Balancing cell adhesion and Wnt signaling, the key role of β-catenin

Brembeck, Felix H.; Rosário, Marta; Birchmeier, Walter

doi:10.1016/j.gde.2005.12.007

Cited by 615 publications

(528 citation statements)

References 103 publications

(153 reference statements)

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“…This suggests that the AJ formation and function is lost following RASSF8 depletion. Lack of stabilization of b-catenin at AJs allows b-catenin relocalization to the nucleus, where it can promote activation of the canonical Wnt signaling pathway by interacting with the T-cell factor/lymphoid enhanced factor (TCF-LEF) family of transcription factors and facilitating the activation of TCF-dependent genes (Brembeck et al, 2006;MacDonald et al, 2009). We observed a significant increase in b-catenin/ TCF-dependent promoter activity following RASSF8 depletion.…”

Section: Discussionmentioning

confidence: 77%

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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The Ras-assocation domain family (RASSF) of tumor suppressor proteins until recently contained six proteins named RASSF1-6. Recently, four novel family members, RASSF7-10, have been identified by homology searches for RA-domain-containing proteins. These additional RASSF members are divergent and structurally distinct from RASSF1-6, containing an N-terminal RA domain and lacking the Sav/RASSF/Hpo (SARAH) domain. Here, we show that RASSF8 is ubiquitously expressed throughout the murine embryo and in normal human adult tissues. Functionally, RNAi-mediated knockdown of RASSF8 in non-small-cell lung cancer (NSCLC) cell lines, increased anchorage-independent growth in soft agar and enhanced tumor growth in severe combined immunodeficiency (SCID) mice. Furthermore, EdU staining of RASSF8-depleted cells showed growth suppression in a manner dependent on contact inhibition. We show that endogenous RASSF8 is not only found in the nucleus, but is also membrane associated at sites of cell-cell adhesion, co-localizing with the adherens junction (AJ) component b-catenin and binding to E-cadherin. Following RASSF8 depletion in two different lung cancer cell lines using alternative small interfering RNA (siRNA) sequences, we show that AJs are destabilized and E-cadherin is lost from the cell membrane. The AJ components b-catenin and p65 are also lost from sites of cell-cell contact and are relocalized to the nucleus with a concomitant increase in b-catenin-dependent and nuclear factorjB (NF-jB)-dependent signaling following RASSF8 depletion. RASSF8 may also be required to maintain actin -cytoskeletal organization since immunofluorescence analysis shows a striking disorganization of the actincytoskeleton following RASSF8 depletion. Accordingly, scratch wound healing studies show increased cellular migration in RASSF8-deficient cells. These results implicate RASSF8 as a tumor suppressor gene that is essential for maintaining AJs function in epithelial cells and have a role in epithelial cell migration.

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Section: Discussionmentioning

confidence: 77%

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

et al. 2010

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“…Mutational analysis of some of the Wnt components including Axin, APC and b-catenin so far have identified very few genetic abnormalities in esophageal cancer, indicating that mechanisms other than mutations are responsible for activation of this pathway in esophageal cancer. [29][30][31] Figure 5 E-cadherin nuclear translocation was also found in primary colorectal cancer and metastasis. E-cadherin nuclear translocation was detected in primary colorectal cancers and in some areas of the corresponding liver metastasis of a colorectal tumor with nuclear E-cadherin (a).…”

Section: Discussionmentioning

confidence: 99%

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

et al. 2008

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Esophageal squamous cell carcinoma is frequently associated with poor prognosis, as a result of high levels of lymph node metastasis. So far, very few genetic abnormalities have been associated with this disease, and its molecular etiology remains largely unknown. To assess whether the Wnt pathway contributes to esophageal squamous cell carcinoma, we characterized the expression and subcellular localization of the key Wnt signaling components in all 30 cases of esophageal squamous cell carcinomas analyzed. We found abnormal expression and/or localization in glycogen synthase kinase-3 a/b (34%), Axin2 (48%), a-catenin (31%), MYC (73%) and cyclin D1 in 46% of cases. Only 13% of tumors showed nuclear accumulation of b-catenin. By contrast, 60% showed nuclear expression of E-cadherin using an antibody that recognizes the cytoplasmic domain of E-cadherin. When the same tumors were stained with antibody raised against the extracellular domain of E-cadherin, the expression was lost. A direct correlation was found between nuclear E-cadherin and the increased nuclear cyclin D1, one of the AP-1 target genes in these tumors. By transfection experiments, the cytoplasmic portion of E-cadherin was found to activate the AP-1 transcription factor pathway and induced cyclin D1 promoter activity, but b-catenin/Tcf transcription activity was unaffected. Nuclear expression of E-cadherin was also detected in tumors other than squamous cell carcinoma, including pancreatic and colon cancers, albeit at lower frequency. Nuclear accumulation of a portion of E-cadherin in esophageal squamous cell carcinoma and the other types of tumors indicates that, in addition to the previously implicated tumor suppressor activity of E-cadherin, modified forms of this glycoprotein might also play a role in growth promotion. Keywords: Wnt signaling; esophageal squamous cell carcinomas; pancreatic cancer; colon cancer; E-cadherin Esophageal cancer is one of the deadliest but least studied forms of cancer and the sixth ranking cause of death from cancer in North America. It shows a varied geographical distribution and very poor survival rates. 1 Esophageal cancer accounts for 5% of all gastrointestinal cancers, and the overall number of new cases each year is steadily increasing. 2 Esophageal cancer can be divided into squamous cell carcinomas and adenocarcinomas. So far, very few genetic abnormalities have directly been linked to esophageal carcinogenesis. In this study, we sought to examine the expression and localization of the key components of the Wnt signaling pathway that have previously been shown to play important roles in colorectal, breast, stomach and prostate cancer. Wnt signaling regulates cell growth, motility and differentiation. Upon binding to their receptor, specific Wnt ligands trigger phosphorylation of LRP5/6 (low density lipoprotein) by glycogen synthase kinase-3 (GSK3a/b) and casein kinase-1 (CK1g), which distances Axin (Axin1 and Axin2) from the b-catenin destruction-complex. [3][4][5][6] As a result, the b-catenin is stabilized a...

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“…Snail short-hairpin RNAs (shRNAs) or a dominant-negative (DN) allele blocked transformation of RK3E cells by Gli1, whereas exogenous Snail cooperated with Gli1 to induce transformation (Li et al, 2006). E-cadherin (E-cad) is a type I integral membrane protein that localizes to adherens junctions and mediates Ca 2 þ -dependent, cell-cell adhesion (Cavallaro and Christofori, 2004;Nelson and Nusse, 2004;Gumbiner, 2005;Brembeck et al, 2006). The C terminus of E-cad is linked to a-catenin and the actin cytoskeleton through association with b-catenin.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to its role in cellcell adhesion, b-catenin is a nuclear effector of Wnt signaling, inducing cell proliferation and transformation. Wnt signals inhibit glycogen synthase kinase (GSK3b), which normally phosphorylates the N terminus of b-catenin and targets it for degradation (Nelson and Nusse, 2004;Bienz, 2005;Brembeck et al, 2006). The increased b-catenin then translocates to the nucleus where it associates with the DNA-binding proteins Lef/ Tcf.…”

Section: Introductionmentioning

confidence: 99%

“…Participation of b-catenin in cell-cell adhesion or Wnt signaling is determined by competitive binding of b-catenin to a-catenin and the actin network versus Wnt signaling components in the cytoplasm (Gottardi and Gumbiner, 2004;Nelson and Nusse, 2004;Bienz, 2005;Gumbiner, 2005;Brembeck et al, 2006). Switching of b-catenin from cell adhesion to Wnt signaling can be induced by tyrosine phosphorylation of b-catenin, which promotes binding to BCL9-2 instead of a-catenin.…”

Section: Introductionmentioning

confidence: 99%

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Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin

et al. 2007

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Balancing cell adhesion and Wnt signaling, the key role of β-catenin

Cited by 615 publications

References 103 publications

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

The RASSF8 candidate tumor suppressor inhibits cell growth and regulates the Wnt and NF-κB signaling pathways

Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas

Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin

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