Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus.

Fagotto, François; Funayama, Noriko; Glück, Ursula; Gumbiner, Barry M.

doi:10.1083/jcb.132.6.1105

Cited by 313 publications

(238 citation statements)

References 44 publications

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“…19 In healthy epithelial cells, E-cadherin plays an important role in cell-cell adhesions by homophilic interaction on adjacent cells. 18,19 Our experiments have demonstrated that MT1A2 cells express E-cadherin, maintain cell-cell adhesions, and also express EphA2 and EphrinA1 on the cell surface, but the majority of EphA2 remains unphosphorylated suggesting that Ecadherin alone is not effective in mediating EphrinA1 interaction with EphA2.…”

Section: Discussionmentioning

confidence: 92%

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Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy

et al. 2004

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EphA2, a receptor tyrosine kinase, is elevated in many invasive human breast cancers, and the majority of EphA2 remains unphosphorylated. The successful attachment of ligand EphrinA1 present on the surface of adjacent cells to EphA2 initiates EphA2 phosphorylation leading to its turnover. In vivo efficacy of various approaches targeting EphA2 for breast cancer therapy is usually evaluated in nude mice bearing human breast cancer xenografts. In order to establish an immunocompetent mouse model of breast cancer for EphA2-targeted therapies, we evaluated a mouse breast cancer cell line (MT1A2) for EphA2 expression and phosphorylation. Overexpression of EphA2 was observed in MT1A2 cells and the majority of it remained unphosphorylated signifying that EphA2 in MT1A2 cells behaved similar to that of human breast cancer cells. Human adenovirus subtype 5 (HAd5) vectors expressing secretory forms of EphrinA1 were used for in vitro and in vivo targeting of MT1A2-derived EphA2. MT1A2 cells infected with HAd-EphrinA1-Fc (HAd expressing extracellular domain of human EphrinA1 attached to Fc portion of human IgG1 heavy chain) induced EphA2 activation and its turnover. This led to inhibition in MT1A2 cell colony formation in soft agar and cell viability in monolayer culture. In addition, MT1A2 cells-infected with HAd-EphrinA1-Fc failed to form tumors in syngeneic FVB/n mice at least 32 days postinoculation. Moreover, intratumoral inoculation of FVB/n mice-bearing MT1A2-induced tumors with HAd-EphrinA1-Fc slowed the tumor growth and also resulted in the development of vector-specific immune response. These results indicate that FVB/n mice-bearing MT1A2-induced tumors could serve as an immunocompetent model of breast cancer for EphA2-targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 92%

“…18,19 It has been proposed that phosphorylation levels of tyrosine kinases maintain a balance between cell-extracellular matrix and cell-cell adhesions. 20 Apparently, MT1A2 cells seem to have better cell-to-cell adhesions compared to MDA-MB-231 cells (data not shown).…”

Section: Epha2 Expression and Phosphorylation In Had Vector-infected mentioning

confidence: 99%

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy

et al. 2004

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“…There is also evidence that cadherins can sequester catenins away from the Wnt signal (58,59). Therefore, down-regulation of Ncadherin by Wnt-3A may serve a dual function in our system, i.e.…”

Section: Wnt-3a Signaling In Bmp-2-mediated Chondrogenesismentioning

confidence: 99%

Wnt-3A Enhances Bone Morphogenetic Protein-2-mediated Chondrogenesis of Murine C3H10T1/2 Mesenchymal Cells

Fischer

Boland

Tuan

2002

Journal of Biological Chemistry

141

112

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We show that overexpression of either Wnt-3A or kinase-dead GSK-3␤ enhances BMP-2-mediated chondrogenesis. Furthermore, Wnt-3A overexpression results in decreases in both N-cadherin and GSK-3␤ protein levels, whereas Wnt-3A as well as kinase-dead GSK-3␤ overexpression increase total and nuclear levels of both ␤-catenin and LEF-1. Direct cross-talk between Wnts and BMP-2 was also indicated by the up-regulated interaction between ␤-catenin and SMAD-4 in response to BMP-2. These results suggest that Wnt-3A acts in a manner opposite to that of other Wnts, such as Wnt-7A, which were previously identified as inhibitory to chondrogenesis, and is the first BMP-2-regulated, chondrogenesis-enhancing member of the Wnt family.

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“…Binding of-catenin to E-cadherin protects Ecadherin from degradation [79]. Additionally, the interaction between these two proteins helps regulate -catenin signaling in the cell: one study found that overexpressing cadherins resulted in sequestration of the cytosolic pool of -catenin leading to reduced -catenin signaling [134]. Another study found that E-cadherin competed with LEF-1, one of -catenin's transcriptional factor binding partners, for binding to -catenin.…”

Section: Modulation Of β-Catenin At the Cell Membranementioning

confidence: 99%

“…However, the protein has been found to bind to the nuclear envelope directly. Additionally, translocation of -catenin is energy-dependent, suggesting that it can be imported into the nucleus independent of a signal sequence or other proteins [134].…”

Section: β-Catenin Nuclear Translocation and Transcriptional Activitymentioning

confidence: 99%

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

Zirnheld

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We identified and characterized a novel defect in β-catenin expression in bone marrow derived dendritic cells (BMDC) from NOD mice, a model for human Type Idiabetes. This protein is expressed at high levels throughout the lifespan of the mouse and correlates with increased pro-inflammatory cytokine production by the BMDC and IFNγ induction by T cells cocultured with the BMDC. These defects, including a similar pattern of pro-inflammatory cytokine production, are also observed in human monocytederived DC from diabetic patients. After exploring several potential mechanisms involved in the accumulation of β-catenin in NOD BMDC, we found that β-catenin is phosphorylated at higher levels in NOD BMDC at two residues associated with increased stabilization of this protein. Upon inhibition of the two kinases responsible for these phosphorylations, Akt and PKA, β-catenin expression is reduced. Therefore, β-catenin accumulates in NOD BMDC through an Akt and PKA-mediated mechanism. We also explored mechanisms by which β-catenin influences pro-inflammatory cytokine production and found that inhibition of β-catenin leads to decreased activation of the transcription factor NFκB, suggesting that pro-inflammatory cytokine production is increased in NOD BMDC through an NFκB-dependent mechanism. Finally, we v performed several in vivo experiments aimed at inhibiting β-catenin activity or reducing β-catenin expression to reduce disease incidence and/or increase survival. Treatment of NOD mice with quercetin, a β-catenin inhibitor, led to reduced disease incidence and a decreased inflammatory environment. Transfer of β-catenin siRNA-treated BMDC into NOD mice also reduced disease incidence. These studies reveal that β-catenin plays a role in the inflammation leading to diabetes development.vi

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Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus.

Cited by 313 publications

References 44 publications

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy

Immunocompetent mouse model of breast cancer for preclinical testing of EphA2-targeted therapy

Wnt-3A Enhances Bone Morphogenetic Protein-2-mediated Chondrogenesis of Murine C3H10T1/2 Mesenchymal Cells

The involvement of beta-catenin in the inflammatory response leading to autoimmune diabetes development.

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