◽  
Intracellular Localization ◽  
Beta Catenin ◽  
Wild Type ◽  
Binding Partners ◽  
Mutant Forms ◽  
Wnt Signal

Drosophila Armadillo and its vertebrate homolog beta-catenin are key effectors of Wingless/Wnt signaling. In the current model, Wingless/Wnt signal stabilizes Armadillo/beta-catenin, which then accumulates in nuclei and binds TCF/LEF family proteins, forming bipartite transcription factors which activate transcription of Wingless/Wnt responsive genes. This model was recently challenged. Overexpression in Xenopus of membrane-tethered beta-catenin or its paralog plakoglobin activates Wnt signaling, suggesting that nuclear localization of Armadillo/beta-catenin is not essential for signaling. Tethered plakoglobin or beta-catenin might signal on their own or might act indirectly by elevating levels of endogenous beta-catenin. We tested these hypotheses in Drosophila by removing endogenous Armadillo. We generated a series of mutant Armadillo proteins with altered intracellular localizations, and expressed these in wild-type and armadillo mutant backgrounds. We found that membrane-tethered Armadillo cannot signal on its own; however it can function in adherens junctions. We also created mutant forms of Armadillo carrying heterologous nuclear localization or nuclear export signals. Although these signals alter the subcellular localization of Arm when overexpressed in Xenopus, in Drosophila they have little effect on localization and only subtle effects on signaling. This supports a model in which Armadillo's nuclear localization is key for signaling, but in which Armadillo intracellular localization is controlled by the availability and affinity of its binding partners.

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